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Published Research Papers

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Original ResearchVol. 57, Issue 7 • pp. 1164-1174DOI: 10.3724/abbs.2024240

miR-199a-3p suppresses Vldlr expression to promote cardiomyocyte proliferation

Authors: Rui Jiang, Lijuan Pei, Hongjie Zhang, Fenglian He, Yuhan Min, Xinhang Li, Ke Wei

The proliferative capacity of cardiomyocytes is limited in adult mammals, and replacing lost tissue following acute ischemic injury is challenging. Previous studies have demonstrated that miR-199a-3p can promote cardiomyocyte proliferation, but the exact mechanism by which this occurs remains unclear, although multiple targets of miR-199a-3p have been identified. We recently showed that very-low-density-lipoprotein receptor (Vldlr) inhibits cardiomyocyte proliferation, and in this study we aim to test whether Vldlr is a functional target gene of miR-199a-3p. 3′UTR reporter assays demonstrate that miR-199a-3p directly binds to the 3′UTR of Vldlr and inhibits its translation. Overexpressing Vldlr blunts the pro-proliferative effect of miR-199a-3p on cardiomyocytes, suggesting that Vldlr is indeed a functional target of miR-199a-3p. Mechanistically, Vldlr reduces S807/811 phosphorylation of RB1, and inhibiting CDK4/6 to prevent RB1 phosphorylation can block the pro-proliferative effect of both Vldlr knockdown and miR-199a-3p, suggesting that RB1 phosphorylation is required for the cardiomyocyte proliferation induced by miR-199a-3p and Vldlr knockdown. The findings of this study reveal Vldlr as a novel functional target of miR-199a-3p in cardiomyocytes and identify RB1 as a downstream effector of cardiomyocyte proliferation. The identification of the role of the miR-199a-3p-Vldlr-RB1 axis in cardiomyocyte proliferation may provide potential therapeutic targets for cardiac regenerative medicine.

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miR-199a-3p suppresses Vldlr expression to promote cardiomyocyte proliferation

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Original ResearchVol. 57, Issue 8 • pp. 1222-1233DOI: 10.3724/abbs.2025041

A positive feedback loop between FOSB and miR-133b controls colon cancer cell proliferation

Authors: Wanwan Li, Qionggui Hu, Changwei Lin, Xiaorong Li, Yang Bai, Min Ma

FOSB, a member of the FOS gene family, forms heterodimers with JUN family proteins to engage in diverse cellular processes. Its biological impacts vary among different types of tumors, yet its specific function in colon cancer (CC) remains ambiguous. In this study, quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) are applied to measure FOSB expression levels, followed by an analysis of the association between FOSB expression and patients’ clinical parameters. In vitro experiments are performed to assess cell proliferation, including growth rate, cell cycle distribution, and apoptosis. A subcutaneous xenograft model in nude mice is utilized to monitor tumor growth in vivo. Additionally, chromatin immunoprecipitation (ChIP) and luciferase reporter assays are conducted to dissect the interactions among FOSB, miR-133b, and POU2F1. The results indicate that FOSB expression is downregulated in CC tissues relative to normal controls. Overexpression of FOSB suppresses proliferation and promotes apoptosis in CC cells. Mechanistically, FOSB binds to the promoter region of miR-133b, enhancing its transcription and subsequently repressing POU2F1 expression. Notably, decreased POU2F1 expression also alleviates the transcriptional repression of the FOSB promoter region, establishing a FOSB-miR-133b-POU2F1 feedback loop that inhibits CC proliferation. In summary, our findings suggest that FOSB acts as a tumor suppressor gene in CC and may exert its inhibitory effects on CC growth via the FOSB-miR-133b-POU2F1 feedback loop.

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A positive feedback loop between FOSB and miR-133b controls colon cancer cell proliferation

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Original ResearchVol. 57, Issue 9 • pp. 1507-1516DOI: 10.3724/abbs.2025023

Reduced expression of the PER2 protein contributes to β1-AA-induced cardiac autophagy rhythm disorders

Authors: Pengjia Li, Jiayan Feng, Jiao Guo, Jin Xue, Yang Li, Shiyuan Wen, Xiaohui Wang, Huirong Liu, Li Wang

Heart failure may be linked to fluctuations in the rhythm of autophagy in cardiomyocytes throughout the day. Circadian rhythms depend on the regulation of core biological clock proteins, with PER2 playing a crucial role. Our previous research confirmed that the presence of β1-adrenergic receptor autoantibodies (β1-AAs) could inhibit myocardial autophagy, leading to cell death and heart failure. However, it remains unclear whether β1-AA induces cardiac autophagy rhythm disorders by affecting PER2 expression. In this study, we find that β1-AA disrupts the autophagy rhythm in cardiomyocytes, which is primarily indicated by decreased expression of the autophagy marker protein LC3. β1-AA disrupts the rhythmic expression of the PER2 protein in myocardial cells, which is manifested mainly by a decrease in PER2 protein expression. Metoprolol is used to verify that the β1-adrenergic receptor contributes to the reduction in the Per2 protein caused by β1-AA. Knockdown of Per2 with lentivirus reduces the inhibition of LC3 expression caused by β1-AA, whereas overexpression of Per2 in cardiomyocytes using lentivirus significantly restores the β1-AA-induced decrease in LC3 expression. Moreover, mTORC1 activation is found to participate in β1-AA-induced autophagy inhibition in cardiomyocytes after pretreatment with the mTORC1 inhibitor rapamycin. Furthermore, the decreased expression of the PER2 protein caused by β1-AA disrupts the myocardial autophagy rhythm by promoting mTORC1 activation through lentiviruses that knock down or overexpress the Per2 gene. This study provides an experimental basis for the precise treatment of cardiovascular diseases from the perspective of biological rhythm.

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Reduced expression of the PER2 protein contributes to β1-AA-induced cardiac autophagy rhythm disorders

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Original ResearchVol. 58, Issue 8 • pp. 1736-1747DOI: 10.3724/abbs.2026076

A protein-RNA complex orchestrated by EMB1006, EMB1270, EMB976, and CFM2 facilitates clpP1 intron 2 splicing in Arabidopsis chloroplasts

Authors: Liqun Zhang, Fangsheng Liao, Ying Wei, Keyi Yang, Yawen Zhu, Li Zhang, Wenyujie Shi, Shuya Zhou, Jirong Huang, Yong-Lan Cui, Weihua Huang

In Arabidopsis, the PPR proteins EMB1006, EMB1270, and EMB976 are all essential for the splicing of plastid clpP1 intron 2 (clpP1.2), although each also targets other distinct RNAs. The precise mechanism underlying their co-ordinated action in clpP1.2 splicing remains unclear. In this study, RNA electrophoretic mobility shift assays, guided by PPR code prediction, confirm that EMB1006 specifically binds to a sequence near the 3′ end of clpP1 exon 2. Additionally, immunoprecipitation coupled with mass spectrometry reveals that EMB1006 forms a complex with EMB1270, EMB976, and CFM2. Direct interactions between EMB1006 and EMB1270 or CFM2 are further supported by yeast two-hybrid (Y2H) and semi-in vivo pull-down assays. However, no direct interactions between EMB976 and EMB1006, CFM2 or EMB1270 are detected by Y2H. Based on these findings and previous evidence that EMB1270 binds to clpP1 intron 2 and interacts with CFM2, we propose a model in which EMB1006 and EMB1270 bind to distinct sites on clpP1 pre-mRNA. Together with CFM2 and possible indirect association with EMB976, they assemble into a protein-RNA complex that facilitates the splicing of clpP1.2 in chloroplasts.

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A protein-RNA complex orchestrated by EMB1006, EMB1270, EMB976, and CFM2 facilitates clpP1 intron 2 splicing in Arabidopsis chloroplasts

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Original ResearchVol. 58, Issue 7 • pp. 1579-1596DOI: 10.3724/abbs.2026054

Tanshinones from Salvia miltiorrhiza alleviate ulcerative colitis via reprogramming the gut microbiota-metabolite axis

Authors: Zhe Liu, Chan Hui, Guochao Zhang, Haicheng Yang, Yi Wang, Yaqian Shi, Chao Wang, Yanfei Liu, Xia Gao, Yuting Wen

The anti-inflammatory properties of the traditional herb Salvia miltiorrhiza Bunge are well-established, yet its precise mechanism of action in ulcerative colitis (UC) remains unclear. Herein, we evaluate the therapeutic potential of four major tanshinones–tanshinone IIA (Tan IIA), miltirone, neocryptotanshinone, and dihydrotanshinone I–in a murine dextran sulfate sodium (DSS)-induced colitis model. Our results show that tanshinones effectively alleviate disease severity, suppress systemic and local inflammation, and restore intestinal barrier integrity. Integrated multi-omics analysis reveals that the therapeutic efficacy originates from a comprehensive reprogramming of the gut microbiota-metabolite axis. Specifically, tanshinones reverse colitis-associated dysbiosis and rectify metabolic disturbances in linoleic acid metabolism, bile acid biosynthesis, and amino acid utilization. Correlation network analysis identifies key functional modules linking beneficial microbes (e.g., Akkermansia) to anti-inflammatory lipid mediators and associating pathobionts (e.g., Desulfovibrio) with disrupted bile acid metabolism. Notably, supplementation with Akkermansia muciniphila synergizes with Tan IIA to amplify barrier restoration and metabolic normalization. Our findings establish that tanshinones ameliorate UC through microbiota-driven metabolic reprogramming, wherein the restructured microbial community actively shapes a therapeutic metabolic output. This work elucidates a metabolite-mediated mechanism of action and positions tanshinones as promising microbiome-targeting therapeutics for inflammatory bowel disease.

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Tanshinones from Salvia miltiorrhiza alleviate ulcerative colitis via reprogramming the gut microbiota-metabolite axis

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Original ResearchVol. 58, Issue 8 • pp. 1761-1771DOI: 10.3724/abbs.2026010

Distinct miR319a identified from Persicaria chinensis mediates cross-kingdom suppression of cervical cancer by targeting ITGA3

Authors: Yueyue Yan, Dan Bai, Lei Li, Leimei Xu, Hua Yang, Yuhui Wang, Han Feng, Lan Zhu

Persicaria chinensis, a well-known traditional Chinese medicinal herb that is both edible and medicinal, has been widely acknowledged for its therapeutic effects, such as anti-inflammatory, antioxidant, and antitumor activities. However, the role of miRNAs from this plant in the cross-kingdom regulation of human diseases has not been investigated. In this study, we analyze the miRNA expression profile of P. chinensis using high-throughput sequencing and identify a total of 673 miRNAs, including 422 novel miRNAs that are unique to this plant and 251 conserved miRNAs. Among the conserved miRNAs, pch-miR319a is found to be the most abundant. Moreover, food-oriented pch-miR319a accumulates in the uterus and tumors and exhibits a rich repertoire of target genes within cancer-related pathways, demonstrating significant cross-kingdom regulatory potential. Utilizing the dual-luciferase reporter gene assay, we demonstrate that pch-miR319a from P. chinensis targets the Itga3 gene, which is associated with cervical cancer progression. Overexpression of pch-miR319a significantly decreases the viability, migration, and induces apoptosis of HeLa cervical cancer cells in vitro. Moreover, in a syngeneic mouse tumor model of cervical cancer, treatment with pch-miR319a effectively inhibits tumor growth and downregulates the expressions of ITGA3 and the proliferation marker Ki-67. Our study highlights the potential of pch-miR319a from P. chinensis as a novel therapeutic agent for cervical cancer by targeting ITGA3 and provides new insights into the cross-kingdom regulatory mechanisms of plant miRNAs in human diseases.

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Distinct miR319a identified from Persicaria chinensis mediates cross-kingdom suppression of cervical cancer by targeting ITGA3

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Original ResearchVol. 58, Issue 8 • pp. 1896-1900DOI: 10.3724/abbs.2026030

Development of an in vitro TurboID labeling assay for the detection of protoRAG-interacting proteins in the amphioxus

Authors: Qingyi Lu, Jie Xu, Junye Hong, Enfan Xiao, Qiuzhu Wei, Yuhe Sun, Zihan Zhao, Yuhang Zhang, Guangrui Huang

The recombination-activating gene (RAG)-mediated V(D)J rearrangement mechanism is essential for generating the diversity of the adaptive immune system in jawed vertebrates. The RAG1 and RAG2 proteins form a tetrameric complex that recognizes and cleaves pairs of recombination signal sequences (RSSs). In jawed vertebrates, the N-terminal region of RAG1 and the C-terminal region of RAG2 are critical for the regulation of physiological function and enhancement of recombination accuracy. Moreover, the intracellular activity of RAG1/2 is rigorously regulated and is thought to represent the aspect shaped by host coevolution. However, these regulatory mechanisms remain incompletely understood, impeding our deeper understanding of the physiological functions of RAG. Previous studies have shown that jawed vertebrate RAG evolved from invertebrate RAG-like (RAGL) transposases and underwent key structural changes during evolution. RAGL genes have been identified in multiple invertebrate species, but from Branchiostoma belcheri (Bb), the RAG-like protein in Bb amphioxus (BbRAG1L) and the RAG2-like protein in Bb amphioxus (BbRAG2L) are among the most extensively characterized to date. Lancelets (amphioxus) represent the most basal extant chordates (cephalochordates) that diverged from the other two chordate lineages (urochordates and vertebrates). Consequently, amphioxus has been considered a “living fossil” for studying the origins and evolution of adaptive immunity. Homologs of the core structural domain of RAG1 were discovered in the amphioxus genome in 2005, and the homologs were subsequently shown to exhibit recombinase activity in cooperation with murine-derived RAG2. A large number of transposon genes were then identified in the amphioxus genome, followed by the identification of target site duplication (TSD) and terminal inverted repeat (TIR) sequences in the amphioxus genome. Notably, BbRAG2L lacks the C-terminal region present in murine RAG2, including the acidic hinge and PHD domain. BbRAG1L coupled with BbRAG2L displays significant transposition activity in vitro and in human cell lines. In contrast, vertebrate RAG exhibits limited transposon activity in vitro and extremely low transposon activity in vivo. This leads to the question of how RAG lost its transposase activity during evolution. Structural comparison and functional experiments of BbRAGL (protoRAG) and vertebrate RAG have revealed that vertebrates undergo essential adaptive changes to eliminate the primitive transposase activity of protoRAG. Research on BbRAGL has therefore provided strong support for the hypothesis that RAG originated from a domesticated transposon. Given the similarity in both structure and function between BbRAG1L and vertebrate RAG and the fact that BbRAGL proteins are the only RAGL proteins that can currently be efficiently expressed in vertebrate cells, characterizing the binding partners of BbRAGL involved in amphioxus is of great significance for understanding the regulation of BbRAGL and its adaptation and evolution. Parallel comparison of BbRAGL and RAG interaction networks may further clarify how BbRAGL transitioned from a transposase to a recombinase during host coevolution and reveal general principles of vertebrate intracellular RAG regulation. In recent years, proximity labeling techniques have greatly facilitated approaches to identifying RAG cofactors. For example, RAG1 fused to biotin ligase RAG1 fused to a biotin ligase found in Escherichia coli (BirM) has been used to define dynamic interaction networks of RAG-associated proteins. Inspired by these advances, we sought to apply a similar approach to identify the BbRAGL cofactors in amphioxus and build a regulatory network of BbRAGL that could shed light on its relationship with host evolution. However, endogenous BbRAGL expression is undetectable in the adult amphioxus (data not shown), and the generation of transgenic amphioxus lines expressing proximity-based labeling proteins remains technically challenging. These constraints make it difficult to analyze native cofactors of endogenous BbRAGL in vivo. Because BbRAGL can be expressed in vertebrate cell lines, we instead developed an in vitro proximity-labeling strategy. We fused TurboID (TbID), an engineered biotin ligase, to the N-terminus of BbRAG1L or BbRAG2L (Figure 1A), purified the fusion proteins, and incubated them with protein lysates prepared from the hepatic cecum and colons of adult B. belcheri amphioxus in vitro to label the interacting proteins. The proteins were finally analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Figure 1B). A pTT5 vector was used to express plasmids encoding maltose-binding protein (MBP) and TurboID with or without full-length BbRAG1L or BbRAG2L, yielding pTT5-MBP-TurboID, pTT5-MBP-TurboID-BbRAG1L, and pTT5-MBP-TurboID-BbRAG2L. Plasmids expressing MBP-BbRAG1L and MBP-BbRAG2L were also generated.

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Development of an in vitro TurboID labeling assay for the detection of protoRAG-interacting proteins in the amphioxus

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Original ResearchVol. 58, Issue 8 • pp. 1905-1909DOI: 10.3724/abbs.2026037

Identification and experimental validation of core genes associated with breast cancer brain metastasis via machine learning

Authors: Zhaoda Duan, Chunjiao Yu, Wenjie Yang, Qiaoling Ruan, Rui Zhang, Yongfang Zhao, Shan Yan

Breast cancer (BC) is the most common malignancy among women, with approximately 2.3 million new cases diagnosed annually, accounting for approximately 11.6% of all cancer cases worldwide. Distant metastasis is the primary cause of mortality in BC patients, with nearly 50% of patients ultimately developing metastatic disease. The predominant metastatic sites of BC include the lung, liver, brain, and bone, each exhibiting distinct biological characteristics that drive the organ-specific tropism of cancer cells. Among these, brain metastasis represents a significant cause of mortality in BC patients and is particularly prevalent in those with human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer (TNBC) subtypes. Breast cancer brain metastasis (BCBM) can manifest in three forms: choroid plexus metastasis (rare), leptomeningeal metastasis (approximately 8%), and parenchymal metastasis, the most common presentation, with multiple lesions in 78% of cases and solitary lesions in 14%. Distinct anatomical regions of the brain provide different micro-environments, which in turn shape epidemiological patterns, biological behaviors, and therapeutic vulnerabilities of metastatic cancer. With the continuous advancement of systemic therapies and imaging surveillance, brain metastases from BC have become increasingly prevalent, accounting for approximately 10%–30% of all metastatic breast cancer (MBC) cases. The continuous progression of BCBM often compromises patients’ cognitive and sensory functions, leading to neurological impairment and severely limiting quality of life (QOL). Notably, the mortality rate within one year after diagnosis remains at 80%. Current therapeutic strategies for BCBM primarily include surgery, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), chemotherapy, or combinations thereof. Although these approaches provide some clinical benefit, the efficacy remains limited due to the blood-brain barrier (BBB), which restricts drug penetration and contributes to chemoresistance. Therefore, elucidating the molecular mechanisms underlying BCBM is imperative to identify novel diagnostic biomarkers and therapeutic targets, with the ultimate goal of improving treatment efficacy and patient prognosis. Bioinformatics provides a powerful platform and data foundation for exploring the mechanisms of tumor initiation and progression. High-throughput platforms for gene expression analysis have gained significant popularity, with next-generation sequencing (NGS) and microarray analysis now widely applied as essential tools in medical oncology. These techniques have diverse clinical applications, including molecular cancer classification, prediction of therapeutic response, prognostic assessment, molecular diagnostics, and the discovery of novel drugs and therapeutic targets. Weighted gene coexpression network analysis (WGCNA) has been widely applied in studies of gene regulatory networks, biomarker discovery, and elucidation of the molecular mechanisms underlying complex phenotypes. In this study, we utilized the BCBM microarray dataset GSE43837. We performed differential expression analysis and WGCNA clustering using the R packages limma and WGCNA to identify potential gene modules and candidate targets. GSE43837 consists of 19 nonmetastatic primary breast tumor samples and 19 breast cancer brain metastasis samples. Differential expression analysis, with thresholds set at |logFC| > 1 and P < 0.05, identified 245 upregulated and 188 downregulated genes (Supplementary Table S1 and Supplementary Figure S1A). WGCNA further confirmed that the constructed network satisfied the scale-free topology criterion, with the optimal soft-threshold power determined to be 14 based on model fit and mean connectivity (Supplementary Figure S1B). Using the dynamic tree cut method, we clustered genes into multiple modules, each representing a group of coexpressed genes with varying degrees of correlation among modules (Supplementary Figure S1C,D). Notably, the midnightblue and black modules showed stronger correlations, and a significant positive relationship was observed between gene significance (GS) and module membership (MM) within these modules (Supplementary Figure S1E). This finding suggests that the core genes in these modules are highly representative and stable within the coexpression network. A total of 89 BCBM-related candidate genes were extracted from these key modules (Supplementary Table S2). To further identify key feature genes associated with BCBM, we applied two machine learning methods, LASSO regression and random forest (RF), to the 29 overlapping genes obtained from the intersection of DEGs and hub module genes (Figure 1A and Supplementary Table S3). In the LASSO regression analysis, the optimal penalty parameter λ was determined by cross-validation, yielding a set of candidate genes with nonzero regression coefficients (Figure 1B). Concurrently, in the RF model, 500 decision trees were constructed, and the classification ...

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Identification and experimental validation of core genes associated with breast cancer brain metastasis via machine learning

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Original ResearchVol. 58, Issue 8 • pp. 1887-1895DOI: 10.3724/abbs.2026014

Super-resolution imaging reveals higher-order structures within common fragile sites in human mitotic chromosomes

Authors: Jiabin Wang, Daniel M. Czajkowsky, Zhifeng Shao

Common fragile sites (CFSs) are large genomic loci that are frequently deleted under replication stress and are thought to play a role in carcinogenesis as well as developmental disorders during early embryogenesis. They often appear as gaps or breaks in mitotic chromosomes by conventional optical microscopy and are also loci that are replicated in mitosis in a process called mitotic DNA synthesis (MiDAS). However, we still have a very poor understanding of the potential mechanisms underlying their genomic instability. We recently found that in normal mitotic chromosomes, there is a two-level hierarchy in the higher-order chromatin structure, with mechanically resistant ~90 nm Mitotic NanoDomains (MNDs) assembling into ~125 nm compact granules (CGs). In this work, we combine multiple super-resolution imaging techniques, including binding-activated localization microscopy (BALM), atomic force microscopy (AFM), and stochastic optical reconstruction microscopy (STORM), to characterize CFSs. Our super-resolution data indicate that sites that appear as gaps by conventional microscopy can be filled with chromatin of the size and shape of MNDs but not CGs. Moreover, we find that MiDAS loci only form an array of MNDs with no CGs. Taken together, our work suggests that under replication stress, CFS loci can not only be replicated but also assembled into higher-order chromatin. However, this organization is limited to the level of MNDs, which suggests that a failure to progress beyond MNDs to form CGs constitutes a key structural deficiency at these loci.

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Super-resolution imaging reveals higher-order structures within common fragile sites in human mitotic chromosomes

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Original ResearchVol. 58, Issue 8 • pp. 1719-1735DOI: 10.3724/abbs.2026058

Biochemical and structural studies reveal the substrate specificity and catalytic mechanism of MYG1 as a two-metal ion-dependent 3′→5′ exonuclease

Authors: Chao Lan, Ziyue Chen, Guanchao Wang, Jianping Ding

Nucleases are a class of enzymes that specifically cleave nucleic acids in all living organisms. They play crucial roles in essential biological processes, including the regulation of gene expression, DNA damage repair, and RNA processing and degradation. MYG1 (melanocyte proliferating gene 1) is a highly conserved eukaryotic protein that exhibits 3′→5′ exonuclease activity. This study systematically characterizes the enzymatic properties of MYG1 and determines its structures in complexes with metal ions and various mono- and poly-(deoxy)nucleotides. The functional roles of key residues involved in metal ion binding and substrate binding in the catalytic reaction are examined through site-directed mutagenesis, enzymatic activity assay, and structure determination. Our biochemical and structural data together demonstrate that MYG1 is a Mn2+- or Mg2+-dependent 3′→5′ exonuclease capable of cleaving a variety of nucleic acids with different structures. It exhibits the highest activity for single-stranded RNA and a nucleotide preference for U in single-stranded RNA and dT in single-stranded DNA. Mechanistically, MYG1 functions as a dimer, with the active site formed by the catalytic domain of monomer 1 and the substrate-binding domain of monomer 2, and cleaves nucleic acids through a two-metal ion-mediated catalytic mechanism. These findings establish a molecular basis for further investigations into the biological functions and molecular mechanisms of MYG1 within cells and its potential roles in human diseases.

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Biochemical and structural studies reveal the substrate specificity and catalytic mechanism of MYG1 as a two-metal ion-dependent 3′→5′ exonuclease

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Original ResearchVol. 58, Issue 7 • pp. 1597-1610DOI: 10.3724/abbs.2025191

The effect of liver-specific ketohexokinase deletion on the intestinal-liver-kidney axis in high-fructose-induced metabolic syndrome mice

Authors: Huiru Yang, Xiaoli Yi, Shanshan Song, Mulan Wang, Wenting Tan, Ying Zhu, Jun Yu, Chuanming Xu

The liver is a crucial site for fructose uptake and metabolism, a function intricately linked to fructose-associated pathologies. This study examines the role of hepatic ketohexokinase (KHK) in metabolic syndrome induced solely by high-fructose intake. Liver-specific Khk-deficient mice are generated and fed with a 20% fructose solution for 3 months, after which the features of metabolic syndrome are examined. Compared with fructose-fed floxed controls, fructose-fed liver-specific Khk-deficient mice present alleviated liver injury and hepatic steatosis, along with lower triglyceride levels in the plasma and liver, plasma aspartate transaminase and alanine transaminase levels, and mRNA levels of genes related to triglyceride and fatty acid synthesis. Liver-specific Khk deficiency also leads to lower uric acid levels in the plasma and urine, as well as xanthine oxidase activity and Glut9 mRNA levels in the liver and kidneys of fructose-fed mice. Although intestinal villus length and epithelial barrier integrity remain unaffected, the deletion of liver Khk significantly reduces fructose-stimulated KHK, Glut2, Glut5, and aldolase B expression in the intestine and kidneys, suggesting inhibited fructose absorption and metabolism in these tissues. In the adipose tissue, fructose-induced increases in adipocyte size and tumor necrosis factor-α and interleukin-6 mRNA levels are blocked by liver-specific Khk deficiency, indicating improved remodeling of adipose tissue and reduced inflammation in adipocytes. Overall, liver-specific Khk deletion is sufficient to protect against metabolic syndrome induced by excessive fructose intake. Our findings underscore the critical role of liver KHK-mediated fructose metabolism in driving the physiological and pathological consequences associated with fructose consumption along the intestinal-liver-kidney axis.

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The effect of liver-specific ketohexokinase deletion on the intestinal-liver-kidney axis in high-fructose-induced metabolic syndrome mice

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Original ResearchVol. 58, Issue 7 • pp. 1557-1567DOI: 10.3724/abbs.2025257

Glycolysis reprogramming predicts poor prognosis and drives therapy resistance via CLN6 in lethal prostate cancer

Authors: Zhouda Cai, Jianming Lu, Shanshan Mo, Jipu Liu, Chuanfan Zhong, Yongding Wu, Fen Zou, Jianheng Ye, Zhaodong Han, Yuxiang Liang, Le Zhang, Fengping Liu, Weide Zhong

Lethal prostate cancer is marked by tumor heterogeneity and resistance to androgen receptor signaling inhibitors (ARSIs). In this study we identify glycolysis as a driver of disease progression and therapy resistance. Using single-sample gene set enrichment analysis (ssGSEA) on the SU2C cohort, we demonstrate that elevated glycolysis activity is associated with poor progression-free and overall survival. The glycolysis-based prognostic score (GLY score) is derived from the HALLMARK_GLYCOLYSIS gene set which includes CLN6, SDHC, B4GALT2, RPE, NANP, and KIF20A, via LASSO-Cox regression. The GLY score effectively stratifies risk in the SU2C and WDCT cohorts, with higher scores predicting worse outcomes and increased SYNE1 mutation frequency. Pan-cancer analysis across TCGA datasets confirm its prognostic value. In vitro, enzalutamide-resistant prostate cancer cell lines exhibit heightened glycolysis, and 2-DG inhibition reverses this effect, restoring drug sensitivity. CLN6 knockdown reduces glycolytic activity and cell proliferation. The GLY score offers robust prognostic value, and CLN6 represents a promising therapeutic target for precision medicine in lethal prostate cancer.

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Glycolysis reprogramming predicts poor prognosis and drives therapy resistance via CLN6 in lethal prostate cancer

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Original ResearchVol. 58, Issue 7 • pp. 1637-1652DOI: 10.3724/abbs.2025206

Total flavonoids of litchi seed attenuates cellular senescence by inhibiting the production of SASP through p65 suppression and ameliorates pulmonary fibrosis

Authors: Xiaocui Li, Yao Wei, Qiuchen Cheng, Suyu Xiao, Sisi Yao, Daikang Yang, Jilong Wang, Liping Chen, Qing Li, Tingzheng Zhan

Anti-aging foods not only benefit elderly individuals but also drive the development of safe and effective natural drugs. Here, we report that the addition of total flavonoids of litchi seed (TFL) delays replicative senescence and stress-induced senescence. TFL alleviates the senescence-associated secretory phenotype (SASP) and reduces the degree of DNA damage caused by bleomycin (BLM). TFL also counteracts stress-induced pulmonary senescence and fibrosis. TFL reduces the protein level of p21 in mouse lung and alleviates pulmonary fibrosis. Transcriptome profiling further reveals that TFL plays a key role in its anti-aging mechanism by inhibiting the SASP. Mechanistically, TFL suppresses p65 protein expression, thereby inhibiting IL-1α and IL-1β and delaying cellular senescence. Gut microbiome analysis reveals that the abundance and functions of the mouse gut microbiome change after BLM exposure and that TFL treatment reverses these changes. Overall, we provide a theoretical basis for the future application of TFL as a potential anti-aging product.

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Total flavonoids of litchi seed attenuates cellular senescence by inhibiting the production of SASP through p65 suppression and ameliorates pulmonary fibrosis

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Original ResearchVol. 58, Issue 7 • pp. 1671-1675DOI: 10.3724/abbs.2026039

Small chemical molecule CPP promotes angiogenesis in surgically created severe lower limb ischemia and diabetes-induced limb vascular reduction models

Authors: Xinyu Dong, Yangyang Zhang, Congyao Zhao, Xiaomeng Yan, Xiaohui Chi, Xinyu Xie, Baoxiang Zhao, Jian Zhang, Li Wang, Junying Miao, Zhaomin Lin

Patients with peripheral artery disease (PAD) commonly experience chronic limb-threatening ischemia (CLTI) in the end stage, leading to severe functional impairment of the limbs, amputation, and even death. Among the various disease factors contributing to PAD, diabetes is significantly associated with PAD risk, leading to more severe symptoms and a poorer prognosis. Promoting angiogenesis at ischemic sites and improving blood flow are key to the recovery of limbs from ischemic injury. Angiogenic therapies based on cells and small-molecule drugs are considered important and promising strategies. Cell-based therapies can be classified based on cell source into allogeneic therapies and autologous therapies. Autologous cells offer the advantage of not requiring immunosuppression but may be limited by factors such as cell unavailability and scarcity due to autologous factors. Allogeneic cells, while offering a more abundant cell source, present drawbacks, including immune incompatibility and ethical concerns, which restrict their application. Small chemical molecules offer advantages such as convenience, low cost, ease of synthesis and storage, and rapid action without the need for introducing exogenous genes. They circumvent the high costs associated with cell therapies and potential side effects from allogeneic cell transplantation, holding significant promise and potential in both biomedical research and clinical applications. Fibroblasts are a cell type with functional and transcriptional heterogeneity and cellular fate plasticity, making them a promising source of seed cells for clinical tissue and organ repair and regeneration. Small molecules have become recognized as crucial tools for the induction of cellular reprogramming. In our laboratory’s previous research, a novel small chemical molecule probe, CPP ((E)-4-(4-(4-(7-(diethylamino)-2-oxo-2H-chromene-3-carbonyl)piperazin-1-yl)styryl)-1-methylpyridin-1-ium iodide), was identified as an inhibitor of prolyl-4-hydroxylase 2 (PHD2). CPP induces the differentiation of cultured human dermal fibroblasts into vascular endothelial cells (VECs) via the PHD2/hypoxia-inducible factor-1α/hairy-related transcription factor 1 (PHD2/HIF1α/HEY1) signaling pathway. The differentiated VECs exhibited therapeutic efficacy in treating lower limb ischemia in mice, indicating that CPP holds promise as a therapeutic candidate for limb ischemia. In this study, we aimed to investigate the capability of CPP to directly induce angiogenesis in vivo under conditions of vascular injury. Critical limb ischemia (CLI) occurs at the end stage of PAD. To evaluate the in situ therapeutic effects of CPP on CLI, a CLI model was established using C57BL/6 mice (Hubei Research Center of Laboratory Animals, Wuhan, China). CPP was synthesized and provided by the laboratory of Professor Baoxiang Zhao at Shandong University (Jinan, China). Following surgery, continuous subcutaneous multipoint injections of CPP were administered for 14 d to mimic localized drug treatment (Figure 1A). Laser speckle blood flow imaging was used to assess lower limb perfusion on days 0, 7, and 14 (Figure 1B, upper panel). The results showed that by day 7 post-surgery, both CPP concentrations significantly enhanced perfusion in the ischemic limb compared to the control group. From days 7 to 14, perfusion changes in both CPP-treated groups plateaued. Meanwhile, the control group showed increased perfusion. Throughout the treatment period, no significant differences were observed between the 1 and 10 mg/kg/day CPP treatment groups (Figure 1C,D). On day 14, the capillary density in the skin and muscle was significantly higher in the 1 mg/kg/day CPP group than in the control group. Although the 10 mg/kg/day group had a slightly higher density than the control, the difference was not statistically significant (Figure 1E–G). In addition, the organ toxicity

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Small chemical molecule CPP promotes angiogenesis in surgically created severe lower limb ischemia and diabetes-induced limb vascular reduction models

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Original ResearchVol. 58, Issue 7 • pp. 1509-1518DOI: 10.3724/abbs.2025223

Fibroblast growth factor 13 deficiency attenuates doxorubicin-induced cardiotoxicity by regulating Parkin-mediated myocardial injury

Authors: Jiabing Han, Xuyan Li, Yiming Dong, Yidan Wang, Simeng Lv, Yiyi Zhang, Ran Zhao, Yingke Yan, Yanxue Han, Yu Wang, Jing Yang, Cong Wang, Chuan Wang

The clinical use of doxorubicin (DOX) as a chemotherapeutic agent is limited by its cardiotoxic effects. Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, has been increasingly recognized as an important regulator of cardiovascular disease. However, its role in doxorubicin-induced cardiotoxicity remains unknown. Therefore, the objective of this study is to investigate the role and mechanism of FGF13 in doxorubicin-induced cardiac injury. C57BL/6 mice are used to establish Dox-induced cardiotoxicity models. The results reveal that mouse weight, cardiomyocyte cross-sectional area, ejection fraction and fractional shortening are decreased in the DOX group. In contrast, Fgf13 deficiency mitigates doxorubicin-mediated cardiotoxicity, as indicated by increased mouse weight, cardiomyocyte cross-sectional area, ejection fraction and fractional shortening. Mechanistically, the protein expressions of bax and cleaved caspase 3 are elevated in the DOX-treated group, along with decreased JC-1 fluorescence intensity and bcl-2 expression, whereas Fgf13 knockout prevents these alterations. In addition, Parkin, but not p53, interacts with FGF13 and is upregulated in response to Fgf13 deficiency in a mouse model of doxorubicin-induced cardiotoxicity. Overall, Fgf13 knockout attenuates doxorubicin-induced cardiomyocyte apoptosis and mitochondrial damage through the modulation of Parkin, indicating that FGF13 may serve as a promising therapeutic target for DOX-induced cardiotoxicity.

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Fibroblast growth factor 13 deficiency attenuates doxorubicin-induced cardiotoxicity by regulating Parkin-mediated myocardial injury

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Original ResearchVol. 58, Issue 7 • pp. 1544-1556DOI: 10.3724/abbs.2025253

A novel biomarker SNHG11 promotes tumor progression and oxidative phosphorylation in clear cell renal cell carcinoma

Authors: Zhuoyuan Lin, Chaojiang Chen, Jianxin Li, Jun Zhao, Jia Xu, Le Zhang, Chuanfan Zhong, Shanshan Mo, Jianming Lu, Yu Zheng

Kidney renal clear cell carcinoma (KIRC) is the most common and aggressive subtype of renal cell carcinoma and is characterized by poor prognosis and high molecular heterogeneity. Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cancer, yet the functional role of SNHG11 in KIRC remains unclear. In this study, we perform integrated multiomics analysis using data from the TCGA and ICGC cohorts and reveal that SNHG11, a methylation-associated lncRNA, is significantly correlated with poor clinical outcomes. In vitro and in vivo assays demonstrate that SNHG11 promotes tumor proliferation and progression. Mechanistically, SNHG11 enhances oxidative phosphorylation, as evidenced by increased ATP production, disrupted mitochondrial membrane potential, and altered NAD+/NADH ratios. Furthermore, SNHG11 expression is associated with somatic mutation patterns, particularly those involving BAP1 and PBRM1, indicating potential crosstalk between epigenetic regulation and genetic alterations. These findings reveal that SNHG11 is a novel biomarker in KIRC and a potential therapeutic target.

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A novel biomarker SNHG11 promotes tumor progression and oxidative phosphorylation in clear cell renal cell carcinoma

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Original ResearchVol. 58, Issue 7 • pp. 1437-1440DOI: 10.3724/abbs.2026110

Metabolic reprogramming—the nexus of cellular adaptations, organ crosstalk, and therapeutic innovations in human diseases

Authors: Jun Ren, Hartmut Schlüter, Marcel Kwiatkowski, Ling Lin

For decades, cellular metabolism was viewed as a static network of biochemical pathways designed solely to produce ATP and fulfill basic energy needs. Classical pathophysiology frequently attributes systemic disorders, including cardiovascular disease, oncogenesis and tissue fibrosis, to structural defects, hormonal dysregulations or localized inflammation. However, advanced multi-omics frameworks have driven a paradigm shift, with metabolic reprogramming being recognized not merely as a passive consequence of disease but also as a primary driver of initiation, progression, and therapeutic resistance across human pathologies. This Special Issue, titled “Metabolic Reprogramming”, brings together 17 comprehensive studies alongside 3 New Phenomena exploring these transformations. The contributions span four interrelated thematic areas: (1) systemic cardiometabolic and gestational syndromes; (2) acute and chronic organ injury; (3) oncological metabolic dependencies; and (4) systemic organ-axis interdependencies. By integrating transcriptomics, metabolomics, single-cell deconvolution, and targeted biochemical analyses, these studies elucidate the precise molecular mechanisms governing metabolic remodeling.

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Metabolic reprogramming—the nexus of cellular adaptations, organ crosstalk, and therapeutic innovations in human diseases

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Original ResearchVol. 58, Issue 6 • pp. 1402-1412DOI: 10.3724/abbs.2025224

Bioinformatics classification of the MgtE Mg2+ channel and de novo protein design for the stabilization of its novel subclass

Authors: Zhixuan Zhao, Kimiho Omae, Wataru Iwasaki, Ziyi Zhang, Fazhi Pan, Eun-Jin Lee, Koichi Ito, Motoyuki Hattori

MgtE channels play crucial roles in Mg2+ homeostasis and are implicated in bacterial survival under antibiotic exposure. Previous structural and biophysical studies have focused predominantly on Thermus thermophilus MgtE, leaving the structural and mechanistic diversity of MgtE family proteins largely unexplored. In this study, via a genome mining approach, we identify diverse MgtE homologs, including a novel subclass termed the “mini-N type”, which lacks the canonical cytoplasmic N and CBS domains but possesses a unique small N-like domain. Despite extensive expression screening, mini-N-type homologs cannot be stably purified. To address this issue, we design a series of de novo proteins and determine their crystal structures. A selected de novo protein is fused to a mini-N-type MgtE, enabling successful purification and preliminary cryo-EM imaging. Our findings demonstrate that de novo-designed protein fusions serve as powerful tools for stabilizing and purifying otherwise unstable membrane proteins, opening new avenues for structural and functional studies of otherwise inaccessible membrane proteins.

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Bioinformatics classification of the MgtE Mg2+ channel and de novo protein design for the stabilization of its novel subclass

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Original ResearchVol. 58, Issue 5 • pp. 1155-1169DOI: 10.3724/abbs.2026055

Atractylenolide I mitigates Alzheimer’s disease pathology in ApoE–/– mice via ARG1/nNOS axis and lipid homeostasis regulation

Authors: Xun Zhou, Rui Wang, Jingsi Yan, Xiaolang Wu, Dongsheng Yuan, Qi Wang, Huilin Li, Wei Zhao

Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer’s disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Atractylodes macrocephala Koidz., exhibits multimodal bioactivities with demonstrated anti-inflammatory and neuroprotective properties. To explore its therapeutic potential against AD pathology, we use high-fat diet (HFD)-fed ApoE knockout (ApoE–/–) mice treated with or without AI for 12 weeks. Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis, particularly cerebral lipid deposition, suppresses neuroinflammation via downregulation of M1 macrophage polarization markers, and restores cognitive function through neuronal preservation in hippocampal regions. Mechanistically, AI orchestrates cholesterol efflux by up-regulating ATP-binding cassette transporter A1 (ABCA1) and liver X receptor (LXR) expression, while concurrently modulating the abundance of arginine biosynthesis metabolites (urea, malic acid, and creatinine) to rebalance neurovascular homeostasis. Notably, western blot and RT-qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1 (ARG1) and simultaneously upregulates the expression of neuronal nitric oxide synthase (nNOS). Further molecular docking and surface plasmon resonance (SPR) analyses confirm the direct binding of AI to ARG1, indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism. These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.

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Atractylenolide I mitigates Alzheimer’s disease pathology in ApoE–/– mice via ARG1/nNOS axis and lipid homeostasis regulation

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Original ResearchVol. 58, Issue 6 • pp. 1281-1290DOI: 10.3724/abbs.2026042

Structural and functional insights into the distinct DNA recognition mechanisms of the terminase small subunit TerS from cyanophages

Authors: De-Qin Dong, Feng Yang, Kang Du, Kang Xu, Wen-Bin Cheng, Yuxing Chen, Cong-Zhao Zhou, Yong-Liang Jiang

Efficient genome packaging is a critical step in the phage life cycle, directly influencing the viral maturation and infectivity. In tailed phages, this process is driven by a packaging motor composed of a portal protein and a terminase complex. The terminase complex usually consists of a large subunit (TerL) and a small subunit (TerS), which cooperate to recognize, cleave, and translocate genomic DNA into the capsid. However, due to the remarkable diversity and complexity of phage packaging systems, the molecular mechanisms governing TerS-mediated DNA recognition remain poorly understood. Here, we report the 3.51 Å cryo-electron microscopy structure of the TerS from the short-tailed cyanophage Pam5, which infects the host Pseudanabaena mucicola Chao 1806. Pam5 TerS assembles into a nonameric ring with a radially symmetric spiral architecture. Biochemical assays show that Pam5 TerS recognizes the genomic DNA via a specific interaction between the N-terminal helix-turn-helix (HTH) domain of TerS and a 21-bp DNA sequence within the terS gene. In contrast, the TerS from another short-tailed cyanophage, Pam1, which infects the same host, binds to DNA in a sequence-independent manner. These findings reveal that cyanophages, even infecting the same host, could adopt two distinct DNA recognition strategies: HTH-mediated sequence-dependent or sequence-independent modes. This work provides structural and mechanistic insights into the diverse DNA-recognition strategies of TerS and advances our understanding of the evolutionary plasticity of viral genome packaging mechanisms.

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Structural and functional insights into the distinct DNA recognition mechanisms of the terminase small subunit TerS from cyanophages

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Original ResearchVol. 58, Issue 6 • pp. 1431-1432DOI: 10.3724/abbs.2026006

Caught the ‘Catch’ of midnolin: structural basis for broad substrate specificity in ubiquitin-independent proteasomal degradation

Authors: Chuanyin Li, Ronggui Hu

Protein homeostasis serves as the foundation for every cellular decision—division, differentiation, stress adaptation, or death—by precisely balancing the proteome across abundance, quality, spatial distribution, and temporal dynamics; its dysregulation drives numerous human pathologies, including cancers and neurological disorders. In the traditional ubiquitin-dependent degradation cascade, target proteins are marked by covalent attachment of polyubiquitin chains, a process requiring E1 activating enzymes, E2 conjugating enzymes, and E3 ligases that confer substrate specificity. This ubiquitin signal is then recognized by the 19S regulatory particle of the proteasome, which unfolds and translocates the tagged protein into the 20S core for proteolytic destruction. The ubiquitin-independent proteasomal degradation pathway mediated by midnolin (MIDN) has recently emerged as a distinct and biologically important mechanism for regulating nuclear protein turnover. While earlier genetic, biochemical, and cryo-electron microscopy studies established MIDN as a proteasome-associated adaptor for immediate-early gene (IEG) products, the molecular logic underlying its broad yet selective substrate recognition remains unresolved. In the current study, Zhong et al. provide a comprehensive structural and biochemical analysis of the MIDN Catch domain bound to IRF4-derived peptides, substantially advancing our understanding of MIDN substrate recognition. By solving multiple crystal structures of the Catch-IRF4 complex, including wild-type and systematically engineered mutants, the authors demonstrate that MIDN recognizes substrates through a conserved β-strand insertion mechanism at the interface of the Catch1 and Catch2 subdomains. This investigation generalizes and expands prior structural observations of MIDN-IRF4 to diverse substrates, demonstrating that β-strand complementation constitutes a universal recognition mechanism utilized by MIDN. A major conceptual advance of this study is the identification of a minimal and generalizable recognition principle centered on two highly conserved positions within the substrate motif. The authors show that a reciprocal phenylalanine-glycine interaction between the substrate and Catch2—forming an “F-G zipper”—constitutes the dominant energetic determinant for binding. Disruption of this zipper severely compromises protein stability and binding, explaining prior functional observations that single-point mutations in IRF4 or EGR1 abolish MIDN-mediated degradation. In contrast, flanking residues within the binding motif display remarkable tolerance to substitution. Through combined mutagenesis, thermostability analysis, AlphaFold3 modeling, and structural determination, the study demonstrates that these positions occupy large and plastic hydrophobic pockets in the Catch domain. This architectural flexibility provides a direct molecular explanation for how MIDN can accommodate a wide spectrum of substrates while preserving selectivity. From these data, the authors derive a concise consensus recognition motif (G/S-x-F/Y) embedded within an unstructured or loop region, offering a predictive framework for identifying additional MIDN targets. Importantly, this work bridges a critical gap between previous cryo-EM studies describing MIDN-proteasome engagement and earlier substrate-specific structural analyses. Whereas prior studies clarified how MIDN delivers captured substrates to the proteasome, the present study elucidates how MIDN initially selects and binds those substrates. Together, these findings unify MIDN biology across structural, biochemical and functional dimensions. Overall, this study represents a significant advance in the field of proteostasis by revealing how a ubiquitin-independent adaptor achieves broad substrate specificity through a simple yet robust structural principle. Beyond MIDN, the work provides a paradigm for short-linear-motif-based proteasomal targeting and has important implications for immune regulation, neurodegeneration and cancer biology.

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Caught the ‘Catch’ of midnolin: structural basis for broad substrate specificity in ubiquitin-independent proteasomal degradation

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Original ResearchVol. 58, Issue 3 • pp. 638-648DOI: 10.3724/abbs.2025148

PDK4-driven metabolic reprogramming enhances mesothelial cell invasion in colorectal cancer peritoneal metastasis

Authors: Lingyu Han, Qinyuan Zhang, Yuchen Wu, Wenqin Luo, Shaobo Mo, Hongsheng Fang, Qingguo Li, Renjie Wang, Guoxiang Cai, Weixing Dai

Mesothelial cells play an important role in colorectal cancer peritoneal metastasis (CRC-PM), where they support tumor growth and invasion. In this study, we investigate the molecular mechanisms by which mesothelial cells contribute to CRC metastasis. Using single-cell RNA sequencing (scRNA-seq) on tissue samples from 12 CRC patients with peritoneal metastasis, we identify PDK4 as a key gene in mesothelial cells during metastasis. The expression of PDK4 is significantly greater in mesothelial cells undergoing mesothelial-to-mesenchymal transition (MMT) compared to normal peritoneal cells, suggesting its involvement in mesothelial cell reprogramming during peritoneal metastasis. In vitro experiments show that coculturing mesothelial cells with CRC cells leads to increased PDK4 expression, which in turn enhances mesothelial cell migration and invasion. Knockdown of PDK4 reduces mesothelial cell invasion, while overexpression of PDK4 increases invasive ability, highlighting its critical role in mesothelial cell invasion. Additionally, PDK4 promotes metabolic changes, specifically increasing fatty acid oxidation (FAO), which is necessary for mesothelial cell invasion. Blocking FAO reduces the invasive ability of PDK4-overexpressing mesothelial cells, while restoring FAO in PDK4-knockdown cells rescues their invasion potential. Further analysis shows that PDK4 enhances the acetylation of β-catenin, a protein involved in cell movement, and that this modification is crucial for mesothelial cell invasion. Our results suggest that PDK4 regulates mesothelial cell invasion through β-catenin acetylation following metabolic reprogramming, offering a potential target for therapies aimed at inhibiting CRC-PM.

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PDK4-driven metabolic reprogramming enhances mesothelial cell invasion in colorectal cancer peritoneal metastasis

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Original ResearchVol. 58, Issue 6 • pp. 1235-1249DOI: 10.3724/abbs.2026002

Biochemical and structural studies of the midnolin Catch domain bound with both wild-type and mutant IRF4 peptides reveal the molecular basis for its broad substrate specificity

Authors: Yanling Zhong, Ziyue Chen, Guanchao Wang, Jianping Ding

The newly discovered midnolin-proteasome pathway is a unique ubiquitin-independent mechanism for degrading nuclear proteins, which is crucial for maintaining cellular protein homeostasis. The Catch domain of midnolin is essential for substrate recognition and binding, yet the underlying mechanism for its broad substrate specificity remains elusive. Transcription factor IRF4, essential for the functions of B and T cells, is a substrate of midnolin. This study presents comprehensive biochemical and structural analyses of the human midnolin Catch domain in complexes with both wild-type and mutant IRF4 peptides. The crystal structure of the Catch-IRF4 complex reveals that the Catch domain creates a substrate-binding groove at the interface of the Catch1 and Catch2 subdomains, recognizing and binding to the 215-QVTGTFYAC-223 sequence motif of IRF4. The binding motif of IRF4 forms a β-strand that is embedded into the substrate-binding groove, resulting in an antiparallel five-stranded β-sheet. The interactions between the IRF4 peptide and the Catch domain are predominantly hydrophobic and exhibit high spatial complementarity. Additionally, the biochemical, modeling and structural data indicate that the V2 and A8 positions of the IRF4 sequence motif can be substituted with other hydrophobic or small polar residues (G/A/V/L/I/M/P/F/Y/C/S/T), but not with large polar and charged residues (D/N/E/Q/H/K/R). The G4 position can be replaced by Ser, while the F6 position can be substituted with Tyr. These results suggest that the Catch domain can recognize and bind to a variety of substrates containing the sequence motif x[G/A/V/L/I/M/P/F/Y/C/S/T]x[G/S]x[F/Y]x[G/A/V/L/I/M/P/F/Y/C/S/T]x or briefly the G/SxF/Y motif (where x represents polar residues) located in an unstructured or loop region on the protein surface, and the hydrophobic interactions and spatial complementarity between the binding motifs of substrates and the Catch domain govern the substrate specificity. Collectively, these findings elucidate the molecular basis for midnolin’s broad substrate specificity.

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Biochemical and structural studies of the midnolin Catch domain bound with both wild-type and mutant IRF4 peptides reveal the molecular basis for its broad substrate specificity

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Original ResearchVol. 57, Issue 12 • pp. 2048-2061DOI: 10.3724/abbs.2025077

Andrographolide prevents necroptosis by suppressing the generation of reactive oxygen species

Authors: Na Lu, Qing Li, Linghan Duan, Rong Xu, Yaping Li, Fuli Shi, Zhiya Zhou, Yingqing Gan, Bo Hu, Jinhua Li, Xianhui He, Dongyun Ouyang, Qingbing Zha

Andrographolide (Andro), a natural product extracted from the Chinese traditional medicine herb Andrographis paniculata, has been applied for the treatment of diverse inflammatory diseases. However, its effects on necroptosis, a lytic form of cell death implicated in various inflammatory diseases, remain uncharacterized. In the present study, we investigate whether Andro and its derivatives can suppress necroptosis. Our results demonstrate that Andro notably inhibits necroptosis in the in vitro cellular models induced by either lipopolysaccharide (LPS) plus IDN-6556 or a combination of TNF-α, LCL-161 (Smac mimetic) and IDN-6556. In these cellular models, Andro inhibits the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), as well as the formation of necrosomes. Specifically, Andro reduces the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide (mtROS), preserves the mitochondrial membrane potential during necroptotic induction, and activates the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). Upon necroptotic stimulation, some mitochondrial proteins, such as Bcl-2 and Bak, oligomerize and co-localize with RIPK1, RIPK3, and phosphorylated MLKL (p-MLKL) in necrosomes. However, this process of necrosome formation can be prevented by Andro. In contrast, derivatives, including dehydroandrographolide, neoandrographolide, 14-deoxy-11,12-didehydroandrographolide, and 14-deoxyandrographolide, have no anti-necroptotic effects and fail to upregulate Nrf2. Collectively, our findings demonstrate that Andro specifically inhibits the RIPK1/RIPK3/MLKL signaling axis to suppress necroptosis, highlighting its therapeutic potential against necroptosis-related disorders.

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Andrographolide prevents necroptosis by suppressing the generation of reactive oxygen species

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Original ResearchVol. 58, Issue 6 • pp. 1423-1426DOI: 10.3724/abbs.2025222

Mixed fungal polysaccharides enhance intestinal health, antioxidant capacity, and microbiota diversity in broiler chickens

Authors: Bingyu Zhu, Enze Zhang, Min Yang, Ye Zhang, Can Liu, Runxin Jiao, Mengling Peng, Jie Zhou, Jianbo Cheng, Juhua Wang

Poultry production faces escalating challenges from intensive farming practices, where stressors, including high stocking density, pathogen exposure, and dietary fluctuations, disrupt intestinal integrity, microbiota balance, and antioxidant defenses. These disruptions impair nutrient absorption, growth performance, and immune function, leading to significant economic losses. Although antibiotics have historically mitigated such issues, growing restrictions due to antimicrobial resistance necessitate natural alternatives. Fungal polysaccharides (FP)—notably lentinan (LNT) from Lentinula edodes and polysaccharide from Ganoderma lucidum (GLP), are promising candidates owing to their immunomodulatory, antioxidant, and prebiotic properties. However, existing research focuses predominantly on individual FP, neglecting potential synergies in blended formulations. Structurally, LNT (β-(1→3)-D-glucan backbone) enhances rumen volatile fatty acid production and fiber degradation, whereas GLP (heterogeneous α/β-glycans) potently activates the Nrf2/HO-1 antioxidant pathway and modulates Th1/Th2 immunity. These divergent mechanisms imply complementary effects when combined. In our previous experiments on broiler feeding, we reported that a combination of GLP (68.32% polysaccharide content, composed of mannose, glucose, arabinose, rhamnose, and galactose at a molar ratio of 1.00:16.37:18.82:1.42:17.42) and LNT (76.52% polysaccharide content, composed of mannose, galacturonic acid, arabinose, galactose, glucose, and rhamnose at a molar ratio of 1.00:15.22:8.23:2.05:1.78:4.26) at a 1:1 ratio maximally promoted broiler growth (unpublished data), but their impacts on intestinal morphology, antioxidant signaling, and the microbiota remain uncharacterized. We therefore hypothesize that mixed FP synergistically may enhance intestinal health by simultaneously improving nutrient absorption, activating antioxidant pathways, and stabilizing microbial ecosystems. To investigate the effects of mixed FP on intestinal development, 240 one-day-old Arbor Acres male broilers were randomly assigned to the 0 mg/kg FP (Control), 200 mg/kg FP (Group I), 400 mg/kg FP (Group II), and 600 mg/kg FP (Group III) groups. Broilers were housed in three-tier battery cages (0.7 m × 0.7 m × 0.4 m; 12 broilers/cage), with five replicate cages per experimental group maintained under identical conditions. The experiments were approved by the College of Animal Science and Technology in Anhui Agricultural University (approval number: SYXK 2016-007). All the cages were subjected to a 16 h light: 8 h dark cycle with ad libitum access to water and twice-daily feeding (09:00/16:00) of basal diets (Supplementary Table S1). On day 42, the duodenum, jejunum, and ileum segments were collected, fixed in 4% paraformaldehyde, sectioned at 5 μm, and stained with hematoxylin-eosin. Villus height (VH), crypt depth (CD), and VH/CD ratios were measured via Case Viewer software. The results revealed that Group II significantly increased VH and VH/CD across all the intestinal segments while reducing CD (Figure 1A; P < 0.05 vs the control); these findings suggest enhanced nutrient absorption capacity and intestinal health. To evaluate antioxidant capacity and signaling pathway activation, intestinal tissues were homogenized in PBS (1:9, w/v). The total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px) activities were determined via commercial kits (Nanjing Jiancheng Bioengineering Institute, Nanjing, China)). For gene expression analysis, total RNA was extracted and reverse-transcribed. The qPCR was performed via specific primers for HO-1, NQO1, CAT, Nrf2, and Keap1, with β-actin used as the reference gene (primer sequences and product sizes are listed in Supplementary Table S2). The results demonstrated that Group II significantly elevated antioxidant enzyme activities (P < 0.05), upregulated HO-1, NQO1, CAT, and Nrf2, and

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Mixed fungal polysaccharides enhance intestinal health, antioxidant capacity, and microbiota diversity in broiler chickens

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Original ResearchVol. 57, Issue 12 • pp. 2034-2047DOI: 10.3724/abbs.2025081

Resident CD24+LCN2+ LPCs aggravate fibrosis and inflammatory progression via the recruitment of TPPP3+COL10A1+ macrophages in NASH

Authors: Min Ding, Xiaoshu Qi, Weijian Huang, Yan Lin, Hexin Yan

Resident CD24+LCN2+ liver progenitor cells (LPCs) reportedly contribute to the expanding ductular reaction and macrophage-mediated inflammation associated with chronic liver damage. Both ductular reactions and macrophage-driven inflammation are associated with liver fibrosis and injury in various mouse liver disorders. This study aims to investigate the molecular phenotypes of LPCs and their regulatory mechanisms in humans with non-alcoholic steatohepatitis (NASH). Single-cell RNA sequencing (scRNA-seq) datasets are used to characterize the status and molecular phenotypes of LPCs in clinical NASH samples. To elucidate the regulatory mechanisms of LPCs, CellChat and NicheNet are employed to assess cell-cell communication between LPCs and other cell types. The findings are validated using RNA sequencing datasets associated with NASH progression, NASH mouse models (CDAHFD and HFD), and human NASH liver samples. Results show that resident CD24+LCN2+ LPCs are identified and found to be significantly enriched in NASH patients. Cell communication analyses predict strong interactions between LPCs and proinflammatory macrophage subtypes. Additionally, in NASH, the liver recruits peripheral blood mononuclear cell (PBMC)-derived macrophages and polarizes them into proinflammatory subtypes. The macrophage subtype MP-2 is identified as the primary recipient of LPC-derived signals, exhibiting marked hyperactivation of the NF-κB pathway and a strong association with liver fibrosis. Finally, the MP-2 markers COL10A1 and TPPP3 are characterized and validated. In summary, this study reveals that resident CD24+LCN2+ LPCs are activated in NASH and contribute to fibrosis progression by promoting the activation of the proinflammatory COL10A1+TPPP3+ macrophage subtype.

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Resident CD24+LCN2+ LPCs aggravate fibrosis and inflammatory progression via the recruitment of TPPP3+COL10A1+ macrophages in NASH

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Original ResearchVol. 58, Issue 2 • pp. 421-436DOI: 10.3724/abbs.2026018

Cardiac PTN-SIRT1 axis alleviates oxidative stress and promotes mitochondrial energy reprogramming to mitigate doxorubicin-induced cardiotoxicity through AMPK/PGC1α signaling

Authors: Yuxiao Sun, Tianwen Wei, Hongping Xu, Hongda Li, Chang Zhou, Xianliang Liu, Yafei Li, Shangwei Huang, Qi Zhang, Xia Duan

Doxorubicin (DOX) remains a cornerstone chemotherapeutic agent for malignancies, yet its clinical utility is severely limited by dose-dependent cardiotoxicity, which can lead to progressive left ventricular dysfunction and heart failure. Pleiotrophin (PTN), a heparin-binding growth factor with diverse physiological functions, regulates glucose and lipid metabolism and promotes oxidative energy pathways. However, whether PTN exerts protective effects against DOX-induced cardiotoxicity (DIC) remains unclear. In this study, we establish cellular and animal models of DIC. DOX administration induces pronounced myocardial injury in both models, characterized by impaired ventricular contractility, increased fibrotic remodeling, and reduced cell viability. Concurrently, PTN protein expression is significantly downregulated in cardiomyocytes under DOX treatment. Overexpression of PTN substantially alleviates these pathological changes. In vitro, PTN reduces mitochondrial oxidative stress and apoptosis while restoring energy production and cell viability. In vivo, PTN improves mitochondrial ultrastructure, decreases cardiomyocyte apoptosis, and enhances cardiac function. Mechanistically, PTN directly binds to SIRT1 and activates AMPK phosphorylation at Thr172, triggering a downstream cascade through the AMPK-PGC1α axis that reprograms mitochondrial energy metabolism and attenuates cardiotoxicity. In conclusion, the PTN-SIRT1 axis protects against DIC by reducing oxidative stress and promoting mitochondrial energy homeostasis via the AMPK/PGC1α pathway, highlighting its potential as a novel therapeutic target for preventing chemotherapy-related cardiac injury.

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Cardiac PTN-SIRT1 axis alleviates oxidative stress and promotes mitochondrial energy reprogramming to mitigate doxorubicin-induced cardiotoxicity through AMPK/PGC1α signaling

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Original ResearchVol. 57, Issue 12 • pp. 2074-2093DOI: 10.3724/abbs.2025100

Characterization of the mechanisms underlying sulfasalazine-induced ferroptotic cell death: role of protein disulfide isomerase-mediated NOS activation and NO accumulation

Authors: Yi-Chen Jia, Jia-Ling Zhong, Xiangyu Hao, Bao Ting Zhu

Sulfasalazine (SAS), a clinically utilized anti-inflammatory drug, has been shown to induce ferroptosis by inhibiting system Xc− activity, thereby causing cellular glutathione depletion. Recently, protein disulfide isomerase (PDI) was shown to be an upstream mediator of the oxidative cell death (oxytosis/ferroptosis) induced by glutamate, erastin, RSL3 and SAS. The present study aims to further characterize the detailed biochemical and cellular mechanisms of SAS-induced ferroptosis in two cell lines, i.e., H9C2 rat cardiomyocytes and BRL-3A rat hepatocytes, with a focus on elucidating the critical role of PDI in mediating SAS-induced toxicity. We find that SAS can induce ferroptosis in H9C2 and BRL-3A cells, which is accompanied by a sequential increase in the buildup of cellular nitric oxide (NO), reactive oxygen species (ROS) and lipid-ROS. SAS activates PDI-mediated dimerization of inducible NO synthase (iNOS) and cellular accumulation of NO, and these effects are followed by ROS and lipid-ROS accumulation. Furthermore, SAS markedly upregulates the iNOS protein levels in these cells. Knockdown of PDI or pharmacological inhibition of PDI catalytic activity effectively suppresses SAS-induced iNOS dimerization, abrogates SAS-induced accumulation of NO, ROS and lipid-ROS, and prevents ferroptosis. On the other hand, PDI activation through the use of TrxR1 inhibitors sensitizes these cells to SAS-induced ferroptosis. These findings provide further experimental support for a pivotal role of PDI in SAS-induced cytotoxicity through the activation of the PDI-NOS-NO axis, which then leads to the accumulation of cellular ROS and lipid-ROS and ultimately the induction of oxidative cell death.

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Characterization of the mechanisms underlying sulfasalazine-induced ferroptotic cell death: role of protein disulfide isomerase-mediated NOS activation and NO accumulation

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Original ResearchVol. 57, Issue 12 • pp. 1983-1998DOI: 10.3724/abbs.2025109

Rhamnose alleviates the proinflammatory response during endotoxemia via the CEACAM1/LGALS9-p38 axis

Authors: Rongjuan Wei, Tao Zhong, Ke Deng, Xianglong Zhang, Dongping Li, Meiling Chen, Ping Chang, Peng Wu, Zhanguo Liu

Gut microbiota plays an important role in orchestrating the host immune response. We previously reported that gut microbiota-derived rhamnose enhances the phagocytosis of macrophages, upon which we further asked whether rhamnose has modulatory effects on inflammation. Here, we show that, in an LPS-induced endotoxic mouse model, plasma rhamnose levels are increased. This bacteria-derived sugar alone does not impact inflammatory cytokine homeostasis or cause organ damage. In contrast, it is able to alleviate endotoxin-induced systemic inflammation and organ damage. Mechanistically, in macrophages in vitro, rhamnose binds to the V39, D40, and T101 sites of carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1), subsequently promoting the interaction between CEACAM1 and galectin 9 (LGALS9), which increases the protein level of dual-specificity protein phosphatase 1 (DUSP1). This inhibits p38 phosphorylation and thus attenuates the LPS-triggered expressions of proinflammatory factors. Collectively, our results suggest that rhamnose signals via the CEACAM1/LGALS9-p38 axis, which suppresses endotoxemia-associated inflammation, and that rhamnose is a candidate anti-inflammatory agent for the control of infection-induced organ damage.

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Rhamnose alleviates the proinflammatory response during endotoxemia via the CEACAM1/LGALS9-p38 axis

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Original ResearchVol. 57, Issue 12 • pp. 1969-1982DOI: 10.3724/abbs.2025145

Angptl4 is upregulated by microenvironmental factors during the wound healing process and promotes epidermal stem cell proliferation via PRL8a6

Authors: Siyuan Yu, Pengxiang Ji, Ting Du, Zuohua Liu, Yuan Yang, Zhenkun Lv, Lei Xu, Qianheng Jin, Weijuan Gong, Yingying Le, Yi Fu, Ruixing Hou

Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during wound healing in mice. Increased Angptl4 expression is positively correlated with increased expressions of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1. Each of these molecules induces Angptl4 expression in mouse EpSCs. RNA sequencing of EpSCs derived from wild-type and Angptl4 knockout (Angptl4–/–) mice reveals altered expressions of genes involved in the cell cycle and cell proliferation in Angptl4–/– EpSCs, including a decrease in cyclin E2/A2/B1 and cyclin-dependent kinase 1 (Cdk1) expression; an increase in Cdk inhibitor 2a (Cdkn2a) and Cdkn2b expression; and a decrease in the prolactin (PRL) family members Prl2a1, Prl8a1, Prl8a9, and Prl8a6. Mechanistic studies reveal that ANGPTL4 stimulates EpSC proliferation via PRL8a6-mediated upregulation of cyclins A2/E2/B1 and Cdk1, downregulation of Cdkn2a, and acceleration of cell cycle progression from the G1 to the S and G2 phases. In vivo studies demonstrate that Prl8a6 mRNA is upregulated by ANGPTL4 in mouse periwound tissue during skin wound healing. Knockdown of Angptl4 or Prl8a6 in periwound skin tissue impairs EpSC proliferation and delays wound re-epithelialization. In conclusion, our study demonstrates that, after skin injury, elevated levels of proinflammatory cytokines and growth factors in periwound tissue stimulate Angptl4 expression in EpSCs and that ANGPTL4 promotes EpSC proliferation by increasing Prl8a6 expression, thereby accelerating wound re-epithelialization.

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Angptl4 is upregulated by microenvironmental factors during the wound healing process and promotes epidermal stem cell proliferation via PRL8a6

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Original ResearchVol. 57, Issue 12 • pp. 2062-2073DOI: 10.3724/abbs.2025097

Integration of the hammerhead ribozyme into structured RNAs to measure ligand-binding events for riboswitch candidates and aptamers

Authors: Shenglan Zhang, Yinghong Lin, Ting Gao, Binfen Chen, Weibin Wu, Shanshan Fang, Kexin Fan, Yuqing Lai, Yezi Lin, Rongqin Ke, Sanshu Li

Some structured RNAs, such as riboswitches and aptamers, can bind to their cognate ligands and have been used in biosensors and gene expression control elements. However, current methods for detecting ligand binding to structured RNAs are either severely limited or inconvenient. In this study, we design a multibase pair bridge to integrate a hammerhead ribozyme into structured RNAs to detect ligand binding events. The experimental results demonstrate that the length of the bridge has a significant effect on the cleavage of the ribozyme; optimal cleavage can be achieved with three to six base pairs in the bridge. The dissociation constant (KD) values obtained through this method are in agreement with those determined by in-line probing techniques, and 1 pmol of allosteric ribozyme RNA is sufficient for measurement. We apply this method to evaluate the binding affinity of the riboswitch candidate Motif_9307. Our findings indicate that this motif has no binding affinity for S-adenosylmethionine or several other tested ligands, which is consistent with the results of the in-line probing experiments. Notably, our method reveals an increase in cleavage activity when yeast extract is added as a mixture of ligands, suggesting that the ligand of Motif_9307 is present in the extract. In conclusion, we develop an alternative approach for measuring ligand binding events associated with riboswitch candidates and aptamers.

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Integration of the hammerhead ribozyme into structured RNAs to measure ligand-binding events for riboswitch candidates and aptamers

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Original ResearchVol. 57, Issue 12 • pp. 1953-1968DOI: 10.3724/abbs.2025089

LPS mediates cuproptosis and inflammation in THP-1 macrophages through HKDC1

Authors: Langlin Ou, Zitong Meng, Jian Mei, Hao Yuan, Xiangrui Zhu, Xiaoying Wang, Ao Shen, Zhaosi Wang, Lixin Zhang, Song Wang, Yingli Chen, Xiangming Pang, Yuxiang Liu, Yadong Xu, Cui Ma

Cuproptosis is a recently identified form of copper-driven cell death characterized by the aggregation of acylated proteins and proteotoxic stress in the mitochondrial tricarboxylic acid cycle, which plays a role in inflammation. Recent studies suggest that hexokinase structural domain protein 1 (HKDC1), a fifth hexokinase, is involved in regulating mitochondrial function. However, the role of HKDC1 in cuproptosis and LPS-induced macrophage inflammation remains unclear. Here, we assess macrophage plasticity using CCK8 viability assays and phagocytosis activity experiments in an in vitro inflammatory model of THP-1 cells. We measure the levels of inflammatory factors and cuproptosis-related proteins using western blot analysis and RT-qPCR. Additionally, we examine the expression and localization of the HKDC1 protein using ChIP-qPCR and immunofluorescence staining. We find that LPS promotes the expressions of inflammatory factors and decreases cuproptosis levels in THP-1-derived macrophages while also activating glycolysis and inducing the expression of HKDC1 via the Toll-like receptor 4 (TLR4) receptor. We further demonstrate that HKDC1 knockdown inhibits glycolysis and induces cuproptosis. Mechanistically, we provide the first evidence that LPS promotes the binding of Yin Yang 1 (YY1) to the HKDC1 promoter, thereby regulating HKDC1 transcription. HKDC1 interacts with heat shock cognate B (HSCB) and ferredoxin 1 (FDX1), leading to increased intracellular copper levels and subsequent cuproptosis. HKDC1 knockdown in vivo alleviates acute sepsis by activating copper-dependent cell death pathways. Collectively, our findings suggest that LPS mitigates cuproptosis and promotes inflammation via HKDC1, suggesting a new cuproptosis-dependent anti-inflammatory strategy.

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LPS mediates cuproptosis and inflammation in THP-1 macrophages through HKDC1

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Original ResearchVol. 58, Issue 5 • pp. 1183-1186DOI: 10.3724/abbs.2025242

Expression characteristics of serum exosomal microRNAs in patients with liver injury induced by anti-tuberculosis drugs

Authors: Yinpeng Jin, Xiaofang Yu, Mingquan Guo, Li Li, Shuangshuang Sun, Liling Yang, Ying Yuan, Qingchun Fu, Rongfeng Shi, Meng Jin

Drug-induced liver injury (DILI) caused by anti-tuberculosis drugs is a serious clinical problem that can lead to acute liver failure and even death. Current diagnosis relies on lagged indicators such as serum transaminase levels, which rise only 48–72 hours after liver injury. This study is the first to systematically analyze the microRNA expression profile of serum exosomes in patients with anti-tuberculosis drug-induced liver injury (TB-DILI) to discover early diagnostic markers. A total of 12 tuberculosis patients and 6 normal controls were included. Serum exosomes were isolated and characterized, and small RNA sequencing identified 701 miRNAs, with 128 differentially expressed between TB-DILI and TB groups. Notably, miR-122-5p was upregulated and has shown early warning value. Target gene prediction and enrichment analysis revealed involvement in GTPase activity regulation, cell migration, and BMP signaling. These findings suggest that exosomal miRNAs, particularly miR-122-5p, may serve as early diagnostic biomarkers for TB-DILI.

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Expression characteristics of serum exosomal microRNAs in patients with liver injury induced by anti-tuberculosis drugs

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Original ResearchVol. 57, Issue 7 • pp. 1139-1150DOI: 10.3724/abbs.2024215

High-resolution imaging atlas reveals the context-dependent role of pancreatic sympathetic innervation in diabetic mice

Authors: Qingqing Xu, Yuxin Chen, Xinyan Ni, Hanying Zhuang, Shenxi Cao, Liwei Zhao, Leying Wang, Jianhui Chen, Wen Z Yang, Wenwen Zeng, Xi Li, Hongbin Sun, Wei L Shen

A better understanding of how sympathetic nerves impact pancreatic function is helpful for understanding diabetes. However, there is still uncertainty and controversy surrounding the roles of sympathetic nerves within the pancreas. To address this, we utilize high-resolution imaging and advanced three-dimensional (3D) reconstruction techniques to study the patterns of sympathetic innervation and morphology in the islets of adult wild-type (WT) and diabetic mice. Our data show that more than ~30% of α/β-cells are innervated by sympathetic nerves in both WT and diabetic mice. Additionally, sympathetic innervated α/β-cells are reduced in diet-induced obese (DIO) mice, whereas sympathetic innervated β-cells are increased in db/db mice. In addition, in situ chemical pancreatic sympathetic denervation (cPSD) improves glucose tolerance in WT and db/db mice but decreases glucose tolerance in DIO mice. In situ cPSD also enhances insulin sensitivity in diabetic mice without affecting WT mice. Overall, our findings advance our understanding of diabetes by highlighting the distinctive impact of pancreatic sympathetic innervation on glucose regulation.

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High-resolution imaging atlas reveals the context-dependent role of pancreatic sympathetic innervation in diabetic mice

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Original ResearchVol. 57, Issue 12 • pp. 1939-1952DOI: 10.3724/abbs.2025171

Single-cell transcriptomics reveals apolipoprotein A4-mediated metabolic-immune reprogramming in lymphocytes during early obesity-related chronic kidney disease

Authors: Yang Wei, Ting Zhang, Yingying Jin, Xiaohuan Liu, Jinting Zhou, Na Huang, Yiying Wang

Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore the role of apolipoprotein A4 (Apoa4) in regulating immune cell metabolism and function, we establish high-fat diet-induced obese (DIO) models using wild-type and Apoa4-knockout (KO) mice. KO mice exhibit exacerbated insulin resistance and renal lipid accumulation. Single-cell RNA sequencing reveals that Apoa4 deletion remodeled the renal immune-metabolic landscape. This remodeling broadly compromises the immune functions of T, NK, and B cells, even as it expands the proportions of cytotoxic Gzma+ NK cells and Derl3+ plasma cells. Mechanistically, Apoa4 deletion aggravates metabolic dysregulation and oxidative stress and downregulates the expression levels of key effector genes, including Ifng and Il1b. Furthermore, the regulatory network activities of key transcription factors, such as Lef1 and Runx3 in Cd8+ T cells; Irf8, T-bet, and Eomes in NK cells; and Tcf4, Lmo2, and Xbp1 in B cells, are perturbed. CellChat analysis predicts disruptions in pro-inflammatory (IFN-II and IL-1), immunoregulatory (FASLG), and metabolic regulatory (ENHO and ANGPTL) signaling, alongside enhanced IL-2-mediated suppression. These findings are corroborated by flow cytometry, immunofluorescence staining, and qPCR. Our results establish Apoa4 as a crucial regulator of lymphocyte metabolic and immune homeostasis in the early stages of obesity-associated CKD.

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Single-cell transcriptomics reveals apolipoprotein A4-mediated metabolic-immune reprogramming in lymphocytes during early obesity-related chronic kidney disease

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Original ResearchVol. 57, Issue 12 • pp. 2124-2128DOI: 10.3724/abbs.2025055

Quantitative liquid chromatography-tandem mass spectrometric analysis of 11dH-TXB2 and creatinine in urine

Authors: Chunyan Li, Wuzheng Liu, Yana Xiao, Tenglong Dai, Yu Su, Yubin Wang, Ao Zhang, Ruichen Liu, Xianglong Zhao, Zhao Zhang, Shangqi Yin, Jun Wu

Platelets circulate in an inactive form in the body until they contact with defective areas of endothelial cells or encounter a clotting cascade [1]. Activated platelets release and express bioactive substances and acquire the ability to bind plasma fibrinogen. Abnormal activation of platelets is involved in atherosclerosis and thrombosis [2,3]. When platelets are stimulated and activated, phospholipase A2 is activated at the same time, which then cleaves membrane phospholipids and frees arachidonic acid (AA) [4]. The latter catalyzes thromboxane A2 (TXA2) via thromboxane synthetase [5], which is induced by the cyclooxygenase COX-1 to produce prostaglandins G2 and H2 [6]. TXA2 is highly unstable, with a half-life of only 30 s, and it is rapidly hydrolyzed to relatively stable thromboxane B2 (TXB2), which is then converted in the liver to 11-dehydrothromboxane B2 (11dH-TXB2), which has a longer half-life and is excreted in the urine [7]. Dehydrothromboxane B2 is the final stable metabolite of thromboxane A2, which is derived only from arachidonic acid metabolism and can represent thromboxane A2 level in the body [8]. Specifically, by inhibiting the action of COX-1, the most important enzyme in the process of arachidonic acid metabolism, aspirin inhibits the production of thromboxane A2, that is, the concentration of TXA2 affects the effect of aspirin on platelet aggregation. However, the half-life of TXA2 (including the metabolic intermediate TXB2) is too short to be accurately measured, so the detection of its metabolic end product 11dH-TXB2 can very accurately reflect the sensitivity of the body to aspirin [7]. The concentration of 11dH-TXB2 in the serum correlates well with the concentration of 11dH-TXB2 in the urine, so the determination of 11dH-TXB2 in the urine can more effectively reflect the production of TXA2 in vivo [8]. The 11dH-TXB2 concentration needs to be corrected with the urinary creatinine concentration to rule out the effects of the urine concentration and renal function, so random urine samples can be used for testing [6]. Aspirin can acetylate serine at the key site of cyclooxygenase and thus irreversibly inhibits the activity of COX-1, reduces the synthesis of TXA2, and blocks the production of TXA2 and its induced platelet aggregation. Low-dose aspirin (30–75 mg/day) can effectively inhibit 95% of COX-1 activity [7]. Since the production of TXA2 in serum is largely dependent on platelet COX-1 (a therapeutic target of aspirin), 11dH-TXB2 can be used as a monitor for aspirin-induced platelet inhibition [3]. Creatinine is a metabolic byproduct of muscle metabolism that is primarily excreted via glomerular filtration, and its level is indicative of renal function [9]. The 24-h creatinine clearance can also be used to determine the integrity of the sample or to correct the urine sample concentration with the creatinine ratio [10]. Currently, creatinine detection methods include the Jaffe method, enzymolysis spectrophotometry, HPLC, capillary electrophoresis, capillary zone electrophoresis, gas chromatography tandem mass spectrometry (GC-MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) [11]. At present, there is no method for the simultaneous detection of 11dH-TXB2 and creatinine. When both analytes are needed, separate tests must be performed, increasing the workload and sample volume requirements. Thus, developing a method that enables the concurrent quantification of 11dH-TXB2 and creatinine in a single assay remains a critical challenge. The aim of this study was to provide a method for the simultaneous detection of 11dH-TXB2 and creatinine and to alleviate the problem that 11dH-TXB2 and creatinine cannot be simultaneously detected. By developing a standardized quantitative approach for measuring 11dHTXB2 and creatinine in human urine, this study aims to provide reliable concentration data, thereby facilitating further clinical research and methodology optimization.

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Quantitative liquid chromatography-tandem mass spectrometric analysis of 11dH-TXB2 and creatinine in urine

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Original ResearchVol. 57, Issue 11 • pp. 1875-1887DOI: 10.3724/abbs.2025091

Unique gene patterns lead to distinct functional phenotypes and chemosensitivity profiles among subclones obtained from a single glioblastoma cell line

Authors: Daxing Xu, Yingdi Jiang, Jie Li, Lingli Gong, Zhenkun Yang, Bo Zhang, Koukou Li, Jian Zou

One of the characteristics of malignant tumors is heterogeneity, which refers to the molecular or genetic differences among progeny cells during tumor growth. This heterogeneity contributes to variations in the tumor growth rate, invasive ability, drug sensitivity, and prognosis. To gain a deeper understanding of the molecular background underlying tumor heterogeneity, we construct monoclonal cell lines derived from the glioblastoma (GBM) cell line U87-MG by limiting dilution assays. The selected CF5 and G11 subclones exhibit completely different cell morphologies and, more importantly, distinct functional phenotypes. CF5 exhibits stronger proliferative properties and chemoresistance, whereas G11 shows greater motility and invasion. Transcriptomic sequencing reveals great differences in gene expression among the CF5, G11, and U87 cell lines, and downregulated genes in individual clones are significantly enriched in gene sets related to extracellular matrix function. ITGA11 and ITGA6, as research subjects, are demonstrated to exclusively regulate functional phenotypes and chemotherapy sensitivity in CF5 or G11 cells. In U87 cells, combined knockdown of these two genes significantly inhibits tumor growth and increases chemotherapy sensitivity, but knockdown of either gene alone does not. In summary, these data reveal that even under uniform growth conditions, the heterogeneity of tumor cells and their diverse genetic backgrounds remain significant and persistent. This finding is crucial for accurately identifying tumor-related genes and their functional phenotypes, and a thorough understanding of the genetic and molecular background underlying tumor heterogeneity is essential for comprehensive cancer treatment.

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Unique gene patterns lead to distinct functional phenotypes and chemosensitivity profiles among subclones obtained from a single glioblastoma cell line

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Original ResearchVol. 57, Issue 11 • pp. 1743-1757DOI: 10.3724/abbs.2025028

ISGylation: is our genome yearning for such a modification?

Authors: Zheng Chen, Zheng Li, Ying Wang, Zaure Dushimova, Kapanova Gulnara, Shunichi Takeda, Zhongjun Zhou, Xingzhi Xu

ISGylation is the post-translational modification of protein substrates covalently conjugated with the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). Although initially linked to antiviral immunity, recent evidence highlights important roles for ISGylation in various biological processes, such as maintaining genomic stability, promoting tumourigenesis, and being involved in other pathological conditions. In this review, we examine the molecular mechanisms underlying ISGylation, its interplay with other post-translational modifications, and its involvement in diverse biological and pathological processes. We propose future research directions to advance the field and discuss how ISGylation might be harnessed to ensure human health, particularly genome instability-associated diseases.

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ISGylation: is our genome yearning for such a modification?

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Original ResearchVol. 57, Issue 12 • pp. 2133-2136DOI: 10.3724/abbs.2025048

Withaferin A combined with ricolinostat: a potent synergistic therapy for cervical cancer through regulating p53 ubiquitination and acetylation

Authors: Tian Chen, Yiting Xu, Kunming Yang, Yutong Du, Zhuan Zhu, Lingling Xu, Xinrong Wang, Yi Yin, Yu Hu, Chengcheng Wang, Ronggui Hu, Chuanyin Li

As a classic tumor suppressor gene, p53 has been extensively studied since its discovery in the mid-1980s. Research findings have revealed that p53 protein expression is suppressed in various cancers [1]. For example, in cervical cancer, p53 predominantly exists in a wild-type form to maintain its biological function [2]. Nevertheless, its tumor-suppressive activity is significantly impaired because of rapid protein degradation, short half-life, and low levels. Post-translational modifications (PTMs) of p53, such as ubiquitination, acetylation, phosphorylation and methylation, are critical regulators of its stability, activity, conformation, localization, and interactions with cofactors [3]. Among these, ubiquitination and acetylation play central roles in controlling p53 protein stability and activity [4]. Therefore, targeting p53 PTMs to modulate its ubiquitination and acetylation levels represents an effective strategy to increase its stability and tumor-suppressive function, offering a promising avenue for cervical cancer drug development. In 99% of cervical cancers (high-risk human papillomavirus-positive), E3 ubiquitin ligase E6-associated protein (E6AP) mediates the ubiquitination degradation of p53 [5], whereas histone deacetylase 6 (HDAC6) deacetylates p53. In this study, we explored the possibility of combining the natural product withferin A (WA) with the HDAC6 inhibitor ricolinostat (RIC) to treat cervical cancer cells, with a focus on the ubiquitination and acetylation of p53 and the consequences for its stability. These results suggested that the combination of WA and RIC is more effective than either treatment alone in inhibiting the degradation and increasing the stability of p53, thereby synergistically slowing the onset and progression of cervical cancer.

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Withaferin A combined with ricolinostat: a potent synergistic therapy for cervical cancer through regulating p53 ubiquitination and acetylation

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Original ResearchVol. 57, Issue 11 • pp. 1834-1846DOI: 10.3724/abbs.2025202

VSIG2 hinders gastric cancer progression by suppressing ANXA2-mediated NF-κB pathway activation

Authors: Qingfeng Ni, Yang Wang, Xinyue Bian, Qiuchan Qu, Boyuan Shen, Yuanjie Niu, Jiawei Yu, Jianwei Zhu

As the fifth most common cancer and the third leading cause of cancer death worldwide, gastric cancer (GC) has long been a serious global health challenge. The purpose of this study was to explore the expression of V-set and immunoglobulin domain containing 2 (VSIG2) in GC and to elucidate its role in GC progression and related mechanisms. Western blot analysis, qRT-PCR and immunohistochemical (IHC) staining are used to detect the expression of VSIG2 in GC cells and tissues. Kaplan-Meier survival curve analysis is performed. The effects of VSIG2 on biological effects related to GC progression in vitro are detected by CCK-8, EdU, Transwell and wound healing assays and in vivo by a nude mouse subcutaneous tumor model and a liver metastasis model. Mechanistically, co-immunoprecipitation, immunofluorescence and ubiquitination experiments are used to explore the regulatory effect of VSIG2 on ANXA2 and the regulatory effect between FBXW10 and ANXA2. VSIG2 is abnormally expressed at low levels in patients with GC and is associated with patient prognosis. Low VSIG2 expression is closely related to tumor size, lymph node metastasis, TNM stage and vascular invasion in GC patients. Functionally, in vitro and in vivo experiments reveal that VSIG2 could inhibit the growth, proliferation and metastasis of GC. Mechanistically, VSIG2 and ANXA2 interact directly in GCs and co-localize at the cell membrane. Further exploration reveals that highly expressed VSIG2 competes with FBXW10 for binding to ANXA2 and relies on FBXW10-mediated K63 polyubiquitination of ANXA2 to induce membrane localization of ANXA2 and further inactivate NF-κB, thereby suppressing GC progression. In summary, VSIG2 is expressed at abnormally low levels in patients with GC, and its low expression is associated with poor patient prognosis. VSIG2 can inhibit the proliferation and migration of GC via the ANXA2/NF-κB pathway. This study elucidates a new mechanism by which VSIG2 inhibits GC progression, which may provide a new perspective for the diagnosis and treatment of GC patients.

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VSIG2 hinders gastric cancer progression by suppressing ANXA2-mediated NF-κB pathway activation

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Original ResearchVol. 57, Issue 12 • pp. 2137-2138DOI: 10.3724/abbs.2025233

Caveolin-1-deficient fibroblasts promote migration, invasion, and stemness by activating the TGF-β/Smad signaling pathway in breast cancer cells

Authors: Qingyun Huang, Longyuan Wu, Yi Wang, Xinyu Kong, Xinhua Xiao, Qiyuan Huang, Miao Li, Yujia Zhai, Fuxiu Shi, Ruichen Zhao, Junpei Zhong, and Lixia Xiong

This is a corrigendum to the article 'Caveolin-1-deficient fibroblasts promote migration, invasion, and stemness by activating the TGF-β/Smad signaling pathway in breast cancer cells' published in Acta Biochim Biophys Sin 54: 1587–1598. The authors identified inaccuracies in the preparation of several figures (Figure 2D, 4A, and 5A) and have replaced them with corrected versions. The errors are strictly confined to figure presentation and do not impact the underlying data, statistical analysis, or main conclusions. The authors apologize for the oversight.

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Caveolin-1-deficient fibroblasts promote migration, invasion, and stemness by activating the TGF-β/Smad signaling pathway in breast cancer cells

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Original ResearchVol. 57, Issue 11 • pp. 1814-1823DOI: 10.3724/abbs.2025057

New feature of hMEIOB and hSPATA22 binding to ssDNA from a single-molecule perspective

Authors: Yating Xu, Wei Qu, Erchi Zhou, Qi Sun, Weihao Gong, Lei Xu, Yaoke Lei, Zhangying Jia, Hanqing Shi, Xinghua Zhang, Mengcheng Luo

MEIOB and SPATA22 are gonad-specific proteins that function in meiosis recombination. Mutations in these two proteins cause oligospermia or azoospermia in human males. It has been reported that the heterodimer composed of MEIOB and SPATA22 recognizes and binds to the single-strand DNA (ssDNA) protected by the replication protein A (RPA) complex to promote DNA damage repair during homologous recombination. However, the amino acid sequences of the two proteins are inconsistent in humans and rodents, which leads to functional differences in meiosis. In this study, human-derived MEIOB (hMEIOB) and SPATA22 (hSPATA22) are expressed and purified for electrophoretic mobility shift assay (EMSA), magnetic tweezer (MT) assay and bio-layer interferometry (BLI) assay to analyze the ssDNA binding patterns. The results show that hMEIOB has low ssDNA-binding affinity and stability alone, but hSPATA22 binds to ssDNA faster and more stably and promotes ssDNA condensation. Strong binding affinity and stability to ssDNA are present when the hMEIOB-hSPATA22 heterodimer is formed. Moreover, we find that multiple hMEIOB-hSPATA22 heterodimers spontaneously aggregate in vitro. hRPA complex weakens the binding affinity of hMEIOB, hSPATA22 and hMEIOB-hSPATA22 heterodimer to ssDNA, and it can also bind to hSPATA22 and hMEIOB-hSPATA22 heterodimer in vitro, which might be related to the proven function of RPA complex to protect ssDNA and recruit proteins related to DNA damage repair during meiosis. Overall, this study is the first time to elucidate the binding patterns of the hMEIOB and hSPATA22 to ssDNA in vitro, and to verify the relationship between the RPA complex and meiosis-related proteins, MEIOB and SPATA22, from single-molecule perspective.

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New feature of hMEIOB and hSPATA22 binding to ssDNA from a single-molecule perspective

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Original ResearchVol. 57, Issue 12 • pp. 1923-1938DOI: 10.3724/abbs.2025099

The dual role of RNA-binding proteins: promotion of tumorigenesis, drug resistance, and emerging therapeutic targets

Authors: Zemei Xu, Yukun Cui

Cancer is a complex and multifaceted disease characterized by a multitude of molecular factors. RNA-binding proteins (RBPs) have emerged as pivotal regulators of tumor development, progression, and chemoresistance through their interactions with target transcripts. These interactions regulate a multitude of processes, including alternative splicing, cleavage and polyadenylation, RNA localization, translation, N6-methyladenosine (m6A) RNA modification, and DNA double-strand break repair. The RBP family comprises over 2000 proteins and plays a critical role in oncogene expression, invasion, metastasis, and inhibition of apoptosis. However, the mechanisms by which RBPs selectively recognize RNAs remain an active area of research. In this review, we examine recent advancements in understanding RNA-binding domains and the RNA processes regulated by RBPs in tumorigenesis, summarize and highlight the roles of RNA-binding domains in cancers and the molecular mechanisms of RBPs in chemotherapy resistance, discuss the potential of targeting RBPs for cancer therapy and review RBPs that are dysregulated in cancers. Additionally, we highlight recently developed tools for predicting RBP-RNA binding activities to provide valuable support for ongoing research efforts.

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The dual role of RNA-binding proteins: promotion of tumorigenesis, drug resistance, and emerging therapeutic targets

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Original ResearchVol. 57, Issue 11 • pp. 1888-1896DOI: 10.3724/abbs.2025125

Construction of an ASFV proteome library via multiple optimization strategies for high-throughput analysis

Authors: Songxin Guo, Li Ouyang, Hui Zhang, Ming Li, Wei Zhou, Ao Liang, Lu Wang, Rui Gong, Dianbing Wang, Chenli Liu, Zhuojun Dai, Shengce Tao, Jiaoyu Deng, Guimin Zhang, Xian-En Zhang, Feng Li

African swine fever virus (ASFV) is a large and structurally complex DNA virus encoding more than 160 proteins, including more than 68 structural proteins. A protein library covering recombinant ASFV proteins is fundamentally important for studies on protein function, antigenicity, vaccine development, and virus-host interactions. Here, to construct an ASFV protein library, we add a glutathione S-transferase (GST) tag at the N-terminus of each ASFV protein to facilitate solubilization and purification and express the recombinant proteins in the yeast host. By optimizing codons, expression vectors and strains and conditions of expression and purification, we achieve satisfactory protein yields for analytical applications and maximized access to the whole proteome of ASFV, with coverage of ca. 95%. Using the library, a protein chip is constructed and used to screen for interactions between ASFV and swine proteins (e.g., IRF3, p65, and IκBα). The ASFV protein library lays the groundwork for understanding and combatting ASFV. The methods for constructing the library are instructive for generating other protein libraries for high-throughput applications.

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Construction of an ASFV proteome library via multiple optimization strategies for high-throughput analysis

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Original ResearchVol. 57, Issue 11 • pp. 1901-1903DOI: 10.3724/abbs.2025060

Osteocalcin carboxylation/undercarboxylation levels and gene variants associated with type 2 diabetes mellitus in the Chinese Han population

Authors: Luyue Qi, Hong Wu, Xiangqi Li, Yang Xu, Liangyong Liu

Type 2 diabetes mellitus (T2DM) is an endocrine metabolic disorder characterized by insulin secretion dysfunction and/or insulin resistance. Osteocalcin (OC), or bone γ-carboxyglutamic acid protein (BGP), is a bone matrix protein predominantly produced by osteoblasts. Vitamin K-dependent carboxylation converts OC into gamma-carboxyglutamic acid (Gla)-rich carboxylated osteocalcin (cOC), which binds to hydroxyapatite and can be decarboxylated to undercarboxylated osteocalcin (ucOC) under acidic conditions. While cOC influences bone formation and mineralization, ucOC regulates energy metabolism. This study aimed to explore the associations between T2DM, serum OC levels (including cOC and ucOC), and OC gene polymorphisms in the Chinese Han population. T2DM patients and a healthy cohort, all of Han ethnicity, were categorized into a T2DM group (n = 456) and a control group (n = 224). Serum levels of cOC and ucOC were determined via ELISA. Insulin sensitivity was assessed via HOMA-IR, and pancreatic β-cell function via HOMA-β. Nine SNPs in the OC gene were genotyped via SNaPshot. Compared with controls, T2DM patients presented significantly lower levels of ucOC, cOC, and ucOC/cOC ratio. Additionally, T2DM subjects had elevated BMI, HbA1c, HOMA-IR, ALP, TG, HDL, and LDL levels, with decreased HOMA-β, ALT, AST, hsCRP, and FFA levels. In terms of bone metabolism, T2DM patients presented increased blood phosphorus, ICTP, P1NP, and 25(OH)D levels and decreased blood calcium, N-MID, PTH, and β-CTX levels. Associations between serum cOC and ucOC and various factors were analyzed. In the T2DM group, cOC was inversely correlated with HbA1c and P1NP, and positively correlated with ALP, LDL, and N-MID. ucOC was positively associated with N-MID. In controls, cOC was positively correlated with HDL, N-MID, and PINP, while ucOC correlated with PINP. The study also examined SNPs in the OC gene and their relationships with serum cOC and ucOC.

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Osteocalcin carboxylation/undercarboxylation levels and gene variants associated with type 2 diabetes mellitus in the Chinese Han population

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Original ResearchVol. 57, Issue 10 • pp. 1660-1669DOI: 10.3724/abbs.2025036

HDAC11 in ovarian granulosa cells coordinates LH in the maturation of oocytes in Tan sheep

Authors: Jiaqi Shi, Donghuan Lv, Yaxiu Xu, Xiangyan Wang, Zhipeng Qi, Yujie Yan, Jinghua Wang, Hongyuan Song, Hui Yang, Luguo Jin, Zhengyi Yang, Xiaoning Yang, Xiumei Kang, Xinfeng Liu, Zhuming Zhang, Chao Wang

Oocyte maturation plays an important role in supporting mammalian reproduction. Histone deacetylase 11 (HDAC11), the only member of the class IV histone deacetylase family and the smallest histone deacetylases (HDACs), has been shown to regulate oocyte maturation in mice and pigs. However, the epigenetic effects of HDACs in follicular granulosa cells in response to LH induction remain elusive in sheep. In this study, the effects of follicular somatic cell-derived HDAC11 on oocyte maturation in Tan sheep are evaluated. The expression changes of HDAC11 and related proteins are detected by means of immunofluorescence, immunohistochemistry, western blot analysis and enzyme-linked immunosorbent assay. Our results indicate that the level of HDAC11 in follicular granulosa cells as well as oocytes in Tan sheep increases with the growth and maturation of the follicles. Specific inhibition of HDAC11 by SIS17 remarkably reduces the oocyte maturation rate under LH supplementation in vitro. Accordingly, the acetylation level of H3K9 in granulosa cells is increased, while the EGF-like growth factor AREG is remarkably decreased. Furthermore, inhibition of HDAC11 markedly decreases the level of YAP1, which is a negative regulator of AREG in granulosa cells. Conclusively, HDAC11 in the granulosa cells of Tan sheep contributes to the LH induced production of AREG during oocyte in vitro maturation by decreasing the level of H3K9 acetylation and increasing the level of YAP1.

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HDAC11 in ovarian granulosa cells coordinates LH in the maturation of oocytes in Tan sheep

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Original ResearchVol. 57, Issue 11 • pp. 1824-1833DOI: 10.3724/abbs.2025047

Increased neutrophil senescence is associated with impaired immunosuppressive activity in systemic lupus erythematosus

Authors: Lei Han, Fengling Huang, Qingchen Zhu, Huan Wang, Tianlin Lu, Chunyuan Xiao, Jing Xu, Xiaoyan Zhang, Yichuan Xiao, Xinfang Huang

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a complex pathogenesis that was previously thought to involve primarily adaptive immunity. Emerging evidence underscores the role of neutrophils in shaping immune dysregulation and inducing organ damage in lupus. This study aims to investigate the dynamics of neutrophil senescence and its relationship with lupus, an area that remains poorly understood. Here, we identify a significantly elevated proportion of CXCR4hiCD62Llo senescence-like neutrophils in the peripheral blood of SLE patients compare to that in the healthy donors. Increased numbers of senescence-like neutrophils are positively correlated with SLE disease activity and autoantibody production in SLE patients. In addition, senescence-like neutrophils derived from SLE patients exhibit an impaired ability to suppress the proinflammatory activity of natural killer (NK) cells and CD4+ T cells. Further mechanistic exploration suggests that these senescence-like neutrophils might exert their immunosuppressive effects via reactive oxygen species (ROS) production under physiological conditions. Our results demonstrate that senescence-like neutrophils could serve as biomarkers for assessing the disease activity of SLE. The compromised immunosuppressive function of senescence-like neutrophils provides a new perspective on SLE pathophysiology and may pave the way for the development of novel therapies.

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Increased neutrophil senescence is associated with impaired immunosuppressive activity in systemic lupus erythematosus

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Original ResearchVol. 57, Issue 11 • pp. 1897-1900DOI: 10.3724/abbs.2025094

KARs negatively regulate the immune response in lamprey

Authors: Ruyu Zhuang, Zihao Yan, Shuyuan Zhang, Meixuan Li, Feng Sun, Ya Pang, Ding Li, Liang Zhao, Yinglun Han

Kainate receptors (KARs) are one of the ionotropic glutamate receptor (iGluR) families, and their antagonists are being investigated for the treatment of several neurological disorders, including Alzheimer’s disease, a neurodegenerative condition, etc. As early as 1990, Bettler et al. [1] first cloned the GRIK1 subunit of KARs, marking a pivotal advancement in understanding these receptors. Members of the iGluR family have been identified in other jawed vertebrates and exhibit conserved structural features. However, research into iGluRs in jawless vertebrates has been limited. Owing to the unique evolutionary position of lampreys, their iGluRs might also present functions distinct from those of jawed vertebrates; therefore, it is particularly important to study iGluRs in lampreys. In this study, we identified four homologous subunits of iGluRs in lampreys, including Lr-GRIA2, Lr-GRIA4, Lr-GRIK1 and Lr-GRIN2B. Lampreys occupy a unique evolutionary position, making phylogenetic analysis of iGluR subunits between lampreys and other species essential for understanding iGluR evolution. Given the distinctive functional characteristics of iGluR family members, particularly KAR subtypes, we focused on the functional validation of Lr-GRIK1. First, we confirmed the expression of Lr-GRIK1 in lampreys and examined its expression profiles across various tissues via qPCR and western blotting. To elucidate the functional role of Lr-GRIK1 in lampreys, we used an siRNA to silence Lr-GRIK1. We subsequently conducted transcriptome sequencing of both the silenced and control groups to construct and analyze their expression profiles. Our analysis revealed differential expression of genes enriched in pathways related to signal transduction and the immune system, highlighting potential roles of Lr-GRIK1 beyond traditional neurotransmission functions. Unlike in jawed vertebrates, transcriptome enrichment provides a new direction for understanding the function of Lr-GRIK1. Therefore, we monitored the changes in Lr-GRIK1 expression in the kidney tissue of lampreys after stimulation. In addition, we confirmed that Lr-GRIK1 affects the expression levels of immune-related molecules during the immune response process. These findings provide insights into the broader functional significance of Lr-GRIK1 in the biology of lampreys.

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KARs negatively regulate the immune response in lamprey

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Original ResearchVol. 57, Issue 11 • pp. 1767-1779DOI: 10.3724/abbs.2025113

Nobiletin suppresses nasopharyngeal carcinoma by regulating the KEAP1/NRF2/ARE pathway

Authors: Yiyao Liang, Minyan Wei, Yunan Yao, Baizhong Chen, Jinji Deng, Shiqi Xu, Liming Li, Wen Liu, Yi Cai, Guodong Zheng

Nasopharyngeal carcinoma (NPC) ranks among the most prevalent malignancies, particularly in East Asia and Southeast Asia. Nobiletin (NOB), an exclusive polymethoxyflavonoid derived from citrus peel, exhibits diverse physiological properties, notably its potent anticancer activity. Kelch-like ECH-associated protein 1 (KEAP1), the repressor protein regulating the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, has emerged as a promising strategy for addressing oxidative stress in various diseases. The KEAP1/NRF2/ARE signal is a fundamental pathway within the cellular homeostatic defense system. This study robustly demonstrates the chemopreventive potential of NOB through comprehensive in vitro and in vivo assessments using subcutaneous tumor mouse models. Furthermore, our groundbreaking findings reveal that NOB effectively hinders the migration and invasion capacities of CNE-2 and 5-8F (NPC) cells in a dose- and time-dependent manner. Mechanistically, NOB, a potent KEAP1 activator, significantly disrupts the NRF2/ARE signaling pathway by accelerating the proteasomal degradation of NRF2 and suppressing its nuclear translocation. Consequently, this cascade reduces the expressions of ARE-driven genes and antioxidant enzymes, thereby increasing intracellular reactive oxygen species (ROS) levels and increasing antitumor immunity. Moreover, the sensitivity induced by NOB is markedly diminished in CNE-2 cells following the gene silencing of KEAP1. These findings underscore the pivotal role of NOB in activating KEAP1. Overall, KEAP1 has emerged as a compelling target for potential malignancy treatment in nasopharyngeal carcinoma cell lines. Our results suggest the promising application of NOB as a natural sensitizer in chemotherapy, opening avenues for promising therapeutic interventions.

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Nobiletin suppresses nasopharyngeal carcinoma by regulating the KEAP1/NRF2/ARE pathway

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Original ResearchVol. 57, Issue 10 • pp. 1611-1624DOI: 10.3724/abbs.2025056

Triptonide facilitates autophagy-mediated apoptosis in esophageal squamous cell carcinoma by targeting the AMPK-mTOR-ULK1 axis

Authors: Jiujun Ju, Nuo Xu, Bohan Li, Dan Shi, Jiahui Cai, Qiusheng Zheng, Lei Ye, Shaosen Zhang, Caixia Wang

Triptonide (TN) is a small-molecule compound initially derived from Tripterygium wilfordii Hook. f used in traditional Chinese medicine. However, its potential antitumor mechanisms are still far from adequately understood. The purpose of this research is to elucidate the antitumor and pharmacological effects of TN on esophageal squamous cell carcinoma (ESCC). Functional assays, such as CCK-8 and colony formation assays, are used to evaluate the effects of TN on KYSE450 and KYSE510 cells. Subsequently, western blot analysis, Hoechst 33258 staining, flow cytometric analysis, autophagic flux detection, and transmission electron microscopy (TEM) are used to determine the effects of TN on apoptosis and autophagy in ESCC cells. Additionally, the autophagy inhibitor 3-methyladenine (3-MA) and the AMPK inhibitor dorsomorphin (Compound C, CC) are administered to explore the molecular mechanisms and crucial pathways in ESCC cells. Our findings provide strong evidence that TN induces autophagy-dependent apoptosis by targeting the AMPK-mTOR-ULK1 axis in ESCC cells. Collectively, this study sheds light on the anticancer mechanisms of TN in esophageal squamous cell carcinoma and suggests that TN is a promising candidate for the antitumor phytomedicine.

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Triptonide facilitates autophagy-mediated apoptosis in esophageal squamous cell carcinoma by targeting the AMPK-mTOR-ULK1 axis

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Original ResearchVol. 57, Issue 10 • pp. 1589-1600DOI: 10.3724/abbs.2025034

Melatonin attenuates kidney injury by alleviating lysosomal damage in diabetic kidney disease

Authors: Jiaqi Chen, Shuting Zhang, Xiaoquan Xue, Xiaoqin Ma, Aomiao Chen, Yichuan Wu, Geningyue Wang, Qian Zhang, Yaoming Xue, Yijie Jia, Zongji Zheng

Proteinuria-induced damage to renal tubular epithelial cells is one of the main causes of diabetic kidney disease (DKD), and the clearance of overloaded albumin by lysosomes is crucial for maintaining the homeostasis of renal tubular epithelial cells. Therefore, lysosomal damage is closely related to the pathogenesis of DKD, but effective prevention and treatment measures are still lacking. Melatonin (MLT) is secreted by the pineal gland and can not only regulate circadian rhythms but also maintain lysosomal homeostasis. In this study, we demonstrate the presence of significant lysosomal damage in the renal tubules of DKD patients, which causes autophagy impairment and a concomitant oxidative stress imbalance; however, MLT can upregulate transcription factor EB (TFEB) to improve lysosomal damage and restore the biosynthesis of this organelle. Mechanistically, MLT may protect lysosomes via the upregulation of TFEB and the miR-205-5p-LRP-1 pathway in renal tubules, thus improving autophagy dysfunction and oxidative imbalance in DKD.

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Melatonin attenuates kidney injury by alleviating lysosomal damage in diabetic kidney disease

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Original ResearchVol. 57, Issue 10 • pp. 1574-1588DOI: 10.3724/abbs.2025102

Nanchangmycin suppresses influenza A virus infection by blocking endosomal acidification

Authors: Hao Zhang, Changhai Liu, Shuo Cai, Yuting Wu, Lu Shang, Fayu Yang, Jing Liu, Nan Wei, Yingchun Liu, Mi Wang, Fei Gao, Qinfang Liu, Hongjun Chen, Guangzhi Tong, Yin Chen, Feng Gu

Influenza A viruses (IAVs) constitute a major threat to human and animal health. Currently, M2 ion-channel inhibitors, neuraminidase (NA) inhibitors, RNA polymerase inhibitors, and cap-dependent endonuclease inhibitors have been applied clinically as therapeutics against IAVs. However, IAVs possess adaptive mutations to these inhibitors, especially M2 ion channel and NA inhibitors. Thus, novel antiviral agents should be developed. In the present study, we screen approximately 5500 compounds and identify an IAV inhibitor, nanchangmycin, which possesses a robust antiviral activity both in vitro and in vivo. In addition, it exhibits broad-spectrum antiviral activity for additional virus infections, including pseudorabies virus, herpes virus, porcine epidemic diarrhea virus, porcine reproductive and respiratory syndrome virus. Most importantly, it has antiviral activity against oseltamivir-resistant strains in sub-μM ranges and promotes the survival of MDCK cells infected with the oseltamivir-resistant influenza A virus strain. Further studies reveal that it blocks the nuclei migration of viral nuclear proteins (NPs), resulting in NP accumulation in the cytoplasm, particularly within perinuclear endosomes. Also, it inhibits IAVs by blocking endosomal acidification. Overall, nanchangmycin has the potential to be developed as an anti-influenza agent.

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Nanchangmycin suppresses influenza A virus infection by blocking endosomal acidification

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Original ResearchVol. 57, Issue 10 • pp. 1625-1635DOI: 10.3724/abbs.2025042

PDGFC secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and immunosuppression in lung adenocarcinoma

Authors: Meimei Cui, Xiaodi Ding, Yu Jiang, Liying Zhang, Wangkai Cao, Yongming Wang, Zhimei Sheng, Wei Sun, Ai Guo, Lihui Gu, Xiurong Zhang, Wanli Duan, Lihong Shi, Baogang Zhang

This study elucidates the mechanisms by which cancer-associated fibroblast (CAF)-derived platelet-derived growth factor C (PDGFC) promotes the progression of lung adenocarcinoma (LUAD) and explores the impact of PDGFC on immune regulation within the tumor microenvironment (TME). Our results show that there is higher expression of PDGFC in CAFs than in nontumor tissue fibroblasts (NFs) and that higher expression of PDGFC is correlated with poor prognosis in LUAD patients. Furthermore, CAF-derived PDGFC promotes epithelial-mesenchymal transition (EMT) in cancer cells as well as matrix metalloproteinase 2 (MMP2) expression through the PDGF receptor A (PDGFRA)-mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Moreover, our study demonstrates that CAF-derived PDGFC is essential for the activation and infiltration of fibroblasts in the TME, as well as the inflammatory infiltration of different immune cell types and the immunosuppressive conditions within the TME. In particular, PDGFC induces increased PDGFRA expression in both tumor cells and fibroblasts, which can lead to reciprocally positive feedback to accelerate malignant tumor progression. This discovery provides a novel TME-targeted strategy for LUAD treatment.

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PDGFC secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and immunosuppression in lung adenocarcinoma

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Original ResearchVol. 57, Issue 10 • pp. 1684-1695DOI: 10.3724/abbs.2025045

TLR4 mediates lipotoxic β-cell dysfunction by inhibiting the TMEM24/PI3K/AKT pathway

Authors: Chao Lan, Yan Li, Zhiyan Weng, Wei Pan, Wanxin Lin, Zhen Jiang, Liyong Yang, Ximei Shen

Immune imbalance is the core pathophysiological mechanism of the deterioration of β-cell function driven by lipid metabolism disorders. Toll-like receptor 4 (TLR4) inflammatory signaling is a key pathway that mediates lipotoxic injury in β-cells, but the underlying mechanism needs to be further elucidated. Transmembrane protein 24 (TMEM24) is a key transporter that regulates pulsatile insulin secretion, but its pathophysiology in lipotoxicity remains unclear. In this study, we investigate whether TLR4-mediated lipotoxicity is affected by the inhibition of TMEM24 expression. The PPI network shows that TLR4 is associated with both insulin secretion and ER stress proteins in islets from obese rats. Using in vitro lipotoxic β-cell models, we found that TMEM24 is the target signal of palmitic acid (PA)-induced insulin secretion impairment in islet β-cells, and TLR4 plays a mediating role in this process. Mechanistically, TLR4 mediates lipotoxicity by binding to TMEM24 and downregulating its protein expression to suppress PI3K/AKT signaling, leading to β-cell dysfunction. TLR4 knockout ameliorates islet function impairment through TMEM24/PI3K/AKT signaling in HFD-induced obese rats. Taken together, our results show that TLR4 mediates lipotoxicity in islet β-cells by inhibiting the TMEM24/PI3K/AKT pathway, and the mechanism of TLR4-mediated lipotoxicity is elucidated from the perspective of insulin vesicular secretion.

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TLR4 mediates lipotoxic β-cell dysfunction by inhibiting the TMEM24/PI3K/AKT pathway

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Original ResearchVol. 57, Issue 10 • pp. 1557-1573DOI: 10.3724/abbs.2025071

CD47-mediated tumor microenvironment remodeling: a central mechanism in immune evasion

Authors: Hemei Yuan, Lingling Zhu, Longhuan Yang, Yong Yi, Tao Lv

Immune evasion is a crucial strategy for tumor growth and survival, with the tumor microenvironment facilitating tumor immune evasion and cancer progression. CD47, a transmembrane protein highly expressed in various cancer cell types, interacts with its ligands SIRPα and TSP-1 to induce immune tolerance, enabling tumor cells to evade immune surveillance and phagocytosis by immune cells. Understanding the pathways driving CD47 signaling and related activation factors is essential. In this review, we discuss the interactions between CD47 and its ligands SIRPα and TSP-1; their roles in inhibiting the functions of immune cells (macrophages, dendritic cells (DCs), glial cells, T cells, NK cells, etc.); and the mechanisms involved. Furthermore, we also explore the influence of factors within the tumor microenvironment, including TNF-α, IFN-γ, ILs, HIF-1, oncogenes, isocitrate dehydrogenase 1, metabolic enzymes, and exosomes, on CD47-mediated immune evasion. Recent monoclonal antibody drugs targeting CD47 for cancer treatment have shown side effects and cause economic losses. Researchers can explore alternative approaches, such as designing targeted drugs with minimal side effects or investigating other related molecules or pathways. Combination therapy and further research into the molecular mechanisms of CD47 could offer new directions for antitumor drug development.

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CD47-mediated tumor microenvironment remodeling: a central mechanism in immune evasion

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Original ResearchVol. 57, Issue 10 • pp. 1601-1610DOI: 10.3724/abbs.2025063

FOXD3 promotes homologous recombination repair and genomic stability by facilitating MRE11-mediated DNA end resection

Authors: Shibin Xu, Jingyu Zhang, Congwen Gao, Ziyi Xiong, Yamin Gong, Bao Chai, Hongxiang Chen, Xingzhi Xu

Homologous recombination (HR) is crucial for the high-fidelity repair of DNA double-strand breaks (DSBs), ensuring the maintenance of genome stability. In this study, we show that FOXD3 interacts with poly (ADP-ribose) polymerase 1 (PARP1) and is recruited to DSBs in a PARP1-dependent manner. FOXD3 directly binds to the DSB repair protein MRE11 and promotes its recruitment to DSB sites, ensuring proper end resection. Inhibition of FOXD3 expression compromises HR-mediated DSB repair and chromosome stability and sensitizes cancer cells to ionizing radiation. Collectively, our findings demonstrate that FOXD3 promotes HR-mediated DSB repair and genome stability.

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FOXD3 promotes homologous recombination repair and genomic stability by facilitating MRE11-mediated DNA end resection

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Original ResearchVol. 57, Issue 10 • pp. 1709-1717DOI: 10.3724/abbs.2025005

ATF3 triggers M2 macrophage polarization to protect against pulp inflammation through WNT4 regulation

Authors: Liu Liu, Jie Wang, Jie Yu, Jing Wang, Jinhua Yu

Pulpitis is a common inflammatory oral disease that can lead to pulp necrosis. The aim of this study is to investigate the expression and regulatory mechanisms of ATF3, a potential therapeutic marker, in pulpitis. A mouse pulpitis model with different degrees of inflammation is established, and the expression of ATF3 in pulpitis is explored. The histological features of healthy pulp and pulpitis are analyzed by HE staining, and classical inflammatory factors are detected by immunohistochemistry (IHC). In an in vitro study, we investigate the role of ATF3 in the regulation of WNT4 transcription and explore the effects of the ATF3/WNT4 axis on the polarization of RAW264.7 macrophages, the inflammatory response and the osteogenic differentiation of human dental pulp stem/stromal cells (hDPSCs). Our results show that ATF3 is expressed at low levels in inflamed pulp tissues; overexpression of ATF3 reduces the area of pulp necrosis, decreases the level of pro-inflammatory factors, and promotes macrophage polarization toward the M2 type. Furthermore, we reveal that ATF3 binds to the WNT4 promoter region and positively regulates the expression of WNT4 and that ATF3 downregulates M1 markers and increases the expression of M2 markers by regulating WNT4 expression. In addition, ATF3 promotes the osteogenic differentiation of dental pulp stem cells. In summary, this study reveals that ATF3 promotes M2 macrophage polarization by regulating WNT4, which in turn inhibits pulpal inflammatory responses and promotes the osteogenic differentiation of dental pulp stem cells. These findings suggest that ATF3 may be a potential target for pulpitis treatment.

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ATF3 triggers M2 macrophage polarization to protect against pulp inflammation through WNT4 regulation

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Original ResearchVol. 57, Issue 10 • pp. 1647-1659DOI: 10.3724/abbs.2025070

Schisandrin A ameliorates the diabetes-associated memory impairment by alleviating inflammation and ferroptosis

Authors: Guandi Ma, Min Lei, Shuang Guo, Yuqing Zhang, Yixuan Sun, Huimin Ji, Changhan Ouyang, Xiaosong Yang, Youzhi Zhang, Xiufen Liu, Baoqing Zhao, Xiying Guo

Schisandrin A (SchA), a bioactive lignan that was isolated from the dried fruit of Schisandra chinensis, has attracted much attention because of its diverse spectrum of pharmacological effects. The aim of this study is to clarify the function of SchA in diabetes-related fear memory impairment and its molecular mechanisms. Rats are randomly assigned to 4 groups: the control group (Con group), the DM group, the DM + SchA group, and the Con + SchA group. The results demonstrate that SchA treatment improves insulin sensitivity, reduces blood glucose, and significantly reduces memory impairment. SchA treatment also prevents histological damage, enhances synaptic protein production, and significantly decreases Aβ42 formation in the diabetic prefrontal cortex. Further research reveals that SchA therapy decreases microglial activation and the expression levels of variables linked to inflammation while increasing the phosphorylation of proteins implicated in the insulin resistance signaling pathway. Furthermore, in the prefrontal cortex of diabetic rats, SchA decreases ferroptosis by increasing the protein expressions of GPX4, SLC7A11, Nrf2, HO-1, and SIRT1. Overall, our findings suggest that SchA may lessen diabetes-associated fear memory impairment symptoms by, most likely, lowering ferroptosis and inflammatory responses in the prefrontal brain of diabetic rats. SchA may be a useful therapy for diabetes, including memory impairment.

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Schisandrin A ameliorates the diabetes-associated memory impairment by alleviating inflammation and ferroptosis

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Original ResearchVol. 58, Issue 8 • pp. 1875-1886DOI: 10.3724/abbs.2025208

Long noncoding RNA HNF1A-AS1 promotes ovarian cancer growth and M2 macrophage polarization by counteracting miR-214-mediated suppression of semaphorin 4D signaling

Authors: Yang Liu, Yanzhi Wu, Yujie Gengxiao, Yan Li, Jiamei Song, Chunyi Sun

To determine whether lncRNA HNF1A-AS1 affects epithelial ovarian cancer (EOC) growth and macrophage polarization through miR-214/SEMA4D, the endogenous HNF1A-AS1 and miR-214 levels in human EOC cell lines are compared with those in normal ovarian epithelial IOSE80 cells. HNF1A-AS1 is overexpressed or silenced to investigate whether HNF1A-AS1 regulates miR-214/SEMA4D in SKOV3 cells and xenograft tumors, as well as the phenotypic switching of THP-1 cells. Compared with IOSE80 cells, EOC cells present significantly higher HNF1A-AS1 level and lower miR-214 level. Fluorescence in situ hybridization reveals predominant cytoplasmic localization of HNF1A-AS1, supporting its role as a competing endogenous RNA. HNF1A-AS1 and miR-214 antagonize each other in SKOV3 cells. In vitro, HNF1A-AS1 inhibits SKOV3 apoptosis and promotes migration and invasion. HNF1A-AS1 overexpression enhances miR-214 downstream of SEMA4D/PLEXIN-B1/TIAM1/RAC signaling, but miR-214 mimics significantly reverses this effect. Compared with control tumors, xenograft tumors derived from HNF1A-AS1-overexpressing SKOV3 cells present increased tumor growth, attenuated miR-214 expression, and activated SEMA4D/PLEXIN-B1/TIAM/RAC signaling. Knockdown of HNF1A-AS1 has the opposite effects. Additionally, HNF1A-AS1 promotes M2 phenotypic switching in THP-1 cells, which could be reversed by miR-214 overexpression or SEMA4D silencing. Our study suggests that by antagonizing miR-214, HNF1A-AS1 activates the SEMA4D/PLEXIN-B1/TIAM/RAC pathway, facilitating EOC growth and potentially promoting M2 macrophage polarization in the tumor microenvironment. HNF1A-AS1 represents a compelling therapeutic target for treating EOC.

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Long noncoding RNA HNF1A-AS1 promotes ovarian cancer growth and M2 macrophage polarization by counteracting miR-214-mediated suppression of semaphorin 4D signaling

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Original ResearchVol. 57, Issue 10 • pp. 1740-1742DOI: 10.3724/abbs.2025107

ArfGAP2 deficiency ameliorates autoinflammation by regulating STING signaling and proton channel activity

Authors: Min Zhang, Yufei Wang, Zhenwang Zhao, Xiaobo Hu

The cGAS-STING pathway is a critical regulator of innate immunity. When cyclic GMP-AMP synthase (cGAS) detects aberrant cytosolic DNA, it synthesizes the second messenger 2′3′-cGAMP, which binds and activates stimulator of interferon genes (STING) on the endoplasmic reticulum (ER). Activated STING then translocates to the Golgi apparatus, where it recruits and mutually phosphorylates TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates to the nucleus, where it drives the production of type 1 interferons (IFN-1). In addition to being activated by IFN-1, STING also engages the nuclear factor kappa-B (NF-κB) pathway to induce the production of proinflammatory cytokines and chemokines. Moreover, IFN-1 signaling upregulates the expressions of interferon-stimulated genes (ISGs) through the IFN-α receptor (IFNAR). STING-associated vasculopathy with onset in infancy (SAVI) is a severe pediatric autoimmune disease caused by heterozygous gain-of-function mutations in STING, such as the N154S variant in humans and N153S in mice. Initially, classified as an interferonopathy due to constitutive activation of the STING pathway, SAVI is characterized by systemic inflammation, vasculopathy, interstitial lung disease, T-cell cytopenia, skin ulcerations, and premature death. However, recent studies challenge this paradigm, demonstrating that SAVI pathology develops independently of IFNAR-1 and IRFs (IRF3 and IRF7) [1,2], suggesting that alternative mechanisms drive disease progression. Emerging evidence indicates that STING restricts microbial infection through noncanonical autophagy and cell death pathways [3,4]. These functions may depend on its recently identified role as a proton channel in the Golgi apparatus [4,5]. Xun et al. [4] demonstrated that ligand-bound STING forms an ion channel in its transmembrane domain, facilitating proton efflux from post-Golgi vesicles and inducing Golgi deacidification. This raises a critical question: could STING-mediated Golgi deacidification be a potential mechanism underlying SAVI pathogenesis? A recent study by Poddar et al. [6] identified ADP ribosylation factor GTPase-activating protein 2 (ArfGAP2), which is involved in coatomer protein-1 (COP-1) coating in Golgi vesicles, as a key regulator of both STING signaling and proton channel activity, offering novel therapeutic insights for SAVI. First, to elucidate the role of STING in SAVI pathogenesis, they conducted a genome-wide CRISPR-Cas9 screen in T cells resistant to chronic STING activation and identified ArfGAP2 as a critical STING modulator among multiple Golgi-related proteins. Further investigation revealed that genetic ablation of ArfGAP2 in Jurkat T cells significantly attenuated STING-mediated ISG induction. Compelling evidence indicates that STING activation is associated with its subcellular location [7]. While ArfGAP family proteins typically regulate Golgi membrane trafficking, vesicle transport, and cargo sorting [8], Poddar et al. [6] surprisingly reported that ArfGAP2 enhances STING-mediated ISG induction and promotes LC3 lipidation without altering STING palmitoylation or its Golgi localization. Further experiments revealed that ArfGAP2 enhances STING signaling and IFN-β secretion in mouse bone marrow-derived macrophages (BMDMs). In addition to promoting IFN-1 induction, ArfGAP2 promotes the secretion of NF-κB-dependent proinflammatory cytokines activated by STING in THP-1 monocytes [6]. In addition to inducing ISGs and NF-κB signaling, activated STING acts as a proton channel triggering Golgi deacidification [4]. Given the well-established importance of the Golgi pH in regulating enzyme activity, protein modification, and membrane trafficking [9], researchers have further explored how STING and ArfGAP2 modulate cargo transport and secretion. They reported that the loss of ArfGAP2 impairs STING-mediated proton channel activity in the Golgi, leading to a lower luminal pH. Moreover, ArfGAP2-deficient cells presented significant alterations in the cell surface proteome upon STING activation, accompanied by altered sorting, secretion and trafficking rates of specific protein cargos in the Golgi [6].

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ArfGAP2 deficiency ameliorates autoinflammation by regulating STING signaling and proton channel activity

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Original ResearchVol. 57, Issue 9 • pp. 1539-1547DOI: 10.3724/abbs.2025068

Intracellular acetyl phosphate modulates Escherichia coli pyruvate metabolism

Authors: Ling Zhang, Hongmei Shi, Zixiang Liu, Jing Gu, Jiaoyu Deng

Lysine acetylation has been shown to be an abundant and vital post-translational modification (PTM) that utilizes acetyl phosphate (AcP) as one of the acetyl group donors in bacteria. The pyruvate dehydrogenase (PDH) complex catalyzes the conversion from pyruvate to acetyl coenzyme A (acetyl-CoA). Thus far, the connection between lysine acetylation and pyruvate metabolism has not been thoroughly investigated. In this study, we show that AcP could acetylate Escherichia coli pyruvate dehydrogenase (AceE) in vitro and in vivo, which could be reversed by protein lysine deacetylase (CobB). In vitro treatment of AceE with AcP also causes increased phosphorylation of the protein, whereas deleting ackA does not affect the phosphorylation of the protein. As a result, in vitro treatment of AceE by AcP leads to decreased enzymatic activity. In contrast, deleting ackA leads to increased acetylation and enzymatic activity of AceE, and deleting pta results in the decreased acetylation and enzymatic activity of AceE. As expected, deleting pta in E. coli causes pyruvate accumulation. Although deleting ackA also causes pyruvate accumulation, decreased expression of the two genes involved in pyruvate metabolism (ldhA and poxB) is observed in the mutant, indicating that AcP could affect pyruvate metabolism by other routes in addition to modulating the AceE activity. Thus, our results demonstrate that intracellular AcP could modulate pyruvate metabolism in E. coli. For the first time, a linkage between AcP-mediated protein lysine acetylation, pyruvate dehydrogenase activity, and pyruvate metabolism is established.

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Intracellular acetyl phosphate modulates Escherichia coli pyruvate metabolism

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Original ResearchVol. 57, Issue 9 • pp. 1433-1445DOI: 10.3724/abbs.2025051

Vesicle-mediated transport-related gene SEC23A promotes cell proliferation by regulating cell cycle leading to gastric cancer progression

Authors: Kang Wang, Shihao Rao, Xujin Wei, Wen Xie, Zhijun Hong, Jia Cheng, Xin Chen, Jingjing Hou, Huiqin Zhuo

Gastric cancer (GC) is a highly prevalent and lethal gastrointestinal cancer. Dysregulation of vesicle-mediated transport-related genes (VMTRGs) is closely associated with tumorigenesis and disease progression. However, the prognostic value of VMTRGs in GC remains unclear. In this study, on the basis of our proteomics data and public databases, we identify differentially expressed VMTRGs in infiltrative-type GC with more metastases and recurrences identified by Ming’s classification. Least absolute shrinkage and selection operator (LASSO) regression identifies 3 VMTRGs (SEC23A, RAB31, and GABARAPL2) from 41 infiltrative-associated VMTRGs, based on which a risk model Vesicle-Infiltrative Lasso System (VILS) is constructed, and its effectiveness and potential importance are validated by immune microenvironment analysis and functional enrichment analysis. As an independent prognostic factor for GC, VILS, combined with other clinically independent prognostic factors to form a nomogram, is effective in predicting GC prognosis. The VILS high-risk group has higher M2 macrophage and cancer-associated fibroblast infiltration, and lower infiltration of Th1 cells and natural killer cells. SEC23A is highly expressed in GC tissues and cells. The importance of SEC23A in GC cells is evaluated by in vitro assays including colony formation assay and CCK-8 assay, and by in vivo assay using a subcutaneous xenograft mouse model. The results show that SEC23A promotes GC cell proliferation and tumor growth through regulation of the cell cycle in vitro and in vivo. VILS provides excellent prognostic prediction for GC patients and is correlated with antitumor immune cell infiltration. SEC23A, the dominant gene of VILS, is highly expressed in GC and promotes GC growth and malignant progression through various molecular mechanisms. Our study reveals the effect of SEC23A on the proliferation of gastric cancer cells for the first time. Therefore, SEC23A has the potential to be a new therapeutic target for the diagnosis and treatment of GC.

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Vesicle-mediated transport-related gene SEC23A promotes cell proliferation by regulating cell cycle leading to gastric cancer progression

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Original ResearchVol. 57, Issue 9 • pp. 1420-1432DOI: 10.3724/abbs.2024232

Inhibition of HMOX1 alleviates diabetic cardiomyopathy by targeting ferroptosis

Authors: Huiping Yang, Gongyi Xiao, Dinghui Wang, Tianhua Xiong, Jing Wang, Xiaodong Jing, Bingquan Xiong, Junmei Xie, Bin Liu, Qiang She

Diabetic cardiomyopathy (DCM) is an important complication of chronic diabetes mellitus. However, its pathologic process and pathogenesis have not been fully elucidated. This study aims to investigate the role of ferroptosis in DCM and clarify the effect of heme oxygenase-1 (HMOX1) on DCM by targeting ferroptosis. In vivo, an animal model of DCM is established by subjecting mice to a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) injection. We induce an in vitro DCM model by exposing H9C2 cells to high glucose and palmitic acid. Transcriptome sequencing reveals that the differentially expressed genes (DEGs) are enriched primarily in fatty acid metabolism and mitochondrial fatty acid β-oxidation, which are closely related to ferroptosis. The experimental results show that the diabetic microenvironment induces ferroptosis both in vivo and in vitro. Western blot analysis reveals the decreased expressions of the antioxidant proteins GPX4, SLC7A11 and ferritin in the DCM group. However, qPCR demonstrates the elevated expressions of the ferroptosis markers PTGS2 and ACSL4. Biochemical indicators further support the occurrence of ferroptosis, with increased levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH), along with decreased level of glutathione (GSH). In vitro, intervention with high glucose and palmitic acid in H9C2 cells results in ferroptosis, which is reversed by ferrostatin-1 (Fer-1). Results show the elevated expression of HMOX1 in DCM. Moreover, knockdown of HMOX1 ameliorates ferroptosis, thereby alleviating diabetic cardiomyopathy by reducing cardiac fibrosis and improving cardiac function. Our study elucidates the role of HMXO1 in DCM pathogenesis and provides a potential therapeutic strategy for clinical treatment.

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Inhibition of HMOX1 alleviates diabetic cardiomyopathy by targeting ferroptosis

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Original ResearchVol. 58, Issue 8 • pp. 1842-1854DOI: 10.3724/abbs.2025205

Effective resistance to UVB-induced skin damage through the encapsulation of chebulinic acid in mulberry-derived exosome-like nanoparticles

Authors: Weiwei Zhao, Ruobing Liu, Siqi Yang, Chaozhi Liu, Songlin Guo, Guihong Sun, Mingxiong Guo

Ultraviolet-B (UVB) radiation induces significant skin damage by penetrating into the dermal layer, leading to reactive oxygen species (ROS) generation and triggering cellular necrosis and apoptosis. Conventional sunscreens focus primarily on UVB blocking but are limited in their ability to repair dermal damage due to insufficient permeability. In this study, we discover that chebulinic acid (CA), one of the principal monomers in Terminalia chebula Retz., has superior efficacy in promoting recovery from UVB-induced skin damage compared with other major monomers. Mechanistically, CA’s anti-UVB function involves regulating the expression of IL-6 and IFN-β through activation of the MAPK pathway. To overcome the formidable barrier posed by the skin, we identify mulberry exosome-like nanoparticles (MELNs) as an efficient transdermal delivery system and develop CA@MELNs loaded with CA. Furthermore, we demonstrate that the dissociative CA within the CA@MELNs delivery system significantly enhances both transdermal penetration and anti-UVB efficiency in vitro and in vivo. Our findings suggest the substantial potential of CA as an effective ingredient and CA@MELNs as a robust and accessible platform for mitigating UVB damage.

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Effective resistance to UVB-induced skin damage through the encapsulation of chebulinic acid in mulberry-derived exosome-like nanoparticles

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Original ResearchVol. 57, Issue 9 • pp. 1457-1468DOI: 10.3724/abbs.2024239

MYB represses ζ-globin expression through upregulating ETO2

Authors: Zejun Dong, Yuhua Ye, Wei Zhang, Hualei Luo, Jialong Li, Qianqian Zhang, Xinhua Zhang, Xiang Guo, Xiangmin Xu

Reactivating the embryonic ζ-globin gene represents a potential therapeutic approach to ameliorate the severe clinical phenotype of α-thalassemia and sickle cell disease. The transcription factor MYB has been extensively proven to be a master regulator of the γ-globin gene, but its role in the regulation of ζ-globin remains incompletely understood. Here, we report a mechanistic study on the derepression of ζ-globin both in vivo and in vitro. We show that MYB depletion in mouse models and human hematopoietic stem cells leads to consistent and remarkable reactivation of ζ-globin. Furthermore, multiomics analysis and functional validation of MYB-knockout and wild-type cell lines reveal that ETO2 functions as a novel repressor of ζ-globin through coordination with NuRD nucleosome remodeling and the deacetylation complex to modulate histone deacetylation of ζ-globin. Additionally, we evaluate the clinical significance of these findings by knocking out ETO2 in primary CD34+ cells from nondeletional hemoglobin H patients, which results in a significant increase in ζ-globin expression. The RNA-seq data reveal that key erythroid genes are more co-regulated by Myb and Eto2 than by Myb and Klf1, highlighting a distinctly enhanced erythroid-specific transcriptional impact within the MYB-ETO2 regulatory axis. Compared with ETO2 knockout alone, codepletion of ETO2 and BCL11A did not significantly activate ζ-globin, suggesting that the MYB-ETO2 pathway primarily silences ζ-globin. Our study reveals a linear MYB-ETO2 signaling pathway crucial for ζ-globin repression and offers new targets for treating α-thalassemia and sickle cell disease.

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MYB represses ζ-globin expression through upregulating ETO2

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Original ResearchVol. 57, Issue 8 • pp. 1270-1280DOI: 10.3724/abbs.2025043

D-mannose suppresses the angiogenesis and progression of colorectal cancer

Authors: Yu Du, Xinchao Zhang, Yixin Xu, Yuefan Zhou, Yanping Xu

Angiogenesis is an important factor influencing the development of solid tumors, and vascular endothelial growth factor receptor-2 (VEGFR2) is a central regulator of angiogenesis. Antibodies and inhibitors against VEGFR2 have been widely used in various malignancies. However, the regulatory mechanism of VEGFR2 has not been fully clarified. Here, we show that D-mannose can significantly inhibit angiogenesis and tumor growth by degrading VEGFR2. Specifically, D-mannose inactivates GSK3β by promoting the phosphorylation of GSK3β at Ser9, enhances the nuclear translocation of TFE3, and promotes lysosomal biogenesis, thereby increasing the lysosome-mediated degradation of VEGFR2. Thus, D-mannose significantly inhibits the proliferation, migration, and capillary formation of human umbilical vein endothelial cells (HUVECs) in vitro. Oral administration of D-mannose dramatically inhibits angiogenesis and tumor growth in mice. Our findings reveal a previously unrecognized anti-tumor mechanism of D-mannose by destabilizing VEGFR2 and provide a new strategy for the clinical treatment of colorectal cancer (CRC).

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D-mannose suppresses the angiogenesis and progression of colorectal cancer

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Original ResearchVol. 58, Issue 8 • pp. 1783-1792DOI: 10.3724/abbs.2025209

cGAS-STING pathway reprograms macrophage polarization and is highly expressed in responding tumors after neoadjuvant immunotherapy in head and neck carcinoma

Authors: Zhaohong An, Xiwei Zhang, Lin Li, Dilinaer Wusiman, Zhaoyang Wang, Fa Zhang, Xiaohui Zhao, Changming An, Zhenzhen Yin, Wei Gao

Given the critical role of the cGAS-STING pathway in antitumor immunity, this study investigates the functional role of STING in head and neck squamous cell carcinoma (HNSCC) to evaluate the therapeutic potential of STING agonists. Analysis of the TCGA-HNSC dataset reveals that elevated expression of the STING-encoding gene TMEM173 is significantly correlated with increased M1 macrophage infiltration and enrichment of macrophage polarization-related signaling pathways. In vitro experiments in which RAW 264.7 cells are co-cultured with tumor cell-conditioned medium demonstrate that the STING agonist MSA-2 effectively reprograms tumor-induced M2-polarized macrophages toward the M1 phenotype. This MSA-2-induced M1 polarization is accompanied by increased expressions of IFN-α, IFN-β, IFN-γ, TNF-α, and IL-6, while the STING inhibitor H-151 reverses these effects. Flow cytometry further reveals that MSA-2 treatment reduces PD-1 and increases MHC II expression on macrophages. Immunohistochemical analysis of clinical samples confirms that high STING expression is correlated with increased numbers of CD68⁺ and CD80⁺ (M1-like) macrophages. In support of translational relevance, analysis of single-cell RNA-seq data from HNSCC patients receiving neoadjuvant immunotherapy indicates that TMEM173 is expressed primarily in T cells and macrophages and that the cGAS-STING pathway score is significantly higher in patients who respond to treatment. Collectively, these findings provide systematic clinical and experimental evidence supporting the potential of STING agonists, such as MSA-2, to enhance antitumor immunity in HNSCC, particularly when combined with immunotherapy.

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cGAS-STING pathway reprograms macrophage polarization and is highly expressed in responding tumors after neoadjuvant immunotherapy in head and neck carcinoma

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Original ResearchVol. 58, Issue 8 • pp. 1822-1833DOI: 10.3724/abbs.2025161

Serum starvation induces density-dependent apoptosis via HIF-1 activation and JNK suppression

Authors: Qifan Yang, Yaofeng Hu, Jiahui Lv, Jiaqi Xue, Jiaqi Chen, Changwan Wang, Fajian Hou

Serum deprivation is a well-established inducer of apoptosis, yet the molecular mechanisms governing this process remain incompletely understood. Here, we show that serum starvation selectively triggers intrinsic apoptosis in high-density murine embryonic fibroblasts (MEFs) through coordinated HIF-1α activation and JNK signaling suppression. Knockdown of HIF-1α abolishes caspase-3 activation and apoptosis induced by serum deprivation, whereas upregulation of HIF-1α in low-density cells recapitulates the apoptotic response observed in high-density cultures. Simultaneously, serum deprivation leads to the suppression of the JNK pathway, which contributes to apoptosis. Notably, combined HIF-1α activation and JNK inhibition in low-density cells fully mimics the apoptotic phenotype of high-density conditions, underscoring the interplay between these pathways. Together, these findings define a density-dependent apoptotic switch in which HIF-1α drives metabolic stress adaptation, whereas JNK suppression removes a critical survival signal, converging to promote mitochondrial-mediated cell death. This work provides a mechanistic framework for understanding nutrient stress-induced apoptosis and suggests potential therapeutic targets for diseases characterized by aberrant cell survival.

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Serum starvation induces density-dependent apoptosis via HIF-1 activation and JNK suppression

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Original ResearchVol. 58, Issue 8 • pp. 1866-1874DOI: 10.3724/abbs.2025170

The catalase gene CAT2 and its role in the virulence of one sub-cluster of Cryptococcus gattii VGI clinical isolates

Authors: Yemei Huang, Hengyu Deng, Xuelei Zang, Enqi Zhao, Yan Zhuo, Wencong He, Chen Wang, Yangyu Zhou, Jiahui Huang, Rui Liu, Tingyue Tian, Chen Yang, Jing Liu, Ping Zhang, Liye Zhang, Xinying Xue

Cryptococcus gattii causes cryptococcosis and life-threatening cryptococcal meningitis. Currently, the pathogenic virulence mechanisms of C. gattii remain a significant area of ongoing research with considerable unexplored aspects. On the basis of our established research, a sub-cluster of strains with independent evolutionary relationships from WM276 in the phylogenetic analysis of VGI-type strains is identified. In vivo infection experiments on this sub-branch of strains reveal that there are hypervirulent strains and hypovirulent strains among these strains, and the virulence differences are significant (P < 0.001). Bioinformatic interrogation of differentially expressed genes reveals that the catalase-encoding gene CGB_J0620W, CAT2, is a pivotal virulence-associated gene. The hypervirulent clinical isolate G4 (G4-WT) is selected as the parental strain, from which an isogenic CAT2-knockout mutant (cat2Δ) is constructed via homologous recombination, which shows increased sensitivity to oxidative stress, as well as growth defects in response to hyperosmosis, 5-fluorocytosine, fluconazole and amphotericin B. The cat2Δ::CAT2 strain exhibits phenotypic restoration to wild type (WT). In the mouse experiments, significant differences in survival (P < 0.001), pulmonary fungal burden (P < 0.01), and alveolar structural damage are observed between the WT and cat2Δ strains, which are completely different from C. neoformans. Moreover, comparative transcriptome analysis is performed on the WT and cat2Δ strains, which reveals that enzymes encoded by CAT2 may be involved in oxidative stress, metabolism and sugar transport. In conclusion, this study may explain the differences in virulence among different genetic evolutionary processes of a sub-cluster of the VGI geneotype of C. gattii and provide a theoretical basis for targeted therapy in a specific genotype population in the future.

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The catalase gene CAT2 and its role in the virulence of one sub-cluster of Cryptococcus gattii VGI clinical isolates

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Original ResearchVol. 57, Issue 8 • pp. 1260-1269DOI: 10.3724/abbs.2024221

NCOA6 knockdown enhances RSL3-induced ferroptosis in pancreatic cancer cells and increases the sensitivity to gemcitabine

Authors: Yuming Jia, Zeng Ye, Xin Wang, Yanli Deng, Chao Wang, Zhilei Zhang, Guixiong Fan, Wuhan Yang, Xiaowu Xu, Yi Qin, Li Peng

Ferroptosis is a type of programmed death characterized by iron-dependent lipid peroxidation, and targeting ferroptosis has been shown to efficiently kill highly aggressive cancer cells. Previously, we confirmed that nuclear receptors regulate ferroptosis in pancreatic cancer. However, whether nuclear receptor co-activators regulate ferroptosis is unclear. Here, we show that knocking down the nuclear receptor co-activator, NCOA6, enhances the sensitivity of pancreatic cancer cells to ferroptosis. Mechanistically, NCOA6 knockdown promotes the expression of ACSL4 while inhibiting the expression of SCD1, resulting in changes in lipid metabolism, sensitivity to RSL3-induced ferroptosis, and sensitivity to gemcitabine in pancreatic cancer. The relationships between NCOA6 and ACSL4 or SCD1 are further explored in clinical specimens. This study reveals that targeting NCOA6 might alleviate gemcitabine resistance in pancreatic cancer.

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NCOA6 knockdown enhances RSL3-induced ferroptosis in pancreatic cancer cells and increases the sensitivity to gemcitabine

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Original ResearchVol. 57, Issue 9 • pp. 1556DOI: 10.3724/abbs.2025129

Corrigendum to: Magnolol promotes the autophagy of esophageal carcinoma cells by upregulating HACE1 gene expression

Authors: Kenan Huang, Biao Zhang, Yu Feng, Haitao Ma

This is a corrigendum to the article 'Magnolol promotes the autophagy of esophageal carcinoma cells by upregulating HACE1 gene expression' published in Acta Biochimica et Biophysica Sinica 2024, 56(7): 1044–1054. In the original publication, the corresponding author's email address was personal. To comply with the institution's publishing policy, it has been changed from '[email protected]' to the institutional address '[email protected]'. The authors apologize for any confusion it may have caused.

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Corrigendum to: Magnolol promotes the autophagy of esophageal carcinoma cells by upregulating HACE1 gene expression

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Original ResearchVol. 58, Issue 8 • pp. 1855-1865DOI: 10.3724/abbs.2025164

MAN1A1 promotes colorectal cancer liver metastasis by maintaining TGFBR2 protein stability

Authors: Yingxi Hu, Yinwen Xu, Kai Chen, Shihua Guan, Huiling Zhou, Tao Li, Rongrui Liang, Min Tao, Yiyi Yu, Xinxin Ge, Yuanyuan Ruan

Emerging biochemical and genetic evidence has firmly established aberrant protein glycosylation as a critical regulator of oncogenic transformation, with glycocalyx remodeling profoundly influencing tumor microenvironment dynamics and metastatic progression. Despite the well-documented association between metastatic dissemination and poor clinical outcomes in patients with colorectal cancer, the underlying molecular mechanisms remain incompletely characterized. Through integrative analysis of single-cell RNA sequencing data from a public database, we identify the Golgi-resident α-1,2-mannosidase MAN1A1 as a consistently upregulated enzyme in malignant epithelial cells derived from colorectal cancer liver metastases. Clinically, elevated MAN1A1 expression is correlated with reduced overall survival, suggesting that MAN1A1 is both a prognostic biomarker and therapeutic target for colorectal cancer liver metastases. Genetic manipulation of MAN1A1 in colorectal cancer cells demonstrates that although the proliferation capacity of colorectal cancer cells remains unchanged, MAN1A1 overexpression significantly enhances migratory and invasive capacities in transwell assays, suggesting its specific involvement in metastatic progression. Mechanistic investigations reveal that MAN1A1 exerts its pro-metastatic effects by significantly prolonging the TGFBR2 protein half-life. Together, our work identifies MAN1A1 as both a prognostic biomarker and a promising therapeutic target, highlighting the critical role of glycan remodeling in the metastatic progression of colorectal cancer.

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MAN1A1 promotes colorectal cancer liver metastasis by maintaining TGFBR2 protein stability

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Original ResearchVol. 57, Issue 8 • pp. 1281-1291DOI: 10.3724/abbs.2025013

GWAS study of myelosuppression among NSCLC patients receiving platinum-based combination chemotherapy

Authors: Hanxue Huang, Junyan Liu, Qi Xiao, Chenxue Mao, Lei She, Lulu Yu, Bing Yu, Mengrong Lei, Ying Gao, Baimei He, Pinhua Pan, Xi Li, Jiye Yin, Zhaoqian Liu

Platinum-based chemotherapy remains the mainstay for non-small cell lung cancer (NSCLC), but it frequently causes dose-limiting myelosuppression, with significant individual variability in susceptibility. However, the genetic basis of myelosuppression side effects remains elusive, greatly hindering personalized therapeutic approaches. In this study, we perform a comprehensive genome-wide association analysis on 491 NSCLC patients receiving platinum-based chemotherapy, examining 4,690,998 single-nucleotide polymorphisms (SNPs) to identify relevant genetic variants. LDBlockShow, FUMA, and MAGMA are utilized to explore linkage disequilibrium, expression quantitative trait loci (eQTLs), chromatin interaction, and conduct gene-based and gene set-based analysis of candidate SNPs. The GWAS results reveal that rs6856089 and its linked SNPs are significantly associated with platinum-based chemotherapy-induced myelosuppression. Specifically, patients with the A allele of rs6856089 have a significantly lower risk of myelosuppression [odds ratio (OR) = 0.1300, P = 7.59 × 10–8]. Furthermore, gene-based analysis reveals that EMCN (P = 2.47 × 10–5), which encodes endomucin, a marker for hematopoietic stem cells, might mediate myelosuppression. This study provides a scientific basis for the individual differences in platinum-based chemotherapy-induced myelosuppression.

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GWAS study of myelosuppression among NSCLC patients receiving platinum-based combination chemotherapy

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Original ResearchVol. 57, Issue 8 • pp. 1350-1362DOI: 10.3724/abbs.2025014

Knockdown of lncRNA XR_877193.1 suppresses ferroptosis and promotes osteogenic differentiation via the PI3K/AKT signaling pathway in SONFH

Authors: Huixia Yang, Ning Ding, Shi Qing, Yinju Hao, Cilin Zhao, Kai Wu, Guizhong Li, Huiping Zhang, Shengchao Ma, Zhigang Bai, Yideng Jiang

Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Recent research has suggested that ferroptosis in osteoblasts contributes to steroid-induced osteonecrosis of the femoral head (SONFH). However, the relationship between ferroptosis and SONFH remains unclear. In this study, in vitro experiments show that dexamethasone (Dex) treatment reduces the expressions of key ferroptosis regulators, SLC7A11 and GPX4, in MC3T3-E1 cells. This reduction leads to a decrease in intracellular glutathione (GSH) levels, accompanied by elevated levels of total iron, malondialdehyde (MDA), and reactive oxygen species (ROS). Importantly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reverses Dex-induced ferroptosis in MC3T3-E1 cells. Furthermore, RNA-seq analysis reveals that the long noncoding RNA (lncRNA) XR_877193.1 is significantly upregulated in Dex-treated MC3T3-E1 cells. Functional studies demonstrate that the knockdown of lncRNA XR_877193.1 promotes osteogenic differentiation by inhibiting Dex-induced ferroptosis in MC3T3-E1 cells, whereas its overexpression exacerbates cell death via ferroptosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis reveals that the differentially expressed lncRNA XR_877193.1 is enriched in ferroptosis-related pathways, including the PI3K/AKT signaling pathway. Moreover, PI3K/AKT inhibitors reverse ferroptosis in MC3T3-E1 cells inhibited by lncRNA XR_877193.1 knockdown. Collectively, our findings indicate that lncRNA XR_877193.1 knockdown exerts anti-ferroptosis effects by stimulating the PI3K/AKT signaling pathway, suggesting a promising therapeutic strategy for attenuating SONFH.

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Knockdown of lncRNA XR_877193.1 suppresses ferroptosis and promotes osteogenic differentiation via the PI3K/AKT signaling pathway in SONFH

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Original ResearchVol. 57, Issue 8 • pp. 1371-1375DOI: 10.3724/abbs.2025016

CRATS: a one-pot CRISPR-Cas12b and RPA combined assay with a temperature switch for highly sensitive detection of monkeypox virus

Authors: Guangxi Yu, Yue Wang, Yukang Chen, Jiangyuan Liu, Hongtao Kang, Xiaodong Luan, Song Gao, Pei Wang

CRISPR-Cas nucleases have been extensively used in molecular detections, especially highly sensitive nucleic acid detections. In these detections, Cas nucleases are programmed by the guide RNA to respond to the detection targets and cleave the chemically labelled molecular beacons by the trans-cleavage activity to produce the detection signal. To improve sensitivity, nucleic acid amplification technologies are usually introduced to give a pre-amplification of the nucleic acid targets, increasing the detection sensitivity extraordinarily. Polymerase chain reaction (PCR) technology has been used for pre-amplification in laboratories, and isothermal amplification technologies are applied to meet point-of-care testing (POCT) needs because they avoid the use of sophisticated thermal cycling devices. The recombinase polymerase amplification (RPA) technology that amplifies nucleic acid targets isothermally at 37–42°C has been combined with CRISPR-Cas nucleases to establish advantageous nucleic acid detection assays, e.g., the SHERLOCK, which combines with Cas13a, and the DETECTR, which combines with Cas12a. It has been challenging to integrate Cas nucleases and RPA in a one-pot reaction system because the cleavage activity of Cas stimulated by even small amounts of the targets can interfere with amplification by digesting the primers or the newly amplified fragments. Thus, many assays based on Cas nucleases and RPA are in a two-step setting, with pre-amplification and Cas cleavage being isolated as two independent procedures. The two-step setting ensures that amplification and cleavage occur under favorable conditions but sacrifices operational convenience and introduces the risk of cross-contamination. In efforts to establish one-pot RPA-Cas assays, many strategies have been applied, including the use of photocontrolled guide RNA to activate the Cas nuclease at a preferred timepoint, the use of a suboptimal protospacer adjacent motif (PAM) to suppress Cas activity, the generation of dynamic aqueous multiphase with sucrose or glycerol to partially separate the two reactions, and extensive optimization of the RPA-CRISPR reaction system to achieve a subtle balance between the two reactions. In this study, a one-pot CRISPR-Cas12b and RPA combined assay with a temperature switch (CRATS) was established utilizing the reaction temperature difference between RPA and CRISPR-Cas12b cleavage. The Cas12b used in this study, AaCas12b, is a type V-B CRISPR‒Cas nuclease from Alicyclobacillus acidiphilus. It has a bi-lobed architecture consisting of an α-helical recognition lobe containing the REC domains and a nuclease lobe containing the WED, RuvC and Nuc domains. As a dual-RNA-guided DNA endonuclease, Cas12b can be guided by a chimeric single-guide (sg) RNA, and its trans-cleavage activity is specifically activated by the DNA target and results in nonspecific cleavage of single-stranded (ss) DNA molecules, which can be used to produce detection signals if the ssDNA is appropriately labelled as the molecular beacon. As the temperature for RPA is 37°C and the trans-cleavage of Cas12b is active at 60°C, CRATS uses temperature switching to adjust the major on-going reaction in the one-pot system and realizes sequential amplification of the target and cleavage reactions for signal detection. The detection target of this study, monkeypox virus, is an infectious pathogen that has caused the announcement of the Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) twice in recent years. In this one-pot CRATS assay, the reaction reagents of CRISPR-Cas12b and RPA are mixed in a single tube. After the addition of the sample containing the detection target, the reaction was carried out at 37°C for 20 min for amplification, followed by 60°C for 20 min for Cas12b cleavage. The fluorescently labelled molecular beacon is cleaved by Cas12b to release the FAM fluorophore from quenching, producing a fluorescence signal that is visualized under blue light. CRATS shows a high sensitivity of 100 copies of the target DNA per reaction and good specificity, providing a novel strategy of temperature switching to integrate CRISPR-Cas and RPA in a one-pot reaction system. Moreover, it provides a POCT-friendly tool for the detection of the important infectious pathogen monkeypox virus.

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CRATS: a one-pot CRISPR-Cas12b and RPA combined assay with a temperature switch for highly sensitive detection of monkeypox virus

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Original ResearchVol. 58, Issue 7 • pp. 1499-1508DOI: 10.3724/abbs.2025121

Carfilzomib triggers cardiotoxicity by suppressing SENP1-mediated deSUMOylation of DDX17

Authors: Sheng Wang, Jingjing Wang, Xin Li, Zhigao Dai, Tiantian Li, Yixuan Wang, Ziyi Peng, Mengqi Wang, Hao Cheng, Linchuang Jia, Danchen Su, Mu Qiao, Jingya Wang, Ying Xie, Jing Guo, Xiaozhi Liu, Tong Liu

Carfilzomib (Cfz) is a second-generation proteasome inhibitor approved for the treatment of relapsed/refractory multiple myeloma (RRMM). Previous studies have shown that Cfz is associated with a higher incidence of severe adverse cardiac effects than bortezomib (Btz); however, the underlying mechanisms remain to be elucidated. The aim of this study is to identify key regulators of cardiotoxicity induced by Cfz and to investigate the mechanisms by which these factors exert their effects. We establish a mouse model of cardiac toxicity induced by Cfz and confirm the phenotype through cardiac functional analysis, morphology assessment, myocardial fibrosis, and apoptosis analysis. We subsequently perform RNA sequencing to identify differentially expressed genes (DEGs) and further validate their functions and mechanisms. We find that Cfz induces myocardial hypertrophy and myocardial injury, along with the suppression of SENP1 expression in mouse heart tissues and in vitro cultured neonatal rat cardiomyocytes. Suppression of SENP1 exacerbates Cfz-induced injury and remodeling in cardiomyocytes by directly binding to and deconjugating the SUMO1-mediated SUMOylation of the RNA helicase DDX17. This process leads to a reduction in K-48 ubiquitin-linked polyubiquitination and degradation of DDX17, resulting in increased expressions of anti-apoptotic genes and maintenance of mitochondrial homeostasis. Therefore, the overexpression of SENP1 using AAV vectors alleviates Cfz-induced cardiotoxicity in mice. In summary, our findings reveal a previously unknown role of the SENP1-DDX17 axis in protecting against cardiotoxicity induced by Cfz, providing a potential foundation for developing therapeutic strategies to mitigate cardiac side effects in the clinical management of MM patients.

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Carfilzomib triggers cardiotoxicity by suppressing SENP1-mediated deSUMOylation of DDX17

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Original ResearchVol. 57, Issue 8 • pp. 1207-1221DOI: 10.3724/abbs.2025020

Essential role of the metabolite α-ketoglutarate in bone tissue and bone-related diseases

Authors: Zuping Wu, Yuzhe Guan, Qian Chen, Ruifeng Song, Jing Xie, Xin Zhang, Yan Wang, Qianming Chen, Xiaoyan Chen

Bone metabolism in bone tissue is constantly maintained in a state of dynamic equilibrium. The mass of bone and joint tissues is determined by both bone formation and bone resorption. It is hypothesized that disrupted metabolic balance leads to osteoporosis, osteoarthritis, rheumatoid arthritis, and bone tumors. Such disruptions often manifest as either a reduction or abnormality in bone mass and are frequently accompanied by pathological changes such as inflammation, fractures, and pain. α-Ketoglutarate (α-KG) serves as a pivotal intermediate in various metabolic pathways in mammals, significantly contributing to cellular energy metabolism, amino acid metabolism, and other physiological processes. α-KG may be a therapeutic target for a variety of bone-related diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, because of its role in maintaining the metabolic balance of bone. After the application of α-KG, bone loss and inflammation in bone tissue are alleviated. This review focuses on the regulatory effects of α-KG on various cells in bone and joint tissues. Owing to the regulatory effect of α-KG on the balance of bone metabolism, the application of α-KG in the treatment of osteoporosis, osteoarthritis, rheumatoid arthritis, bone tumors, and other bone tissue diseases has been clarified.

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Essential role of the metabolite α-ketoglutarate in bone tissue and bone-related diseases

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Original ResearchVol. 58, Issue 7 • pp. 1667-1670DOI: 10.3724/abbs.2025193

Investigation of the cardioprotective potential of dantrolene in mitigating arsenic-induced cardiac dysfunction in rats

Authors: Chuncui Chen, Ruoxi Chen, Xueting Guo, Lei Huang, Kuican Liu, Wenrong Shi, Caiyun Zhang, Kunxuan Liu, Huan Liu, Shanshan Dong, Guilin Lu, Wenjuan Qin

Arsenic, a toxic metalloid, exists in organic or inorganic states within the Earth’s seawater, river water, soil, atmosphere, food sources, and diverse biological tissues [1]. It poses a threat to the health of hundreds of millions of people globally [2]. Arsenic exposure has toxic effects on the cardiovascular system of organisms, thus endangering human health [3]. Research has indicated that the harmful effect of arsenic exposure on the heart is associated with abnormal calcium handling in myocardial cells [4]. The cardiac ryanodine receptor type 2 (RyR2) is a primary channel involved in the surface of the endoplasmic reticulum in cardiac myocytes that regulates the release of Ca2+ during the systolic phase [5]. The integrity of its function is crucial for maintaining calcium homeostasis in cardiac myocytes. However, when myocardial tissue is damaged and undergoes pathological changes, the spatial structure of the RyR2 protein becomes unstable and becomes excessively activated, thereby triggering Ca2+ leakage [6]. Dantrolene (Dan), which serves as a stabilizer of RyR1, is frequently employed in clinical settings for the treatment of malignant hyperpyrexia and relieves spastic muscle tension [7]. Previous studies have demonstrated that dantrolene also has a stabilizing effect on RyR2 [8]. Research has shown that dantrolene can prevent calcium leakage in myocardial cells by stabilizing the tertiary structure of the RyR2 protein and thereby inhibiting the pathological hyperactivity of RyR2 [9]. Therefore, this study hypothesizes that dantrolene, by virtue of this stabilizing effect, can alleviate myocardial injury caused by arsenic exposure to some extent and plays a role in protecting cardiac function. For this purpose, we established an arsenic exposure model and a Dan intervention arsenic exposure model to verify the protective effect of Dan on the myocardial tissue and cardiac function of arsenic-exposed rats.

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Investigation of the cardioprotective potential of dantrolene in mitigating arsenic-induced cardiac dysfunction in rats

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Original ResearchVol. 57, Issue 8 • pp. 1304-1311DOI: 10.3724/abbs.2025039

Puerarin prevents cadmium-induced endoplasmic reticulum stress via SIRT1-dependent PERK-CHOP pathway in HepG2 cells

Authors: Di Huang, Mengqi Qiu, Kuanhong Luo, Yanzhe Zhu, Siyu Zhang, Zhen He, Xiaobo Hu, Zhaohui Cao

Cadmium (Cd) is a high-risk heavy metal that induces oxidative stress, endoplasmic reticulum (ER) stress and inflammation, damaging organs such as the liver. Puerarin (PUE) has been shown to treat liver injury and especially prevent Cd-induced hepatic damage via its antioxidant activity. Sirtuin 1 (SIRT1), a histone deacetylase, is a key protector against various stress insults. However, its role in the protection of PUE against Cd-induced liver damage has not been clarified. Thus, this study is designed to elucidate the molecular mechanism in the human hepatoma cell line HepG2. The results first reveal that Cd-induced apoptosis is significantly restored by PUE pretreatment, as confirmed by the CCK-8, flow cytometric, Hoechst 33258 and TUNEL assays. Mechanistically, PUE significantly decreases ROS production and increases SOD levels in Cd-treated HepG2 cells. Moreover, PUE pretreatment alleviates ER stress by inhibiting the PERK-eIF2α-ATF4-CHOP axis and subsequently partially restores ER function as revealed by decreased Ca2+ release from the ER. In addition, further study demonstrates that PUE upregulates SIRT1 expression, which suppresses the PERK signaling cascade and reduces CHOP levels. Collectively, our results first demonstrate that PUE protects HepG2 cells from Cd-induced apoptosis at least partially by inhibiting the PERK-eIF2α-ATF4-CHOP pathway in a SIRT1 expression-dependent manner. Puerarin appears to have great potential as a hepatoprotective agent.

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Puerarin prevents cadmium-induced endoplasmic reticulum stress via SIRT1-dependent PERK-CHOP pathway in HepG2 cells

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Original ResearchVol. 57, Issue 8 • pp. 1234-1243DOI: 10.3724/abbs.2024217

Ageing-associated gut dysbiosis deteriorates mouse cognition

Authors: Huihui Ju, Yile Zhou, Wanting Wei, Yan Hu, Hongwei Fang, Zhouyi Chen, Xia Sun, Yi Shi, Hao Fang

Ageing is an independent factor for cognitive dysfunction. Ageing-associated alterations in the gut microbiota also affect cognition. The present study is designed to investigate changes in the gut microbiota and their participation in ageing-associated cognitive impairment. Both 10-week-old and 18-month-old mice are used. Mouse cognition is examined by novel object recognition and T-maze tests. Mouse feces are collected for sequencing and transplantation. Protein expression in the mouse intestine and hippocampus is studied using immunohistochemistry and immunofluorescence staining. Senescent neurons are induced by hydrogen peroxide in vitro. The cell lysates are used for western blot analysis and adenosine triphosphate (ATP) measurement. Our results show that 18-month-old mice exhibit cognitive dysfunction compared with young mice. In aged mice, transplanting the microbiota of young mice increases the protein presence of synaptophysin in the hippocampus and partially restores cognition. The protein expressions of mucin-2 and E-cadherin in the intestine are reduced in aged mice but are increased by transplantation. Gut microbiota analyses reveal that the reduced abundance of the microbe Bacilli-Lactobacillales-Lactobacillaceae-Lactobacillus in aged mice is restored by transplantation. Fecal microbiota transplantation in young mice increases the serum level of acetic acid in aged mice. Hydrogen peroxide stimulation induces senescence and reduces the protein expression levels of synaptophysin and acetyl-coenzyme A synthetase member 2 (ACSS2) in primary neurons. Incubation with acetic acid upregulates the protein expressions of ACSS2 and synaptophysin and further increases ATP production in senescent neurons. In summary, gut microbiota transplantation increases the abundance of Lactobacillales, elevates serum acetic acid level, and improves cognitive function in aged mice. Gut microbiota transplantation has therapeutic importance for ageing-associated cognitive decline.

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Ageing-associated gut dysbiosis deteriorates mouse cognition

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Original ResearchVol. 58, Issue 7 • pp. 1473-1485DOI: 10.3724/abbs.2025165

Levosimendan ameliorates cardiomyocyte injury and mitochondrial dysfunction in an Nrf2-dependent manner in mice with sepsis-induced cardiomyopathy

Authors: Xinyuan Zhu, Hongyan Zhai, Huishuang Shao, Dawei Wu, Jun Ren, Daqing Sun, Sujuan Liu

Sepsis-induced cardiomyopathy (SIC) is a severe complication of sepsis and septic shock and is characterized by cardiac dysfunction. Levosimendan (LEVO), a calcium sensitizer, has shown therapeutic potential in SIC, although its underlying mechanism remains unclear. Nrf2, a pivotal regulator of antioxidant and anti-inflammatory responses, may represent a potential target for SIC treatment. In this study, we examine the effects of LEVO on SIC and explore the mechanistic role of Nrf2 in mediating its cardioprotective effects. A murine SIC model is established via cecal ligation and puncture (CLP), and cardiomyocyte injury is induced in vitro via lipopolysaccharide (LPS) exposure in HL-1 cells. The CLP procedure significantly elevates serum cTnI and IL-6 levels and reduces the survival rates of mice. Echocardiographic analysis reveals impaired cardiac structure and function, accompanied by mitochondrial morphological and functional damage, in SIC mice. Interestingly, these pathological changes in SIC are markedly attenuated by LEVO treatment. Similarly, LEVO administration restores proliferative capacity; increases mitochondrial ATP, mitochondrial membrane potential (MMP) and NADH levels; and reduces ROS production and intracellular calcium overload. Notably, the protective effects of LEVO on cardiomyocyte viability and mitochondrial function are significantly diminished following Nrf2 inhibition or Nrf2 knockout (KO). Collectively, these findings demonstrate that LEVO mitigates cardiomyocyte injury and mitochondrial dysfunction in SIC through an Nrf2-dependent mechanism.

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Levosimendan ameliorates cardiomyocyte injury and mitochondrial dysfunction in an Nrf2-dependent manner in mice with sepsis-induced cardiomyopathy

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Original ResearchVol. 57, Issue 7 • pp. 1037-1046DOI: 10.3724/abbs.2025025

The role of cryptochrome (CRY) in cancer: molecular mechanisms and clock-based therapeutic strategies

Authors: Shuzhao Zhang, Xue Chen, Jiayi Li, An’an Xu, Ann M. Bode, Xiangjian Luo

The circadian rhythm is a phenomenon in which physiological, behavioral, and biochemical processes within an organism naturally fluctuate over a period of approximately 24 hours. This phenomenon is ubiquitous in living organisms. Disruption of circadian rhythms in mammals leads to different diseases, such as cancer, and neurodegenerative and metabolic disorders. In specific tissues, numerous genes have been found to have circadian oscillations, suggesting a broad role for rhythm genes in the regulation of gene expression. This review systematically summarizes the role of cryptochromes (CRYs) in the initiation and progression of different types of cancer and discusses the relationships between clock genes and the tumor microenvironment (TME), as well as clock-based therapeutic strategies.

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The role of cryptochrome (CRY) in cancer: molecular mechanisms and clock-based therapeutic strategies

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Original ResearchVol. 57, Issue 6 • pp. 955-967DOI: 10.3724/abbs.2024235

Gastrodin inhibits reactive astrocyte-mediated inflammation in hypoxic-ischemic brain damage through S100B/RAGE-Smad3 signaling

Authors: Pengxiang Wang, Hanjun Zuo, Haolong Shi, Zhao Wang, Xueqi Ren, Jinsha Shi, Tao Guo, Xianfeng Kuang, Min Zhao, Jinghui Li, Juanjuan Li

Activated astrocytes and their associated inflammatory responses play critical roles in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Gastrodin (GAS), an anti-inflammatory herbal agent, is known to suppress microglial activation. Here, we investigate whether it exerts a similar effect on activated astrocytes and whether it acts through S100B/RAGE-Smad3 signaling. The expression changes of S100B/RAGE-Smad3 signaling pathway-related proteins, inflammatory factors and A1/A2 astrocyte markers were detected by ELISA, western blot analysis, immunofluorescence and immunohistochemistry. The results show that GAS decreases the expression of sRAGE in the brain tissue and S100B in the serum and brain tissue of HIBD mice. However, it promotes the expression of sRAGE in the serum of HIBD mice. Moreover, GAS inhibits the expressions of RAGE, p-Smad3, TNF-α, and C3 (A1 astrocyte marker), and promotes the expressions of S100A10 (A2 astrocyte marker) and BDNF in HIBD model mice, as well as in oxygen glucose deprivation (OGD)-treated TNC-1 astrocytes. The immunofluorescence and immunohistochemical results of RAGE and p-Smad3, as well as the immunofluorescence results of C3 and S100A10, reveal the same trend. Interestingly, FPS-ZM1 (a specific inhibitor of RAGE) inhibits the expressions of p-Smad3, TNF-α, C3, and S100A10, but promotes that of BDNF compared with those in the OGD group. The combination of GAS and FPS-ZM1 further decreases the expression of C3. These results indicate that GAS can inhibit the activation of Smad3 through S100B/RAGE signaling and regulate the expression of A1/A2-type astrocytes.

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Gastrodin inhibits reactive astrocyte-mediated inflammation in hypoxic-ischemic brain damage through S100B/RAGE-Smad3 signaling

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Original ResearchVol. 57, Issue 8 • pp. 1244-1251DOI: 10.3724/abbs.2024208

D-CAPS: an efficient CRISPR-Cas9-based phage defense system for E. coli

Authors: Mingjun Sun, Jie Gao, Hongjie Tang, Hengyi Wang, Liyan Zhou, Chuan Song, Yongqiang Tian, Qi Li

Escherichia coli is widely used in industrial chemical synthesis but faces significant challenges due to bacteriophage contamination, which reduces product quality and yield. Therefore, developing an efficient antiphage system is essential. In this study, we develop a CRISPR-Cas9-based antiphage system (CAPS) targeting essential genes of the T7 phage (gene 5 and gene 19) with single gRNAs transformed into MG1655 strains expressing Cas9. While CAPS provides limited resistance, with plating efficiencies ranging from 10–5 to 10–1, further optimization is needed. To enhance efficacy, we design a double-site-targeting CRISPR-Cas9-based antiphage system (D-CAPS). D-CAPS demonstrates complete resistance, with no plaques observed even at a high multiplicity of infection (MOI of 2), and growth curve analysis reveals that antiphage E. coli strains grow normally, similar to the wild-type strain, even at a high multiplicity of infection. Furthermore, D-CAPS is effective against BL21(DE3) strains, showing strong resistance and demonstrating its versatility across different E. coli strains. Protein expression analysis via green fluorescent protein confirms that E. coli carrying D-CAPS could maintain normal protein expression levels even in the presence of phages, comparable to wild-type strains. Overall, D-CAPS offers a robust and versatile approach to enhancing E. coli resistance to phages, providing a practical solution for protecting industrial E. coli strains and improving fermentation processes.

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D-CAPS: an efficient CRISPR-Cas9-based phage defense system for E. coli

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Original ResearchVol. 58, Issue 7 • pp. 1458-1472DOI: 10.3724/abbs.2025199

Pregnancy-induced metabolic reprogramming in skeletal muscle: a multi-omics interrogation of transcriptional and metabolic adaptations

Authors: Zhongliang Lin, Kejing Zhu, Renke He, Xueying Liu, Qinyu Luo, Jianzhong Sheng, Jiexue Pan, Hefeng Huang

Pregnancy induces profound physiological adaptations to meet the dynamic nutritional demands of fetal development, including a deliberate reduction in maternal insulin sensitivity to ensure fetal glucose availability. However, excessive insulin resistance may precipitate gestational diabetes mellitus (GDM), increasing the risk of both obstetric complications and long-term metabolic disorders in mothers and offspring. Although the role of adipose tissue in pregnancy-associated metabolic adaptation has been extensively studied, the contribution of skeletal muscle remains poorly understood. Here, we systematically characterize pregnancy-induced molecular and metabolic changes in maternal skeletal muscle through multi-omics profiling. We use transcriptomic, metabolomic, computational single-cell deconvolution, and qPCR validation in an established C57BL/6J mouse pregnancy model (8-week-old females). Pregnancy triggers remarkable skeletal muscle remodelling, featuring histological reorganization with myofiber depletion and expanded endothelial compartments. Concurrent metabolic disturbances include insulin resistance, dysregulated TCA cycle activity, and impaired ubiquinone biosynthesis. This study represents a multi-omics-based systematic elucidation of pregnancy-induced maternal skeletal muscle adaptations. Our findings demonstrate that pregnancy induces profound structural reorganization and metabolic reprogramming in maternal skeletal muscle, characterized by prioritized fetal nutrient provision at the expense of maternal tissue utilization. These observations not only reveal previously unrecognized mechanisms of pregnancy-specific metabolic regulation but also, more importantly, establish a critical theoretical foundation for developing skeletal muscle-targeted intervention strategies to prevent gestational diabetes mellitus.

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Pregnancy-induced metabolic reprogramming in skeletal muscle: a multi-omics interrogation of transcriptional and metabolic adaptations

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Original ResearchVol. 57, Issue 7 • pp. 1068-1080DOI: 10.3724/abbs.2025026

The protective effect of naringenin on ulcerative colitis in mice through increasing Nrf2 pathway activity

Authors: Jiaxiang Li, Li Hua, Meichun Hu, Ni Zhu, Sijin Dong, Xiaoli Jing, Zihuan Zhu, Yifei Liu, Yanhong Zhou

Ulcerative colitis (UC) is a chronic inflammatory disease with an increasing prevalence worldwide. Naringenin (NAR) has been proven effective in preventing UC, but its mechanism has not been fully elucidated. In this study, network pharmacology and bioinformatics methods are used to screen the genes associated with NAR and UC. A mouse model of dextran sulfate sodium (DSS)-induced UC is established. After treatment with NAR, the disease activity index (DAI) is scored, and colonic histopathology is observed via hematoxylin-eosin (HE) staining. The expressions of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and inflammation-related factors in the colons of UC mice are examined via western blot analysis and immunohistochemistry (IHC). The results of the animal experiments reveal that the model group of UC mice present the most severe weight loss and the highest DAI scores. After the administration of NAR, weight loss is alleviated, and DAI scores are reduced (P < 0.05). NAR improves pathological manifestations in the mouse colon, such as reducing inflammatory cell infiltration and restoring goblet cell loss (P < 0.05). NAR significantly increases the protein expression levels of Nrf2, heme oxygenase 1 (HO-1), and NAD(P)H dehydrogenase [quinone] 1 (NQO1) in the colon (P < 0.05) but decreases the protein expression levels of nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) (P < 0.05), thus alleviating the inflammatory response in UC model mice.

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The protective effect of naringenin on ulcerative colitis in mice through increasing Nrf2 pathway activity

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Original ResearchVol. 57, Issue 7 • pp. 1081-1092DOI: 10.3724/abbs.2025003

Regulation of immune responses by a tumor necrosis factor in pearl oysters: insights from PmTNF gene expression and function

Authors: Yifan Wu, Bidan Liang, Haiying Liang

Tumor necrosis factor (TNF) is a multifunctional cytokine that regulates cellular processes such as inflammation, apoptosis, differentiation, and proliferation and activates various functions of the immune system. This article reports the discovery and characterization of a novel tumor necrosis factor gene in the pearl oyster Pinctada fucata martensii, which is named PmTNF. The deduced PmTNF protein sequence displays the typical structural characteristics of a TNF domain, and phylogenetic analysis of the sequences of PmTNF and its putative orthologs shows that they conform to the current taxonomy. Analysis of PmTNF mRNA expression via real-time PCR reveals its constitutive expression in all the examined tissues, with the highest expression in the gills. Furthermore, PmTNF expression in the gills varies upon exposure to pathogen-derived stimuli, with modest upregulation in response to lipopolysaccharides, but with significant downregulation in response to polyinosinic:polycytidylic acid. Nucleus insertion surgery induces an increase in PmTNF mRNA level in the gills at 12 h postoperation. Knocking down PmTNF through RNA interference significantly inhibits the expressions of immune-related genes in the NF-κB signaling pathway in the gills by 24 h (P < 0.05). The function of PmTNF is further characterized by studying the activity of an engineered recombinant PmTNF protein (rPmTNF) in vivo. Upon nuclear insertion, treatment with rPmTNF for 6 h upregulates several genes in the NF-κB pathway. Similarly, rPmTNF increases the activities of the antioxidant enzymes, including superoxide dismutase, glutathione and peroxidase, which reflect the total antioxidant capacity. Collectively, these results indicate that PmTNF participates in pearl oyster immunity by modulating the NF-κB pathway and activating the antioxidant defense system.

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Regulation of immune responses by a tumor necrosis factor in pearl oysters: insights from PmTNF gene expression and function

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Original ResearchVol. 57, Issue 7 • pp. 1115-1124DOI: 10.3724/abbs.2025018

Atrial APD prolongation caused by the upregulation of RAGE and subsequent INaL increase in diabetic patients

Authors: Yingchun Luo, Wenbo Ma, Qi Kang, Han Pan, Ling Shi, Jiudong Ma, Jiahui Song, Dongmei Gong, Kai Kang, Xuexin Jin

Diabetes mellitus (DM) is a risk factor for the development of atrial fibrillation (AF). The action potential duration (APD) has been demonstrated to be prolonged in the atrium of diabetic mice. In contrast, the APD is generally shortened in AF patients. It is unclear what change occurs in the atrial APD of diabetic patients. In this study, we explore the APD change of atrial myocytes from diabetic patients and the underlying molecular mechanisms. The whole-cell patch-clamp technique is used to detect single-cell electrical activity in diabetic and nondiabetic human samples. The results show that both APD50 and APD90, the APD at 50% and 90% repolarization, are increased in diabetic patients compared with those in nondiabetic controls. The density of late sodium current (INaL) in the atrial myocytes of diabetic patients is greater than that in the myocytes of nondiabetic patients. The expression of receptor for advanced glycation end products (RAGE) is increased in the atria of diabetic patients. In cultured HL-1 cells, high glucose (HG) treatment increases INaL, and the expression of RAGE prolongs APD. The siRNA-mediated knockdown of RAGE reduces the INaL and shortens the APD. The APD is prolonged in the atria of diabetic patients because of the upregulation of RAGE and the subsequent increase in INaL. Our findings provide novel insights into atrial electrical remodeling in diabetic patients.

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Atrial APD prolongation caused by the upregulation of RAGE and subsequent INaL increase in diabetic patients

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Original ResearchVol. 57, Issue 7 • pp. 1151-1163DOI: 10.3724/abbs.2024230

AKR1C3 protects cardiomyocytes against hypoxia-induced cell apoptosis through the Nrf-2/NF-κB pathway

Authors: Wenlu Zhang, Wei Tian, Xin Xia, Hua Tian, Ting Sun

Hypoxia-induced apoptosis plays a critical role in the progression of various cardiac diseases, such as heart failure and acute myocardial infarction (AMI). Aldosterone reductase 1C3 (AKR1C3), a member of the aldo-keto reductase superfamily, participates in the metabolism of steroid hormones and redox reactions in vivo. Imbalances in prostaglandin levels have been linked to coronary events. However, the function and molecular mechanism by which AKR1C3 influences AMI are not yet fully understood. This study aims to investigate the role of AKR1C3 in hypoxia-induced myocardial cell damage and elucidate its mechanism. Our findings reveal that a hypoxic microenvironment triggers cardiomyocyte apoptosis and elevates AKR1C3 expression in H9C2 and AC16 cells, as well as in cardiac tissue from rats and mice with AMI. The overexpression of AKR1C3 promotes cardiomyocyte proliferation and cell vitality, whereas the silencing of AKR1C3 exerts the opposite effects in vitro. AKR1C3 protects cardiomyocytes against hypoxia-induced cell apoptosis by reducing ROS levels, preventing mitochondrial damage, and maintaining the oxygen consumption rate (OCR) and ATP production; conversely, AKR1C3 knockdown leads to adverse outcomes. Moreover, the application of a ROS inhibitor (MitoQ10) mitigates the increase in mitochondrial ROS in cardiomyocytes induced by AKR1C3 knockdown under hypoxic conditions. Mechanically, AKR1C3 increases Nrf-2 expression through the ubiquitin-proteasome pathway in cardiomyocytes and subsequently inhibits the NF-κB signaling pathway, thereby inhibiting Bax/caspase-3 signaling. Collectively, these results suggest that AKR1C3 prevents hypoxia-induced cardiomyocyte injury by modulating the Nrf-2/NF-κB axis, suggesting new insights into the mechanisms underlying myocardial protection.

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AKR1C3 protects cardiomyocytes against hypoxia-induced cell apoptosis through the Nrf-2/NF-κB pathway

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Original ResearchVol. 57, Issue 7 • pp. 1205-1206DOI: 10.3724/abbs.2025088

Corrigendum to: Vitamin B6 prevents Isocarbophos-induced posterior cerebral artery injury in offspring rats through up-regulating S1P receptor expression

Authors: Yanhua Liu, Kunli Yang, Ling Wang, Jinfang Yang, Yang Wang, Hu Luo, Peng Li, Yaling Yin

This corrigendum corrects errors in the original article 'Vitamin B6 prevents Isocarbophos-induced posterior cerebral artery injury in offspring rats through up-regulating S1P receptor expression' published in Acta Biochim Biophys Sin 2021, 53(12): 1691–1701. The errors were found in Figure 2B (Vit B6 + Fingolimod), Figure 5 (Saline), and Figure 7 (Isocarbophos/Control). The correct figures are shown. The authors apologize for the error. The corrigendum does not affect the interpretation of data and conclusions.

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Corrigendum to: Vitamin B6 prevents Isocarbophos-induced posterior cerebral artery injury in offspring rats through up-regulating S1P receptor expression

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Original ResearchVol. 58, Issue 6 • pp. 1329-1341DOI: 10.3724/abbs.2025178

circDCBLD2 regulates the Th1/Th2 immune balance via the miR-26a-5p/PTEN axis

Authors: Yue Zhao, Guangling Liu, Rui Li, Shuting Yu, Beibei Zhu, Xunzhou Liu, Hanyi Jiang, Jinya Wang

Asthma is a prevalent chronic respiratory disease in children. Recently, adjusting the Th1/Th2 imbalance has become a significant focus in asthma immunotherapy. The present study aims to investigate the roles and mechanisms of circDCBLD2 in maintaining the Th1/Th2 immune balance. CircDCBLD2 is downregulated in CD4+ T cells from asthmatic patients and in CD4+ T cells from an OVA-induced asthmatic mouse model. Additionally, circDCBLD2 levels are significantly decreased in the PBMCs of asthmatic mice. The expression of circDCBLD2 is positively correlated with the Th1 cytokines IFN-γ and IL-2 but negatively correlated with the Th2 cytokines IL-4 and IL-13. Flow cytometry and ELISA analyses demonstrate that circDCBLD2 overexpression increases the proportion of Th1 cells (CD4+IFN-γ+) and the levels of Th1 cytokines while decreasing the proportion of Th2 cells (CD4+IL-4+) and the levels of Th2 cytokines. Furthermore, circDCBLD2 overexpression alleviates the asthma phenotype in OVA-induced mice, reduces the infiltration of inflammatory cells in the lungs, and corrects the Th1/Th2 imbalance. Mechanistically, circDCBLD2 is found to target miR-26a-5p. Rescue experiments indicate that circDCBLD2 regulates the Th1/Th2 immune balance by targeting miR-26a-5p. Additionally, PTEN has been identified as a direct target of miR-26a-5p. The overexpression of PTEN partially reverses the effects of miR-26a-5p on the Th1/Th2 immune balance. These findings indicate that circDCBLD2 increases the proportion of Th1 cells and decreases the proportion of Th2 cells via the miR-26a-5p/PTEN axis, providing a promising target for asthma treatment.

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circDCBLD2 regulates the Th1/Th2 immune balance via the miR-26a-5p/PTEN axis

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Original ResearchVol. 58, Issue 6 • pp. 1374-1386DOI: 10.3724/abbs.2025152

A Mycobacterium tuberculosis multi-epitope DNA vaccine encoding adaptive immune antigens provokes IFNγ/Th1 immunity and confers potential protection

Authors: Jingyao Xue, Yumeng Li, Chi Li, Yu Zhang, Chiuan Yee Leow, Gaoqian Feng, Minjun Ji, Qiao Liu, Zhipeng Xu

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a significant global health threat. However, the licensed Bacille Calmette-Guérin (BCG) vaccine provides only limited protection in adults, underscoring the urgent need for more effective preventive strategies. Recent studies have shown that multi-epitope DNA vaccines are superior to traditional vaccines in terms of immunogenicity, safety and stability. In this study, we develop a multi-epitope DNA vaccine that contains CD8+ T-cell epitopes, CD4+ T-cell epitopes, and B-cell epitopes using bioinformatics tools. These epitopes are derived from three genome-encoded proteins, ESAT-6, Rv2660c, and RpfB, which exhibit stage-specific immunodominance in the early, resting, and convalescent stages of MTB infection. Using reverse vaccinology and computational immunomodulation, we demonstrate that the multiepitope vaccine increases antigen-specific antibody titres, activates CD8+ T and CD4+ T cells, and enhances IFN-γ secretion. In vitro validation studies in HEK293T cells confirm high-yield expression of multi-epitope-encoded antigens, whereas in vivo immunization experiments reveal significant expansion of NK cells and Th1-polarized lymphocytes, with concomitant upregulation of pro-inflammatory mediators. Collectively, these results highlight the potent activation of adaptive immunity through Th1-driven mechanisms and IFN-γ-mediated mycobacterial clearance, which are crucial for defending against MTB.

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A Mycobacterium tuberculosis multi-epitope DNA vaccine encoding adaptive immune antigens provokes IFNγ/Th1 immunity and confers potential protection

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Original ResearchVol. 57, Issue 6 • pp. 1029-1032DOI: 10.3724/abbs.2025040

Histone acetylases are required for iron homeostasis in yeast

Authors: Jian Zhang, Yong Xue, Xinya Zhang, Renjie Qi, Yaqi Zhang, Chen Lu, Zhidan Luo

Iron, an ancient and essential transition metal, is involved in various biological functions, including oxygen transport, DNA synthesis, heme production, and iron-sulfur clusters, which participate in electron transport, DNA repair, and other cellular processes. However, excessive iron can lead to oxidative stress, lipid peroxidation, and cell damage. Thus, maintaining the iron content within an appropriate safe range and maintaining the balance of iron metabolism play crucial roles in both cellular function and human health [1]. An important aspect of maintaining the balance of iron homeostasis is the regulation of the iron uptake system. In Saccharomyces cerevisiae, cells can either obtain iron from the external environment via the non-reducing siderophore transport system or transport iron from the extracellular space to the intracellular space via the reducing iron transport system [2]. Iron uptake system-related genes are regulated mainly by the transcription factor Aft1p. During iron deficiency, Aft1p translocates into the nucleus, binds to genes involved in iron metabolism, and regulates the expressions of genes involved in iron uptake systems [3]. In addition, when there is a problem in the synthesis of iron-sulfur clusters in the mitochondria, such as the lack of the iron chaperone Yfh1p, which promotes the synthesis of iron-sulfur clusters, the transcription and nuclear entry of the transcription factor Aft1p are also activated, thereby regulating the expressions of iron metabolism-related genes [4]. In addition to transcription factors, gene expression is also regulated by histones and their modifications at the epigenetic level. For example, histone H3K4 methylation is related to gene activation, H3K36 methylation plays an important role in the elongation of transcription, and histone acetylation results in the loss of nucleosome structure and facilitates gene expression [5]. Therefore, histone modifications should also play important roles in the regulation of iron homeostasis. The relationship between histone modifications and iron homeostasis has been reported in the literature. For example, the DNA methylation-binding protein MBD5 can change histone acetylation in the promoter region of the ferritin gene by recruiting the histone acetylase KAT2A protein [6]. Histone acetylation has also been reported to be reduced in iron-deficient environments [7,8], and direct effects of histone acetylation on iron homeostasis gene loci have also been reported both in C. albicans [9] and mammals [10]. More recently, the histone H3-H4 tetramer was found to be a copper reductase enzyme, and H3-mediated Cu+ toxicity is a major determinant of the cellular functional pool of iron-sulfur (Fe-S) clusters [11,12]. However, information on the role of histone modifications in the regulation of iron homeostasis is limited. The mechanism by which and how histone modifications are involved in the transcriptional regulation of iron uptake-related genes or the iron deficiency response require further investigation. To determine whether histone acetylation and methylation are involved in the iron deficiency response, we first deleted the histone acetylase genes, including GCN5 (histones H2B and H3 N-terminal lysine acetylase, partial deletion of the ADA2 interaction sequence [13]), RTT109 (H3 lysine 9 and 56 acetylase), SAS2 (H4 lysine 16 acetylase), and YNG2 (subunit of the histone acetyltransferase complex NuA4 for acetylation of histone H4 or histone H2A) in the wild-type (WT) strain, as well as the histone methyltransferases SET1 (H3 lysine 4 methyltransferase), SET2 (H3 lysine 36 methyltransferase) and DOT1 (H3 lysine 79 methyltransferase). The genomic deletions were confirmed by colony PCR and genomic coverage analysis, as depicted in Supplementary Figures S1 and S2. The sensitivity of single histone modification enzyme mutants to iron deficiency induced by the iron chelator bathophenanthroline disulfonate (BPS) was tested. As shown in Supplementary Figure S3, the histone acetylation-related mutants gcn51–316, rtt109Δ, sas2Δ, and yng2Δ did not exhibit significant growth defects compared with the WT on the YPD + BPS plate. None of the histone methyltransferase knockout strains presented significant growth defects. As a positive control, the iron-responsive transcription factor gene AFT1 knockout strain grew slowly on YPD + BPS plates. It is possible that histone modifications do not have a strong effect on the equilibrium status of iron deficiency but still regulate transcription induction during the iron deficiency response. To investigate the role of histone modifications during the induction of the iron deficiency response, the expressions of iron response genes in the wild-type and mutant strains before and 4 h after BPS treatment were examined.

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Histone acetylases are required for iron homeostasis in yeast

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Original ResearchVol. 58, Issue 6 • pp. 1413-1422DOI: 10.3724/abbs.2025176

The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice

Authors: Zhenglong Guo, Yibing Lv, Jianmei Huang, Yingying Shao, Yuwei Zhang, Yibin Hao, Bingtao Hao, Zhenbo Cheng, Shixiu Liao

The iron regulatory protein IREB2 (Iron Responsive Element Binding Protein 2) plays a crucial role in maintaining cellular iron homeostasis through the posttranscriptional regulation of genes involved in iron metabolism. Mutations in the IREB2 gene have been linked to NDCAMA (OMIM#618451), a rare genetic neurological disorder characterized by early-onset neurodegeneration, choreoathetoid movements, and microcytic anemia. However, the absence of an IREB2-mutated animal model has left the underlying pathogenic mechanisms poorly understood. To investigate this, we establish a CRISPR-Cas9-mediated Ireb2D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA. Behavioral studies, including the Morris water maze (MWM), open field test (OFT), and Y-maze, reveal significant neurobehavioral deficits, such as impaired spatial learning and memory and reduced motor activity, in Ireb2D826V/D826V mice. Furthermore, we observe increased microglial activation and decreased dendritic spine density in the hippocampus, along with impaired long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), indicating synaptic dysfunction. Mechanistically, Ireb2D826V/D826V mice present reduced Ireb2 protein levels, dysregulated iron metabolism, and an altered expression profile associated with neurological function. This study elucidates the molecular mechanisms underlying NDCAMA and establishes Ireb2D826V/D826V mice as a model for iron metabolism-driven neurodegeneration. This finding links the instability of IREB2 to synaptic failure and neuroinflammation, highlighting potential therapeutic implications for neurodegenerative diseases.

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The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice

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Original ResearchVol. 57, Issue 1 • pp. 1036DOI: 10.3724/abbs.2025079

Corrigendum to: Stattic sensitizes osteosarcoma cells to epidermal growth factor receptor inhibitors via blocking the interleukin 6-induced STAT3 pathway

Authors: Shenglin Wang, Yunqing Wang, Zhen Huang, Hongxiang Wei, Xinwen Wang, Rongkai Shen, Wenbin Lan, Guangxian Zhong, Jianhua Lin

This is a corrigendum to the original article published in Acta Biochim Biophys Sin (Shanghai) 2021, 53(12): 1670–1680. In the original version, errors were found in Figure 2 and Figure 6. The correct figures are shown in this corrigendum. The authors apologize for the error.

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Corrigendum to: Stattic sensitizes osteosarcoma cells to epidermal growth factor receptor inhibitors via blocking the interleukin 6-induced STAT3 pathway

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Original ResearchVol. 58, Issue 6 • pp. 1250-1264DOI: 10.3724/abbs.2025236

Biochemical and structural studies of NFIA and NFIC reveal a conserved mechanism for specific DNA recognition and provide insight into potential pathogenicity of disease-associated mutations

Authors: Shuli Pan, Wenjie Pei, Jin Zhang, Jinrong Min, Ke Liu

Nuclear factor I (NFI) transcription factors play essential roles in multiple aspects of nervous system development, including radial glia maturation, neurogenesis, gliogenesis, and brain morphogenesis. Numerous NFI variants have been identified in individuals with neurodevelopmental disorders, yet the molecular basis of their pathogenicity remains unclear. The absence of resolved NFI-DNA complex structures continues to impede mechanistic insights and therapeutic exploration. Here, we define the oligomeric states of NFIA and NFIC, and determine the crystal structures of the NFIC homodimer, as well as the NFIA and NFIC monomers lacking their dimerization region, in complexes with double-stranded DNAs. Structural analysis reveals the molecular mechanism underlying NFI dimerization and recognition of a dyad-symmetric TGGCA(N3)TGCCA sequence motif, and demonstrates that dimerization enhances both DNA-binding affinity and specificity of NFI proteins. The functional importance of key NFI residues and DNA bases involved in the protein-DNA interaction is further validated by mutagenesis and binding assays. Additionally, we systematically evaluate the effects of the neurodevelopmental disorders-associated NFI mutations on DNA binding of NFIA, providing insights into their potential pathogenic mechanisms. Together, our findings elucidate the structural basis of NFI dimerization and dyad-symmetric DNA recognition and highlight pathogenic variants for further mechanistic studies in neurodevelopmental disorders.

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Biochemical and structural studies of NFIA and NFIC reveal a conserved mechanism for specific DNA recognition and provide insight into potential pathogenicity of disease-associated mutations

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Original ResearchVol. 57, Issue 6 • pp. 890-900DOI: 10.3724/abbs.2024202

Similarities and differences in the response and molecular characteristics of peripheral sensory neurons associated with pain and itch

Authors: Li Liu, Jiemin Yin, Youqiang Meng, Congrui Ye, Junhui Chen, Sa Wang, Wen Yin, Po Gao, Yingfu Jiao, Weifeng Yu, Yinghui Fan

Dorsal root ganglion (DRG) neurons are responsible for the primary detection and transmission of peripheral noxious stimuli, mainly pain and itch. However, as two distinct noxious sensations, how DRG neurons respond differently to and code pain and itch is still an attractive topic. Here, we investigate the response and activation spectrum of DRG neurons under peripheral pain and itch stimuli using in vivo two-photon calcium imaging and find differences in the response intensity to pain and itch between multisensory neurons (both pain and itch) and single-sensory neurons (either pain or itch). In addition, single-cell RNA sequencing (scRNA-seq) is used to reveal the heterogeneity of distinct subpopulations on the basis of their expressions of pain- or itch-related marker genes and to determine the similarities and differences in their transcriptomic changes under chronic pain and itch. Our results show that primary sensory neurons with different sensory patterns respond differently to the same nociceptive stimuli. Additionally, distinct clusters of neurons exhibit unique transcriptomic changes in the development of chronic pain and itch, which may offer new insights for treating these conditions.

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Similarities and differences in the response and molecular characteristics of peripheral sensory neurons associated with pain and itch

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Original ResearchVol. 58, Issue 6 • pp. 1313-1328DOI: 10.3724/abbs.2025151

Gut-brain axis and exosome-mediated communication in postoperative cognitive dysfunction associated with colorectal cancer

Authors: Ying Gao, Biao Xi, Yang Zhang, Mei Mei, Ming Zhai, Yunzhi Ling, Weiwei Chu

Postoperative cognitive dysfunction (POCD) is a serious complication in patients undergoing colorectal cancer (CRC) surgery. It is characterized by significant impairments in memory, information processing and attention, and may also result in mood and personality changes, thereby increasing the risk of postoperative mortality. Currently, there are no effective interventions available, highlighting the need for further investigation into its pathogenesis. While the current literature has identified an association between gut microbiota dysregulation and cognitive deficits, the precise mechanisms involved remain insufficiently understood. This study hypothesizes that exosome-like (Exos-like) nanoparticles derived from the gut microbiota contribute to POCD by modulating autophagy-dependent ferroptosis in hippocampal neurons. In a rat model of CRC, significant alterations in the gut microbiota composition, including reduced microbial diversity and changes in the abundance of key taxa, are observed. Exosomes derived from these microbiota enhance neuronal uptake and trigger markers of ferroptosis, as evidenced by increased expressions of ATG5 and COX2, along with decreased levels of GPX4 and FTH1. These findings establish a mechanistic link between microbial dysbiosis, ferroptosis, and cognitive decline in POCD, providing new insights into potential therapeutic targets for CRC-associated POCD.

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Gut-brain axis and exosome-mediated communication in postoperative cognitive dysfunction associated with colorectal cancer

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Original ResearchVol. 58, Issue 6 • pp. 1342-1355DOI: 10.3724/abbs.2025172

Long noncoding RNA LINC02432 inhibits papillary thyroid cancer via promoting ferroptosis

Authors: Yilin Zhang, Chuimian Zeng, Junxin Chen, Weijian Ke, Yi Zhao, Niandong Yi, Xueying Chen, Jinmei Deng, Xianying Zhu, Yanbing Li, Hongyu Guan

Long noncoding RNAs (lncRNAs) are essential in regulating the development and progression of different types of cancer. However, our insights into their impact and mechanisms in papillary thyroid carcinoma (PTC) are still insufficient. In this study, we investigate the effects of the ferroptosis-associated long noncoding RNA LINC02432 on PTC, which recognizes ferroptosis as a critical mechanism in cancer biology and lncRNAs as significant factors in various malignancies. To identify lncRNAs associated with ferroptosis in PTC, we conduct bioinformatics analyses and perform functional assays to evaluate the biological impact of LINC02432 on PTC cells, as well as its relationship with ferroptosis. Mechanistic studies employ methods such as western blot analysis, flow cytometry, and real-time PCR. Our analysis of transcriptome data from TCGA reveals that LINC02432 is the only lncRNA consistently identified by all 10 machine learning methods used, and its expression is significantly downregulated in PTC. Overexpression of LINC02432 in PTC cells inhibits cell proliferation and migration while promoting ferroptosis through inactivation of the NRF2 pathway. LINC02432 knockdown in PTC cells yields the opposite result. These findings highlight the potential of LINC02432 as a tumor suppressor in PTC progression, offering new insights into the mechanisms underlying the development and progression of this malignancy.

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Long noncoding RNA LINC02432 inhibits papillary thyroid cancer via promoting ferroptosis

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Original ResearchVol. 58, Issue 6 • pp. 1427-1430DOI: 10.3724/abbs.2025180

Yaf9 conditionally contributes to cell size control in Candida albicans

Authors: Wencheng Zhu, Baodi Dai, Yinxing Xu, Jiangye Chen

Candida albicans is an opportunistic fungal pathogen renowned for its ability to transition between distinct phenotypic states, such as the yeast-hyphae transition and the white-opaque switching. This morphological plasticity allows the organism to adapt to various host environments and evade immune responses. The white state is characterized by yeast-like cells with high proliferative capacity, whereas the opaque state features elongated cells with enhanced mating ability. The regulation of white-opaque switching is primarily controlled by a complex network of transcription factors. White-Opaque Regulator 1 (Wor1) serves as a master regulator crucial for the establishment and maintenance of the opaque state by activating the expression of genes required for opaque cell formation [1–3]. Conversely, the Mating-Type Like (MTL) locus in C. albicans acts as a critical barrier to white-opaque switching. The genes present at this locus strictly repress the white-to-opaque transition by the formation of a1/α2 complex; therefore, only MTLa/a or MTLα/α strains frequently switch to the opaque state [4,5]. Although the MTLa/α lab strain CAI4 is typically locked in the white state, some MTLa/α clinical isolates can switch to opaque [6]. Several genes were found to modulate this repression. For example, loss of HBR1, which is an activator of MTLALPHA1 and MTLALPHA2 gene expression, enables switching in MTLa/α cells [7]. Deletion of transcriptional repressors of the opaque state such as TUP1 also facilitates white-to-opaque switching [8]. The SWR1 complex incorporates H2A.Z into chromatin, and loss of Swr1 enhances switching and stabilizes the opaque state in MTL homozygous cells [9]. Our previous work revealed that the NuA4 histone acetyltransferase complex and the SWR1 complex merge into a supercomplex via Yaf9 in white-state yeast cells in C. albicans [10]. Here, we first tested whether Yaf9 is involved in white-to-opaque switching in MTLa/α heterozygous cells. The knockout of the YAF9 gene was validated by genotyping and qRT-PCR, confirming its loss at both the genomic and transcriptional levels (Supplementary Figure S1). The yaf9 null mutant cells were spread onto YPD plates and incubated in 20% CO2 at 25°C. After eight days of growth, sectors containing opaque cells were observed (Figure 1A). The frequency of opaque cell formation in the yaf9 mutant exceeded that in wild-type (WT) cells overexpressing WOR1 (Figure 1B). qRT-PCR analysis confirmed significant upregulation of opaque cell-specific markers, including WOR1 and OP4, in yaf9 mutant opaque cells, whereas the white cell marker WH11 was downregulated (Figure 1C). To examine whether YAF9 deletion affects the expression of MTL genes, we performed qRT-PCR for MTLA1 and MTLALPHA2 in white WT cells and in both white and opaque yaf9 mutant cells. The expression of both genes remained unchanged in yaf9 mutant cells (Figure 1D), suggesting that Yaf9-mediated repression of white-to-opaque switching occurs independently of MTL gene regulation. As Yaf9 is a component of the NuA4 and SWR1 complexes, we next investigated the roles of the NuA4 core enzyme Esa1 and the SWR1 core enzyme Swr1 in white-to-opaque switching in MTLa/α heterozygous cells. As shown in Figure 1E (upper panel), esa1 cells failed to switch to the opaque form under 20% CO2 stimulation, indicating that Esa1 activity is essential for opaque cell formation under the tested conditions. In contrast, swr1 cells readily underwent white-to-opaque switching (Figure 1E, lower panel), similar to the yaf9 mutant. These results indicate that Yaf9 functions as a repressor of white-to-opaque switching and that its deletion bypasses the repression imposed by the MTLa/α configuration. We then examined the role of YAF9 in white-to-opaque switching in MTLa/a cells, where MTL repression is removed. In air, yaf9 cells remained white; however, when exposed to 20% CO2, they frequently (> 50%) switched to the opaque form, which occurred at a significantly higher frequency than WT cells (Figure 2A,B). Notably, yaf9 cells exhibited a novel elongated opaque morphology, which we term e-Op cells. Quantification revealed that e-Op cells had similar width but were two to three times longer than WT opaque cells (Figure 2C). At the transcriptional level, e-Op cells displayed comparable upregulation of WOR1 and OP4 and downregulation of WH11 (Figure 2D). Notably, WH11 expression in yaf9 white cells was slightly higher than that in WT white cells. Like white cells, opaque cells are also capable of forming filaments under specific conditions [11]. To determine whether e-Op cells represent a filamentous form of opaque cells, we examined their gene expression and morphological stability. Multiple lines of evidence indicate that e-Op cells are distinct from these filamentous forms. First, when cultured on SOR medium, which promotes filamentous g

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Yaf9 conditionally contributes to cell size control in Candida albicans

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Original ResearchVol. 58, Issue 5 • pp. 975-988DOI: 10.3724/abbs.2025207

COCA-seq: genome-wide mapping of O-GlcNAc-associated open chromatin

Authors: Chang Ge, Ran Zhao, Hongyu Jiang, Qingbin Chen, Zhentao Yu, Hankai Yang, Xuan Jiang, Qile Ma, Lirui Han, Kairan Yu, Guofang Li, Huang Huang, Wei Wang, Yubo Liu, Qingyue Zhang, Xing Jin

O-GlcNAcylation, a prevalent reversible post-translational modification, intricately alters non-histone proteins, influencing the organization of gene transcriptional regulation within the accessible chromatin environment. This nucleoplasmic landscape, characterized by histone-free regions, fundamentally enables O-GlcNAc-mediated modulation through dynamic accessibility. However, unraveling the O-GlcNAc-open chromatin interplay that governs sophisticated transcriptional regulatory networks remains constrained by current techniques, which lack the resolution to probe this spatiotemporal crosstalk. Here, we report a general strategy to systematically and chemoselectively profile O-GlcNAc-associated chromatin accessibility on a genome-wide scale (COCA-seq). Through comprehensive validation across low- and high-throughput levels, we demonstrate COCA-seq’s dual fidelity in both O-GlcNAc chemoselectivity and open chromatin specificity. We employ it to delve into doxorubicin resistance for breast cancer, scrutinizing pivotal regulatory genes and transcription factors implicated in this complex biological event. By integrating bulk RNA-seq with COCA-seq, we offer a multiomics perspective, shedding light on related biological processes and pathways like drug efflux and stress homeostasis, thereby uncovering potential mechanisms by which O-GlcNAc-associated open chromatin orchestrates tumor drug resistance. COCA-seq emerges as a general and versatile tool across various biological contexts, poised to reveal the landscape of O-GlcNAc-associated open chromatin regions across the genome and decipher the significance of glycosylation behind it.

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COCA-seq: genome-wide mapping of O-GlcNAc-associated open chromatin

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Original ResearchVol. 57, Issue 5 • pp. 758-769DOI: 10.3724/abbs.2024183

Cannabidiol alleviates the inflammatory response in rats with traumatic brain injury through the PGE2-EP2-cAMP-PKA signaling pathway

Authors: Yan Cao, Hengxi Li, Jiali Li, Tenghan Ling, Aiping Yin, Xinyuan Luo, Ying Zhou, Jinghui Li, Hongyan Jiang, Huawei Wang, Li Yang, Haiying Wu, Ping Li

Traumatic brain injury (TBI) is a recognized global public health problem. However, there are still limitations in the available therapeutic approaches and a lack of clinically effective drugs. Therefore, an in-depth exploration of the secondary pathological mechanism of TBI and the identification of new effective drugs are urgently needed. Cannabidiol (CBD), a component derived from the cannabis plant, has potential therapeutic effects on neurological diseases and has received increasing attention. However, few reports on CBD intervention in TBI patients exist. Here, we use the Feeney free-fall method to establish a rat TBI model. CBD significantly improves neurological deficit scores, neuronal damage and blood-brain barrier permeability in rats and significantly inhibits the expressions of the brain injury markers S-100β and NSE. Mechanistically, CBD attenuates TBI-induced astrocyte activation, reduces inflammation, and attenuates the expressions of inflammatory prostaglandin system indicators. The use of TG6-10-1 (EP2 inhibitor) and H-89 (PKA inhibitor) indicates that CBD attenuates TBI-induced neurological damage via the PGE2-EP2-cAMP-PKA signaling pathway. Overall, this research provides a novel drug candidate for the treatment of clinical brain trauma.

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Cannabidiol alleviates the inflammatory response in rats with traumatic brain injury through the PGE2-EP2-cAMP-PKA signaling pathway

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Original ResearchVol. 58, Issue 5 • pp. 989-1007DOI: 10.3724/abbs.2025234

Cancer-specific bivalent promoters featuring low-level H3K27me3 signals favor active transcription and govern the cancer cell state transition

Authors: Fan Yang, Guanlan Fan, Jing Cao, Qiuyan Zhao, Kexiu Guo, Min Liu, Xin Yin, Hongying Zong, Feng Li, Fubing Wang, Jie Xiong

Bivalent chromatin maintains genes in low-expression, poised states in embryonic stem cells (ESCs). However, bivalent promoters correlate with the transcriptional activation of oncogenic programs in malignancies, a seemingly contradiction that remains to be resolved. Here, we identify a class of cancer-specific bivalent promoters (CSBPs) through the integration of a system-level longitudinal framework. Compared with ESCs, CSBPs are characterized by lower and narrower H3K27me3 deposition alongside abundant H3K4me3, thus permitting the persistent expression of genes critical for cancer stem cell (CSC) formation and maintenance, as exemplified by SOX9. The generation of CSBPs is essentially induced by the acquisition of H3K27me3 during cell state transition, which is mediated by specific binding of PRC2.1 and the de novo recruitment of PRC2.2. Notably, disrupting the bivalency of CSBPs significantly increases H3K4me3 levels, leading to hyperactivation of CSBPs and eventually inhibiting clonal expansion of CSCs and impairing tumorigenesis. Our study not only helps explain the puzzle of transcriptionally active bivalent genes in cancer but also provides insights into the development of therapies targeting phenotypic plasticity.

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Cancer-specific bivalent promoters featuring low-level H3K27me3 signals favor active transcription and govern the cancer cell state transition

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Original ResearchVol. 58, Issue 5 • pp. 1102-1118DOI: 10.3724/abbs.2025136

Metabolic analysis and identification of potential biomarkers of early-stage melanoma lung metastasis

Authors: Chunying Gu, Hongyu Liu, Guangyu Jiang, Ying Lv, Jiafu Liu

Tumor cells exhibit a notable ability to adapt to constantly changing microenvironments and possess distinct metabolic traits during metastasis. This study aims to establish a melanoma lung metastasis model in mice to elucidate the metabolic mechanisms involved in early-stage metastasis prior to treatment. The male C57BL/6 mice are divided into five groups based on time intervals of 6, 24, 72, and 120 h post-injection (SKCM-M groups) of melanoma cells, as well as a normal control group (NOR group). Our results demonstrate that platelet activation mainly occurs in the initial phases of metastasis to help tumor cells survive. NMR-based metabolomics analysis of mouse lung tissues identifies distinct metabolites and pathways associated with early-stage metastasis, revealing significant alterations in energy and amino acid metabolism during tumor progression. Further analysis indicates that methylxanthine and allantoin could serve as potential biomarkers for monitoring the early progression of tumor metastasis in cancer patients, providing novel insights into early diagnostic strategies for lung metastasis.

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Metabolic analysis and identification of potential biomarkers of early-stage melanoma lung metastasis

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Original ResearchVol. 57, Issue 6 • pp. 871-878DOI: 10.3724/abbs.2025011

Melanoma-derived versican reactivates tumor-associated macrophages by upregulating pyruvate carboxylase through TLR2-MyD88-RelB axis under normoxia

Authors: Yuxin Shu, Linmin Zhou, Jinqin Qian, Wei-Guo Zhu

Relieving hypoxia in the tumor microenvironment (TME) promotes innate and adaptive immunity. Our previous research demonstrated that reoxygenation of the TME promotes the phagocytosis and tumor-killing functions of tumor-associated macrophages (TAMs) by upregulating pyruvate carboxylase (PCB). However, the mechanism remains obscure. In the present study, we find that versican derived from melanoma cells binds to TLR2 and activates the downstream transcription factor RelB, which transcribes PCB under normoxia. Blocking the versican-TLR2-MyD88-RelB axis not only reverses the upregulation of PCB in TAMs but also hinders the clearance of tumor cells by TAMs. Our work suggests a pathway that modulates the functions of TAMs under normoxia, which could be harnessed for strengthening anti-tumor immunity.

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Melanoma-derived versican reactivates tumor-associated macrophages by upregulating pyruvate carboxylase through TLR2-MyD88-RelB axis under normoxia

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Original ResearchVol. 57, Issue 5 • pp. 834-846DOI: 10.3724/abbs.2025046

TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus

Authors: Chen Li, Ang Ma, Yu Bai, Zitao Liu, Linghan Tian, Ziyuan Wang, Huaishun Ma, Zhengpu Chen, Zhengheng Gao, Shijie Feng, Ping Fu

The cGAS-STING signaling pathway serves as a pivotal surveillance mechanism for cytosolic double-stranded DNA (dsDNA) detection in mammalian systems. While STING-mediated type I interferon production is crucial for host defense, sustained activation of this pathway contributes to autoimmune pathologies, including systemic lupus erythematosus (SLE). Maintaining immune homeostasis requires precise regulation of STING activity to prevent hyperactivation. Our study identifies TRIM21 as a novel positive regulator of cGAS-STING signaling in SLE pathogenesis. Our results demonstrate that TRIM21 overexpression stabilizes STING by suppressing autophagic degradation, whereas TRIM21 depletion accelerates this clearance process. Mechanistically, TRIM21 catalyzes the K63-linked polyubiquitylation of the selective autophagy receptor p62/SQSTM1, disrupting its interaction with STING. This post-translational modification prevents the sequestration of STING into autophagosomes, thereby stabilizing the adaptor protein and amplifying downstream type I interferon responses. Our findings reveal a previously unrecognized regulatory circuit in which TRIM21 orchestrates cross-talk between ubiquitin signaling and autophagy to control STING turnover. The TRIM21-p62 axis represents a potential therapeutic target for attenuating pathological interferon production in STING-dependent autoimmune disorders. This work advances our understanding of immune regulation by demonstrating how E3 ligase-mediated ubiquitin modifications modulate cargo recognition in selective autophagy pathways. The identified mechanism provides new insights into the molecular interplay between protein ubiquitylation and autophagic degradation in maintaining the innate immune balance, offering novel perspectives for developing targeted therapies against interferonopathies associated with cGAS-STING hyperactivity.

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TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus

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Original ResearchVol. 57, Issue 5 • pp. 701-711DOI: 10.3724/abbs.2025008

p53-dependent chromatin relaxation is required for DNA double-strand break repair

Authors: Hongyu Chen, Jin Shan, Wenjing Qi, Lili Chen, Xianlu Zeng

The tumor suppressor p53, an indispensable nuclear transcription factor, plays a central role in orchestrating cellular responses when DNA damage occurs. In this study, we demonstrate that in the initial phases of DNA double-strand break (DSB) repair, p53 is rapidly recruited to sites of damage and the surrounding chromatin, where it enhances DSB repair efficiency. This enhancement occurs through the modulation of chromatin dynamics and the promotion of a more relaxed chromatin configuration, a process influenced by p53 in response to DSB-inducing factors such as etoposide, ultraviolet radiation, and nucleases. These results underscore the pivotal function of p53 as a rapid responder to DSBs, delineating a significant departure from its traditionally recognized role as a downstream transcriptional regulator in DNA damage repair processes. This study emphasizes that the direct engagement of p53 in DNA repair through chromatin structure regulation extends beyond its established involvement in UV irradiation-induced nucleotide excision repair (NER), demonstrating analogous mechanistic attributes in the context of DSB repair. This newly illuminated perspective enhances our understanding of the multifaceted roles of p53 in genome stability and integrity.

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p53-dependent chromatin relaxation is required for DNA double-strand break repair

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Original ResearchVol. 58, Issue 5 • pp. 1045-1054DOI: 10.3724/abbs.2025168

The DNA-PKcs-primary cilia axis maintains ionizing radiation-induced senescence in tumor cells

Authors: Xiuzhu Liu, Li Wei, Rong Zhang, Jiaxin Chen, Tongshan Zhang, Junrui Hua, Jufang Wang, Jinpeng He, Xiaodong Xie

Senescence is a cellular response closely associated with genotoxic stress and plays a critical role in determining cell fate following irradiation exposure. Primary cilia, which are sensory organelles on the cell surface, detect and transmit diverse signaling cues. However, the relationship between primary cilia and senescence in long-term cell fate decisions after ionizing radiation remains poorly understood. Here, we show that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) colocalizes with centromeres during various stages of mitosis, whereas during interphase, phosphorylated DNA-PKcs (p-DNA-PKcs) is confined to the nucleus in tumor cells. Following irradiation exposure, primary cilia are formed and persistently maintained at high levels in senescent tumor cells. Inhibition of DNA-PKcs enhances primary cilia formation, whereas combined inhibition with siDNA-PKcs and irradiation reduces cilia generation. Moreover, chloral hydrate-induced primary cilia removal results in senescent cell death and decreases p-DNA-PKcs protein expression. Notably, treatment with the apoptosis inducer ABT263 also leads to increased cell death and decreased incidence of primary cilia. Inhibition of either primary cilia or DNA-PKcs further enhances the radiosensitivity of tumor cells. These findings suggest that DNA-PKcs contributes to primary cilia formation after irradiation and plays a critical role in both the induction and maintenance of cellular senescence.

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The DNA-PKcs-primary cilia axis maintains ionizing radiation-induced senescence in tumor cells

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Original ResearchVol. 57, Issue 5 • pp. 749-757DOI: 10.3724/abbs.2024182

CD98hc, a novel of galectin-8 receptor, binds to galectin-8 in an N-glycosylation-dependent manner

Authors: Yunlong Si, Jiahui Zhu, Hend Sayed, Kevin H. Mayo, Yifa Zhou, Guihua Tai, Jiyong Su

Glycan-mediated recognition plays a critical role in facilitating cell-cell and cell-matrix interactions. Galectin-8 (Gal-8), classified as a ‘tandem-repeat’ type of galectin, binds to cell surface glycans to modulate various cellular functions, including cell adhesion, migration, apoptosis, pathogen recognition, autophagy, and immunomodulation. Despite the known function of Gal-8 in binding to various glycosylated proteins, only a few interactions have been reported to date. In this study, mass spectrometry is used to identify CD98hc as a novel binding partner for Gal-8. Both the N-terminal and C-terminal carbohydrate recognition domains (CRDs) of Gal-8 (Gal-8N and Gal-8C) bind to CD98hc, an interaction that is specifically inhibited by lactose but not sucrose, as confirmed by pull-down assays. The binding affinity between CD98hc and Gal-8 measured by microscale thermophoresis (MST) is 1.51 ± 0.17 μM. In addition, Gal-8N and Gal-8C have the binding affinities of 0.22 ± 0.03 μM and 10.68 ± 1.69 μM, respectively. Gal-8N and Gal-8C are both involved in the recognition and binding process of CD98hc. Furthermore, both full-length Gal-8 and its individual CRDs bind specifically to N-glycosylated glycans on CD98hc, as demonstrated by the use of tunicamycin to inhibit N-glycosylation in cells. In addition, Gal-8 and its individual CRDs can pull down glycosylated CD98hc-ED but not free CD98hc-ED in vitro, indicating that the binding of Gal-8 to glycosylated CD98hc-ED is N-glycosylation-dependent. Overall, our findings establish CD98hc as a novel binding partner for Gal-8 and provide insights for further exploration of the diverse biological functions of Gal-8.

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CD98hc, a novel of galectin-8 receptor, binds to galectin-8 in an N-glycosylation-dependent manner

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Original ResearchVol. 58, Issue 5 • pp. 1069-1082DOI: 10.3724/abbs.2025163

Myocyte enhancer factor 2A orchestrates vascular redox homeostasis via direct transcriptional activation of SIRT1

Authors: Benrong Liu, Lei Fang, Chunxia Miao, Xinyu Wen, Xiumiao Zheng, Minxing Xu, Junli Lin, Yujuan Xiong, Shi-Ming Liu

Myocyte enhancer factor 2A (MEF2A), a transcription factor implicated in coronary artery disease, remains unexplored in vascular redox regulation. To address this gap and overcome the limitations of current antioxidant therapies, we investigate the role of MEF2A in oxidative defense via human umbilical vein endothelial cells (HUVECs) and murine models. Adenoviral vectors encoding MEF2A-specific shRNAs or mRNAs are used to silence or overexpress MEF2A in HUVECs. For in vivo validation, endothelial-targeted MEF2A knockdown is achieved via AAV1-shRNA delivery in mice fed with a high-fat diet. Systemic redox status is assessed by measuring reactive oxygen species (ROS), glutathione homeostasis (GSH/GSSG ratio), the NADH/NAD+ balance, the mitochondrial membrane potential (ΔΨm), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Mechanistic insights are derived from immunofluorescence, qPCR, western blotting, and dual-luciferase reporter assays. MEF2A silencing induces redox imbalance, characterized by elevated ROS, a reduced GSH/GSSG ratio, and ΔΨm collapse. Conversely, MEF2A overexpression synergizes with SIRT1 to restore the glutathione pool, maintain NAD+ homeostasis, and suppress ROS under oxidative stress. Chromatin immunoprecipitation confirms that MEF2A directly binds to two cis-elements in the SIRT1 promoter, driving transcriptional activation. In vivo, MEF2A-deficient mice present increased vascular oxidative damage, as indicated by elevated DNA damage marker (8-OHdG) and ROS levels. The downregulation of SIRT1/PGC-1α in MEF2A-silenced cells is verified in vivo. Our findings establish MEF2A as a master regulator of endothelial redox defense via the SIRT1-PGC-1α axis, providing a mechanistic foundation for the treatment of oxidative cardiovascular disorders. This work suggests that pharmacological MEF2A activation is a novel strategy for precision antioxidant therapy in vascular medicine.

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Myocyte enhancer factor 2A orchestrates vascular redox homeostasis via direct transcriptional activation of SIRT1

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Original ResearchVol. 58, Issue 5 • pp. 947-962DOI: 10.3724/abbs.2025212

Antibody-oligonucleotide conjugates for spatial proteomics: principles, applications, and challenges

Authors: Yinghui Qiu, Chunlan Li, Peiying Ye, Haiyun Zhang, Yanxiu Liu, Weiyan Ma, Chen Lin, Rongqin Ke

Spatial biology aims to elucidate cellular organization, function, and interactions within native tissue contexts, offering key insights into both normal physiology and disease. Spatial proteomics complements this by enabling high-resolution mapping of protein localization and abundance, directly reflecting functional cellular states. Unlike transcriptomics, which infers potential activity, proteomics captures actual molecular functions, including post-translational modifications and dynamic interactions. However, in situ protein profiling poses significant challenges, as proteins cannot be directly sequenced or easily targeted via nucleic acid hybridization. Antibody-oligonucleotide conjugates (AOCs) address this limitation by converting protein recognition into a DNA-based readout, thereby enabling sensitive and scalable detection. In this review, we outline the core principles of AOC-based spatial proteomic technologies, including multiplexed protein analysis, in situ protein-protein interactions, and integration with other biomolecular data. We highlight their applications in decoding tissue complexity and disease pathology and examine key technical challenges that remain. Overall, AOCs offer distinct advantages, including DNA-mediated signal amplification, spatially resolved proteomic profiling, and compatibility with multi-omics approaches, positioning them as powerful platforms in the advancement of spatial biology.

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Antibody-oligonucleotide conjugates for spatial proteomics: principles, applications, and challenges

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Original ResearchVol. 58, Issue 4 • pp. 819-832DOI: 10.3724/abbs.2025110

Directly targeting G-quadruplexes contributes to the anti-multiple myeloma efficacy of Epimedokoreanin B

Authors: Pingting Jia, Shangzhao Wang, Wanting Huang, Ye Fang, Jian Gao

Multiple myeloma (MM) is a hematological malignancy for which novel therapeutic strategies are urgently needed. Epimedokoreanin B (EKB), an isoprenylated flavonoid compound derived from the medicinal plant Epimedium koreanum, has demonstrated promising antitumor activity. However, its effects on MM have not been previously investigated. This study explores the anti-MM activity and the molecular interaction mechanisms between EKB and G-quadruplexes (G4) through a combination of biological activity assessments and computer-aided methodologies. EKB exhibits potent cytotoxicity against the MM cell lines U266 and RPMI-8226, with IC50 values of 5.28 μM and 6.81 μM, respectively. It induces apoptosis in a concentration-dependent manner and specifically stabilizes the G4 structures of oncogenes such as c-Myc, c-KIT, Bcl-2, and k-RAS, as confirmed by BG4 immunofluorescence staining and fluorescence resonance energy transfer (FRET) assays. Additionally, EKB significantly suppresses the mRNA and protein expression levels of these genes in myeloma cells. Computational studies, including molecular docking, molecular dynamics (MD) simulations, and MM/GBSA calculations, confirm the strong binding affinity and stabilizing effects of EKB on G4s, revealing a mechanism involving π-π stacking and hydrogen bonding. This discovery underscores the unique ability of EKB to increase the stability of G4 structures, which are critical for regulating gene expression and inhibiting cancer cell proliferation. This research highlights the therapeutic potential of EKB in targeting these specific molecular structures, thereby offering a more effective approach to managing MM.

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Directly targeting G-quadruplexes contributes to the anti-multiple myeloma efficacy of Epimedokoreanin B

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Original ResearchVol. 58, Issue 5 • pp. 1023-1031DOI: 10.3724/abbs.2025183

Gut microbiota and bile acids changes in MASLD mice model with hepatic PLD1 knockout

Authors: Yushang Zhao, Huan Wang, Wanling Lin, Hui Wang, Lin-Lin Cao

Hepatocyte phospholipase D1 (PLD1) knockout alleviates metabolic dysfunction-associated steatotic liver disease (MASLD) in mice, but the underlying mechanism is largely unknown. In this study, the mice are divided into four groups: Con (wild-type mice with normal control diet), HFHC (wild-type mice with high-fat diet), Con_KO (hepatocyte PLD1-knockout mice with normal control diet), and HFHC_KO (hepatocyte PLD1-knockout mice with high-fat diet). Intestinal contents of mice are analyzed via metagenomics and metabolomics, and the liver bile acids are assessed by mass spectrometry imaging. The results show that at the phylum level the abundance of Bacillota in the intestines of MASLD model mice is significantly increased, whereas that of Bacteroidota significantly is decreased. However, after the deletion of hepatocyte PLD1, Pseudomonadota and Candidatus Bathyarchaeota are significantly decreased in the MASLD model mice. At the species level, compared with that in the Con group, the abundance of Faecalibaculum rodentium is significantly increased in the HFHC group, whereas hepatocyte PLD1 knockout causes the abundances of Desulfovibrionaceae bacterium LT0009 and Lachnospiraceae bacterium 10-1 to be significantly decreased. In terms of intestinal bile acids, the levels of two bile acids (hyodeoxycholic acid and glycolithocholic acid) differ between the HFHC_KO group and the HFHC group. Association analysis shows that Faecalibaculum co-occurs with DCA, βMCA, ΩMCA and αMCA, while probiotic Bacteroides uniformis is significantly correlated with UDCA, 12-KetoLCA, and 7-KetoLCA. Finally, mass spectrometry imaging reveals that the TCA and TDCA contents in the liver are significantly decreased after PLD1 knockout in hepatocytes. These findings demonstrate that hepatocyte PLD1 knockout alters the gut microbiota and bile acids profiles, suggesting that PLD1 deficiency may modulate MASLD progression by changing intestinal microbiota-bile acid homeostasis.

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Gut microbiota and bile acids changes in MASLD mice model with hepatic PLD1 knockout

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Original ResearchVol. 58, Issue 4 • pp. 709-724DOI: 10.3724/abbs.2025230

Explore antibody repertoire in the era of AI

Authors: Yudi Zhang, Hefei Wang, Chencheng Liu, Fei-Long Meng

The diverse antibodies of adaptive immunity comprise an antibody repertoire that combats various pathogens. This repertoire is shaped by both intrinsic antibody gene diversification and extrinsic cellular selection. Conversely, an antibody repertoire contains multiple layers of immunological information, including the history of pathogen exposure. High-throughput sequencing-based antibody repertoire cloning approaches have revealed unexpected features of adaptive immunity. However, our understanding of antibody repertoire data is still in its infancy. In this review, we introduce the emerging concepts and discuss the application of deep learning approaches to understanding antibody repertoires. First, we introduce the definition and functional features of antibody clonotype. Next, we review the evolution of antibody clonotypes and discuss potential antibody repertoire-directed vaccination approaches. Lastly, we summarize the application of deep learning in predicting antibody binding, generating specific antibodies, and making immunologic diagnoses. Recently, artificial intelligence (AI) has made revolutionary progress in biology. Leveraging high-dimensional antibody repertoire information, deep learning models have the potential to transform our understanding of antibody repertoire.

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Explore antibody repertoire in the era of AI

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Original ResearchVol. 58, Issue 3 • pp. 663-680DOI: 10.3724/abbs.2025114

The TCF7L2/miR-206/Cofilin1 axis promotes the metastasis of bladder cancer cells by regulating the formation of invadopodia

Authors: Yuzhen Jie, Yinggui Yang, Chengyan Guo, Qinghui Wu, Zhewen Ou, Weifu Wang, Ning Xu, Wei Peng, Yingguang Wu, Jiangfan Peng, Shengchao Ma, Shufang Zhang, Fei Wang

Bladder cancer (BCa) is one of the most common malignant tumors of the urinary system, but its pathogenesis is still unclear. T1G3 BCa is particularly invasive and relapses readily after treatment, with progression to invasive cancer or distant metastasis. Therefore, identification of the molecular mechanism by which it invades and metastasizes to guide treatment and predict patient prognosis is needed. Cofilin1 plays an important role in regulating gene expression and the invasiveness of tumors. In this study, we show that Cofilin1 is highly expressed in BCa and lymph nodes with metastasis, which is positively related to the grade of BCa, and is significantly related to clinicopathological parameters and cancer-specific survival. Phenotypic analysis reveals that Cofilin1 knockout inhibits the proliferation and migration of BCa cells, whereas Cofilin1 overexpression promotes the opposite phenotype. Cofilin1 binds to cortactin, thereby reducing the expression of F-actin and promoting the formation of invadopodia in BCa cells. Further experiments reveal that TCF7L2 can bind to the promoter of Cofilin1 and transactivate it, promoting a malignant phenotype. TCF7L2 may also reverse the inhibitory effect of miR-206 on the binding of Cofilin1 and cortactin and promote the metastasis of BCa by inhibiting the transcription maturation of miR-206. This study confirms that Cofilin1 is an oncogene in T1G3 BCa, and the TCF7L2/miR-206/Cofilin1 signaling pathway plays an important role in the formation of invadopodia in BCa.

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The TCF7L2/miR-206/Cofilin1 axis promotes the metastasis of bladder cancer cells by regulating the formation of invadopodia

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Original ResearchVol. 57, Issue 4 • pp. 507-520DOI: 10.3724/abbs.2024228

Annexins: central regulators of plant growth and stress signaling

Authors: Chen Xie, Mingyue Zhu, Ruirui Shi, Liu Yang, Xiaoya An, Chao Wang

Annexins are a family of multifunctional calcium-dependent and phospholipid-binding proteins that are widely distributed in the plant kingdom. They have a highly conserved evolutionary history that dates back to single-celled protists. Plant annexins, as soluble proteins, can flexibly bind to endomembranes and plasma membranes, exhibiting unique calcium-dependent and calcium-independent characteristics. Members of the annexin family have diverse functions, including binding to F-actin, participating in ATP and GTP hydrolysis, and even serving as peroxidases or cation channels. Annexins play pivotal roles in plant growth and stress signaling. They can respond sensitively to environmental, metabolic, and developmental signals, thereby affecting cytoskeleton remodeling and exocytosis mechanisms. Plant annexin gene families have been successfully identified in multiple species, and their expression and intracellular localization are precisely regulated by developmental processes and environmental factors. Although research on plant annexins has aroused great interest, their depth and breadth still need further expansion compared with those of animal annexins. This article provides a comprehensive and in-depth review of the characteristics and functions of plant annexin families, revealing their core roles in plant growth and adaptation, and yielding valuable references and insights for future research.

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Annexins: central regulators of plant growth and stress signaling

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Original ResearchVol. 58, Issue 3 • pp. 516-529DOI: 10.3724/abbs.2025112

Scutellarin inhibits ferroptosis by promoting cellular antioxidant capacity through regulating Nrf2 signaling

Authors: Haiyan Yang, Onkei Chan, Xiaodi Huang, Liang Yan, Nuo Sun, Yaping Li, Zijian Shi, Qingbing Zha, Dongyun Ouyang, Jinhua Li, Xianhui He

Ferroptosis is a lytic form of regulated cell death that is driven by iron-dependent lipid peroxidation and has been implicated in various diseases, including acute kidney injury (AKI). Scutellarin is a flavonoid isolated from Erigeron breviscapus (Vant.) Hand.-Mazz. and possesses various pharmacological activities, including anti-inflammatory and antioxidative properties. However, it is unclear whether scutellarin can inhibit ferroptosis and mitigate related diseases. In this study, we show that scutellarin can inhibit ferroptosis in both human HK-2 cells and mouse bone marrow-derived macrophages stimulated with RSL3 or erastin. Mitochondrial dysfunction and reactive oxygen species generation are counteracted by scutellarin treatment, suggesting the involvement of its antioxidative activity. Furthermore, scutellarin increases the nuclear levels of Nrf2 and the expressions of its target genes, including HO-1 and GPX4. Scutellarin-mediated inhibition of ferroptosis and increases in these proteins are abrogated by co-treatment with brusatol, an Nrf2 inhibitor, indicating an essential role for Nrf2 in this process. In a mouse model of folic acid-induced AKI, scutellarin mitigates acute renal damage, as revealed by histopathological analysis and serum blood urea nitrogen and creatinine assays. Folic acid-induced acute renal injury is associated with increased ferroptosis, as revealed by elevated level of 4-hydroxynonenal (4-HNE), a surrogate marker of ferroptosis, which is diminished by scutellarin co-treatment. Specifically, the elevated 4-HNE levels in macrophages (MAC-2 positive) and other renal cells are suppressed by scutellarin. Overall, scutellarin can inhibit ferroptosis both in cultured cells and in a mouse model of AKI by regulating Nrf2 signaling.

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Scutellarin inhibits ferroptosis by promoting cellular antioxidant capacity through regulating Nrf2 signaling

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Original ResearchVol. 58, Issue 4 • pp. 911-919DOI: 10.3724/abbs.2025182

Structural basis for suramin binding to the C-terminal domain of the SARS-CoV-2 nucleocapsid protein

Authors: Chenyun Guo, Xiao Li, Hao Xu, Jiaxin Yu, Jia Li, Donghai Lin

The global threat posed by COVID-19 persists, largely due to the high mutability of SARS-CoV-2 and the limited availability of effective antiviral therapeutics. The nucleocapsid (N) protein of SARS-CoV-2 is an attractive drug target because of its high degree of sequence conservation and essential role in viral replication. In this study, we show that suramin, a polysulfonated antiviral compound, binds to the C-terminal domain (N-CTD) of the N protein and interferes with its interaction with RNA. Biolayer interferometry (BLI) shows that suramin has a higher binding affinity for N-CTD (Kd, 3.30 μM) than for RNA (Kd, 10.12 μM). Electrophoretic mobility shift assays (EMSAs) further confirms that suramin effectively displaces RNA from N-CTD. NMR titration experiments and site-directed mutagenesis identify the α1-η1 helix (residues 248–262) as the primary suramin binding region, with residues K256, R259 and R262 playing critical roles in ligand recognition. In addition, NMR relaxation and model-free analyses reveal that the α1-η1 helix is highly flexible on the picosecond to nanosecond timescale, a dynamic feature that likely facilitates ligand binding. Furthermore, ITC and EMSA experiments demonstrate that suramin can bind to the full-length N protein at multiple sites and dissociate RNA from the N protein. Taken together, these findings provide structural and biophysical insights into the mechanism of action of suramin and establish a rational basis for the development of targeted antiviral therapies against SARS-CoV-2.

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Structural basis for suramin binding to the C-terminal domain of the SARS-CoV-2 nucleocapsid protein

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Original ResearchVol. 58, Issue 3 • pp. 530-540DOI: 10.3724/abbs.2025142

Combined ex vivo and in vivo evaluation of dolutegravir embryotoxicity: NTDs and yolk sac vascular abnormalities

Authors: Ruifang Ao, Ran Li, Zelin Li, Guicai Wu, Haoran Xu, Xuecong Wang, Jiayi Du, Xiaozheng Zhang, Jun Xie

Dolutegravir (DTG) disrupts mouse embryonic development in a dose-dependent manner, culminating in neural-tube defects (NTDs). Using whole embryo culture (WEC), mouse embryos at embryonic day 8.5 (E8.5) are cultured for 24–48 h with 8, 10, or 12 μM DTG. The results reveal that higher DTG concentrations dose-dependently disrupt yolk sac development and markedly increase the frequency of NTDs. In vivo NTD models are generated by intraperitoneally injecting DTG at a dose of 7.5 mg/kg, and the resulting embryos exhibit disrupted yolk sac blood circulation, embryonic growth restriction, and malformations. Mechanistic studies suggest that DTG contributes to NTDs by inducing apoptosis: DTG exposure activates the Nrf2-SOD1/CAT antioxidant axis, yet it culminates in increased apoptosis and suppressed proliferation, ultimately impairing yolksac vasculogenesis and neuralepithelial closure, thereby producing NTDs. This study provides new evidence for assessing the potential risk of DTG in embryonic development and highlights the need to re-evaluate its clinical safety in future applications.

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Combined ex vivo and in vivo evaluation of dolutegravir embryotoxicity: NTDs and yolk sac vascular abnormalities

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Original ResearchVol. 58, Issue 3 • pp. 649-662DOI: 10.3724/abbs.2025144

Exploring DNA topoisomerase II alpha in adrenocortical carcinoma through multi-omics analysis: a potential biomarker and therapeutic target

Authors: Jianming Lu, Pei Deng, Zhenjie Wu, Yuxiang Liang, Yangjia Zhuo, Yongding Wu, Yingke Liang, Jianheng Ye, Wenjie Xie, Zhouda Cai, Chao Cai, Jiahong Chen, Le Zhang, Junhong Deng, Weide Zhong, Jiaojiao Tang, Zhaodong Han

Adrenocortical carcinoma (ACC) is a rare but aggressive cancer. Recent studies identified DNA Topoisomerase II Alpha (TOP2A) as a potential biomarker for ACC, which can provide new avenues for targeted therapy and improve clinical outcomes. This study aims to elucidate the role of TOP2A in ACC by exploring its prognostic value and identifying inhibitors for ACC therapy. Utilizing RNA sequencing data, mutation data, and clinical information from The Cancer Genome Atlas (TCGA-ACC) and additional datasets from the Gene Expression Omnibus (GEO), differential expression and prognostic analyses are conducted to assess the significance of TOP2A in ACC. Immunohistochemistry and cell assays, including cell viability, colony formation, and transwell assays, are conducted to validate the oncogenic effects of TOP2A. The “IOBR” R package is used to examine the relationship between TOP2A expression and CD8+ T-cell infiltration. The CMap platform is used to identify potential TOP2A inhibitors. In vivo assays verify the therapeutic effect of TOP2A inhibitors on ACC. Our findings indicate that TOP2A is significantly overexpressed in ACC and is associated with poor prognosis. Immunohistochemistry and cell assays confirm the oncogenic role of TOP2A. Furthermore, distinct gene expression patterns related to different TOP2A expression levels are identified, influencing the response to immunotherapy. Potential inhibitors targeting TOP2A are discovered, and the therapeutic effects of resminostat and etoposide are confirmed via in vivo assays, suggesting new therapeutic strategies for ACC treatment. In conclusion, TOP2A serves as a crucial biomarker in ACC and is associated with adverse clinical outcomes and a diminished immune response. The identification of potential inhibitors against TOP2A opens new avenues for the development of targeted therapies for ACC patients.

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Exploring DNA topoisomerase II alpha in adrenocortical carcinoma through multi-omics analysis: a potential biomarker and therapeutic target

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Original ResearchVol. 57, Issue 3 • pp. 473-485DOI: 10.3724/abbs.2025010

Immunopathological characteristics and therapeutic effects of UC-MSCs in a pigeon breeder’s lung mouse model

Authors: Jingran Xu, Li Li, Yaping Zhou, Zulipikaer Abudureheman, Lexin Xue, Chao Wu, Xiaoguang Zou

Hypersensitivity pneumonitis (HP), including pigeon breeder’s lung (PBL), often progresses from acute inflammation to fibrosis, impairing lung function and limiting targeted therapeutic strategies. Mechanistic studies on PBL progression are limited by the lack of preclinical animal models and a predominant focus on patient data. This study explores the immunopathological characteristics of all stages of PBL in mice and evaluates the therapeutic potential of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) during the non-fibrotic stage. PBL models are created in A/J mice through tracheal instillation of pigeon dropping extract (PDE) protein powder. Different doses (0.4 × 106, 0.8 × 106, and 1.6 × 106 cells per animal) and frequencies (1–2 times) are administered to the model. The immunopathological characteristics of PBL and the therapeutic effects of UC-MSCs are assessed using micro-CT, pulmonary function, histopathology, cell counts in BALF, HYP levels, inflammatory factor levels, immunohistochemistry, and fibrosis marker expression in lung tissues. The results show that PDE exposure consistently impairs pulmonary function and increases the levels of inflammation and fibrosis markers as the disease progresses. Model mice experience non-fibrotic stages (acute inflammation) from days 0–36, mild fibrosis from days 37–77, and severe fibrosis from day 78 onwards. UC-MSCs, particularly at the highest dose (1.6 × 106 cells), effectively treat non-fibrotic PBL by improving pulmonary function (lung ventilation area recovers) and reducing inflammation and fibrosis. This study successfully establishes PBL mouse models reflecting both the acute (inflammatory) and chronic (fibrotic) stages, and UC-MSCs have the potential to delay fibrosis, providing new therapeutic options for PBL and other inflammation-induced lung fibrotic diseases.

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Immunopathological characteristics and therapeutic effects of UC-MSCs in a pigeon breeder’s lung mouse model

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Original ResearchVol. 58, Issue 4 • pp. 792-805DOI: 10.3724/abbs.2025150

Rapid detection of Escherichia coli in bloodstream infection via CRISPR-Cas9 engineered reporter phage T7::Nluc and microfluidic chip platform

Authors: Minwei Li, Zhiyun Hao, Jing Yan, Ximeng Chen, Hangyi Li, Chengbin Wang, Chi Wang

Rapid identification of pathogens responsible for bloodstream infection is critical for early intervention and effective treatment. Reporter phages, which are known for their exceptional sensitivity and specificity in pathogen detection, have garnered significant interest. In this study, we systematically evaluate phage genome editing strategies that combine homologous recombination with the CRISPR-Cas9 system. We investigate the impacts of homologous arm length, sgRNA activity, target site, and plasmid interactions on editing efficiency. Our results demonstrate that successful genome editing depends on both sufficient cleavage pressure and optimal homologous arm length, particularly when using low-activity sgRNAs. On the basis of these findings, we develop a highly efficient gene editing strategy TPMSR (triple-plasmid-mediated synchronous recombination) that overcomes the limitations of conventional methods that rely on high-activity sgRNA and restricted editing sites. Using the TPMSR strategy, we integrate the Nluc gene into phage T7, generating the reporter phage T7::Nluc, which is then incorporated into a microfluidic chip. Validation with 51 clinical isolates demonstrates outstanding sensitivity, specificity, and accuracy in detecting Escherichia coli in blood within 1.5 h at concentrations less than 30 CFU/mL. This study presents a robust strategy for phage genome engineering and develops a promising method for the rapid diagnosis of bloodstream infections caused by E. coli.

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Rapid detection of Escherichia coli in bloodstream infection via CRISPR-Cas9 engineered reporter phage T7::Nluc and microfluidic chip platform

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Original ResearchVol. 58, Issue 3 • pp. 574-583DOI: 10.3724/abbs.2025135

Targeting USP2 induces degradation of PML-RARα with or without drug-resistant mutations in acute promyelocytic leukemia

Authors: Jie Zhang, Wenxuan Wu, Yun Wang, Youping Zhang, Yingying Wang, Wenhui Bai, Zhenge Zhang, Chujiao Zhu, Yunzhao Wu, Ziwei Zhang, Li Yang, Hu Lei, Hanzhang Xu, Li Zhou, Yingli Wu

Despite the high efficacy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL), approximately 10%–20% of patients develop drug resistance due to mutations in PML-RARα and other factors. Here, we find that inhibition of USP2 with ML364 or USP2 silencing reduces PML-RARα protein levels in both ATRA-sensitive and ATRA-resistant APL cells, and this effect is reversed by proteasome inhibition. Conversely, USP2 overexpression enhances PML-RARα stability. Mechanistically, USP2 interacts with and deubiquitinates PML-RARα, including its drug-resistant mutants. Consistent with PML-RARα degradation, ML364 treatment significantly induces apoptosis in APL cell lines and primary leukemia cells. In conclusion, this study identifies USP2 as a novel deubiquitinating enzyme for PML-RARα and highlights USP2 inhibition as a potential therapeutic strategy for APL with PML-RARα mutations.

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Targeting USP2 induces degradation of PML-RARα with or without drug-resistant mutations in acute promyelocytic leukemia

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Original ResearchVol. 57, Issue 4 • pp. 646-655DOI: 10.3724/abbs.2025027

Iron overload mediates cytarabine resistance in AML by inhibiting the TP53 signaling pathway

Authors: Yan Jia, Ling Li, Ying Li, Xunxun Zhu, Haiyan Wang, Bin Xu, Qiuping Li, Hao Zhang

Currently, chemotherapy remains the primary treatment for acute myeloid leukemia (AML). Drug resistance in AML cells is a critical factor contributing to the failure of chemotherapy remission and subsequent relapse. Iron overload frequently occurs in AML patients because of hematopoietic suppression or supportive blood transfusion therapy. Previous studies have indicated that iron overload may promote the progression of AML; however, the underlying mechanisms remain unclear. Our results demonstrate that, compared with TP53-wild-type AML cells, TP53-mutant AML cells exhibit increased resistance to cytarabine-induced cytotoxicity. Moreover, reducing TP53 expression in wild-type AML cells diminishes their sensitivity to cytarabine. The TP53 signaling pathway is essential for mediating cytarabine-induced apoptosis in AML cells. In this study, an iron overload model in AML cells via the use of ferric citrate is constructed. Our data indicate that iron overload can suppress the TP53/BCL2/BAX signaling pathway, counteracting cytarabine-induced apoptosis. In TP53 wild-type AML cells, TFR1 participates in iron-mediated resistance to cytarabine by regulating the entry of iron into the cells. These findings provide a foundation for further exploration of the molecular mechanisms involved in AML resistance to cytarabine.

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Iron overload mediates cytarabine resistance in AML by inhibiting the TP53 signaling pathway

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Original ResearchVol. 58, Issue 3 • pp. 700-703DOI: 10.3724/abbs.2025104

A novel method to increase transgene expression and the stability of gene therapy-associated episomal vectors

Authors: Xi Zhang, Rui Liu, Zimeng Han, Zihan Guo, Mengying Ji, Wen Wang, Yanlong Jia, Tianyun Wang, Xiaoyin Wang

Non-viral episomal vectors offer a safe and attractive alternative to viral and integrated vectors by avoiding insertional mutagenesis and position effects, making them ideal expression vectors for gene therapy. The first non-viral episomal vector, pEPI-1, which is based on the full-length scaffold/matrix attachment region (S/MAR), was established by Piechaczek et al. The full-length S/MAR element interacts with the nuclear matrix via the matrix protein, e.g. SAF-A, thereby maintaining mitotic stability and transgene expression. Several strategies, including optimization of the vector backbone and promoter and incorporation of chromatin-modifying elements, have been used to increase expression levels and stability. In our previous work, we constructed the novel vector pEGFP-C1-M on the basis of S/MAR characteristic motifs (only 375 bp). This vector, which is shorter than the prototype episomal vector pEPI-1, resulted in relatively higher transgene expression. Building on the pEGFP-C1-M vector, we further constructed the episomal vector pEMEα with the EF-1α promoter and demonstrated that pEMEα maintained higher transgene expression, stability and copy number. The transgene expression levels of episomal vectors are correlated with gene copy number, that is, the number of plasmid episomes on the host cell chromosome. Previous studies have shown that the episomal maintenance of pEPI-1 vectors is mediated primarily by SAF-A. While the role of SAF-A in maintaining mammalian pEPI-1 episomal vectors has been well established, it remains unknown whether the overexpression of SAF-A promotes transgene expression and stability and whether the 375 bp MAR characteristic sequence retains its interaction with SAF-A. In the present study, we first evaluated whether transgene expression is positively correlated with the expression level of SAF-A. The non-viral episomal vector pEMEα was used as the gene of interest (GOI) vector and was subsequently transfected into CHO-K1 cells using the Lipofectamine 2000 reagent. The cells were cultured in medium containing 800 μg/mL geneticin (G418) 48 h post-transfection, and the G418 concentration was then reduced to 400 μg/mL to obtain monoclonal cell lines using the limiting dilution method. Five monoclonal cell clones were selected, and the eGFP expression levels, measured as the mean fluorescence intensity (MFI), were (6.5 ± 1.0) × 104, (6.8 ± 0.9) × 104, (7.0 ± 1.4) × 104, (23.5 ± 1.2) × 104 and (14.9 ± 0.17) × 104 for Clones 1–5, respectively. qPCR analysis of Clones 1–5 revealed that the relative mRNA levels of SAF-A and eGFP were 0.16 ± 0.13, 0.43 ± 0.11, 0.46 ± 0.23, 2.17 ± 0.41, 1.78 ± 0.15 and 0.51 ± 0.16, 0.71 ± 0.12, 1.05 ± 0.09, 2.47 ± 0.14, and 1.86 ± 0.10, respectively. Our results indicated that eGFP mRNA and protein expression levels are positively correlated with SAF-A mRNA level. To further verify the relationship between SAF-A expression and transgene expression, two shRNA plasmids targeting SAF-A (shRNA1: 5′-GCCACCTGTTGAAGAAGAAGA-3′, and shRNA2: 5′-GCTGGAGGAAGAGCTTCTTAT-3′) which were obtained from Shanghai GenePharma Co., Ltd. were designed and transfected into stable cell pools with the pEMEα vector. qPCR analysis revealed that the relative SAF-A mRNA levels in the shRNA1 and shRNA2 vectors were 0.47 ± 0.01 and 0.19 ± 0.02, respectively, indicating successful downregulation of SAF-A expression. Moreover, flow cytometry and qPCR revealed that, compared with those in the control group, the relative protein and mRNA levels of eGFP were reduced by 0.47- and 0.23-fold, and 0.47- and 0.40-fold in the pools of cells transfected with the shRNA1 and shRNA2 vectors, respectively. On the basis of the above results, the SAF-A overexpression vector pIRES-SAF-A was constructed and transfected into CHO-K1 cells, and the cells were cultured in blasticidin-containing medium 48 h after transfection to obtain stable cell pools. The stable cell pools overexpressing SAF-A were subsequently transfected with the pEMEα vector. Stable cell pools coexpressing SAF-A and GOI were selected, and the relative mRNA levels of SAF-A and eGFP were analyzed. qPCR analysis revealed that the relative mRNA levels of SAF-A and eGFP in the pools of cells overexpressing SAF-A were 2.69-fold and 2.05-fold higher than those in the control group, respectively. Flow cytometry also revealed a 2.07-fold increase in MFI in stable cell pools overexpressing SAF-A compared with the control group. To assess the long-term stability of transgene expression, we measured the MFI in st

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A novel method to increase transgene expression and the stability of gene therapy-associated episomal vectors

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Original ResearchVol. 58, Issue 3 • pp. 584-594DOI: 10.3724/abbs.2025146

FSCN1-mediated hepatic gluconeogenesis is indispensable for neonatal mice survival

Authors: Xiangxiang Liu, Yuanzhao Hu, Liangwei Wu, Yiwen Zhang, Lei Sang, Yake Gao, Lei He, Wenyong Xiong, Shengyu Yang, Jianwei Sun

Actin-bundling protein Fascin1 (FSCN1) is encoded by the Fscn1 gene and is crucial for cytoskeletal remodeling and cellular migration. Although a previous study linked Fscn1 deficiency to neonatal lethality in mice, the underlying metabolic mechanism remains unclear. In this study, we report that systemic knockout (KO) of Fscn1 leads to 52.2% mortality within 24 h post-birth, accompanied by severe hypoglycemia in KO pups compared with their littermates. Remarkably, this lethality is fully rescued by oral glucose administration, indicating a glucose supply-dependent survival mechanism. Surviving Fscn1-KO neonates display persistent developmental deficits, including growth retardation and depleted lipid stores, despite intact canonical insulin-regulated hepatic gluconeogenic pathways. Transcriptomic profiling of P0 livers reveals that Fscn1 loss predominantly disrupts metabolic pathways, with the glycerol phosphate shuttle being the most significantly downregulated module. Mechanistically, Fscn1-KO livers exhibit markedly reduced protein levels of glycerol-3-phosphate dehydrogenase isoforms (GPD1/GPD2), key enzymes bridging glycolysis and gluconeogenesis. Consistently, glycerol tolerance tests demonstrate impaired glycerol-to-glucose conversion in Fscn1-KO mice, confirming defective glycerol-driven gluconeogenesis. Our findings establish FSCN1 as a novel cytoskeletal-metabolic integrator essential for neonatal survival by sustaining hepatic glucose production from glycerol, thus revealing an unexpected role of actin dynamics in coordinating metabolic adaptation during early postnatal development.

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FSCN1-mediated hepatic gluconeogenesis is indispensable for neonatal mice survival

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Original ResearchVol. 58, Issue 3 • pp. 595-609DOI: 10.3724/abbs.2025130

Autophagy-dependent sensitization effects of PARP inhibitors on recurrent nasopharyngeal carcinoma treated with carbon ion and photon irradiation

Authors: Ziyu Le, Haojiong Zhang, Li Chen, Wanzun Lin, Qingting Huang, Shikai Geng, Wei Hu, Huaiyuan Chen, Fangzhu Wan, Xingyu Liu, Jiyi Hu, Fengtao Su, Jiade J. Lu, Lin Kong

Tumor radioresistance and severe toxicity make reirradiation for recurrent nasopharyngeal carcinoma (NPC) a significant clinical challenge. This study aims to investigate the ability of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib to sensitize recurrent NPC cells irradiated with photon or carbon ion (C-ion), and to explore the underlying mechanism of the synergistic promotion of cell death by olaparib and ionizing radiation. The results show that olaparib has significant X-ray and C-ion radiosensitization effects on recurrent NPC cells and the associated HK-RR photon-resistant model. Radiation, particularly C-ion exposure, induces a homologous recombination (HR)-deficient gene signature in HR-proficient NPC cells, potentially increasing their sensitivity to PARP inhibition. C-ion and X-ray irradiation induces similar modes of cell death, and multiple cell death pathways [including apoptosis, necrosis, ferroptosis, senescence, and autophagic cell death (ACD)] contribute to the cytotoxic effects of radiation combined with olaparib, with ACD being the dominant pathway. Both the pharmacological and genetic inhibition of autophagy significantly attenuate the radiosensitization effect of olaparib. In conclusion, olaparib effectively sensitizes recurrent NPC cells to both X-ray irradiation and C-ion irradiation, with autophagy playing a central role in mediating this effect.

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Autophagy-dependent sensitization effects of PARP inhibitors on recurrent nasopharyngeal carcinoma treated with carbon ion and photon irradiation

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Original ResearchVol. 58, Issue 3 • pp. 541-550DOI: 10.3724/abbs.2025179

Pervasive environmental contaminant acrolein compromises myocardial geometry and function through the induction of cuproptosis

Authors: Xiaohu Wang, Shuyi Zhu, Yipin Zhao, Xinlong Di, Lingfei Cao, Russel J. Reiter, Emily Y. He, Yuan Zhou, Bonglee Kim, Yong Cheng, Jun Ren

Acrolein, a highly reactive α,β-unsaturated aldehyde found in cigarette smoke, automobile exhaust, industrial emissions, combustion byproducts, cooking and cyclophosphamide chemotherapy, has raised serious health concerns, although the precise mechanism remains unclear. This study is designed to examine the impact of this pervasive environmental pollutant on myocardial geometry and function alongside the underlying cellular mechanisms. Adult C57BL/6 mice are challenged with acrolein (2.5 mg/kg/day, i.p., for 20 days) prior to the evaluation of myocardial geometry and function. Acrolein exposure evokes evident cardiac remodeling (interstitial fibrosis), compromised echocardiographic (enlarged LVESD, compromised ejection fraction and fractional shortening), cardiomyocyte contractile and intracellular Ca2+ capacities [decreased peak shortening, maximal velocity of shortening and relengthening (±dL/dt), and electrically stimulated rise in Fura-2 fluorescence intensity (ΔFFI), prolonged time-to-90% relengthening (TR90) and intracellular Ca2+ decay], accompanied by overt mitochondrial damage (ultrastructure, aconitase and mitochondrial protein contents), free radical buildup, apoptosis (Bax, Caspase-3, and Bcl2) and cuproptosis (upregulated SLC31A1, DLAT and FDX1), downregulated the Fe-S cluster proteins ACO2 and NDUFS8 alongside unchanged ATP7A and the ferroptosis markers GPX4 and SLC7A11. The levels of copper-sensing protein metal response element binding transcription factor 2 (MTF2), but not MTF1, are increased by acrolein insult. CB-DOCK2 analysis predicts an interaction between acrolein and the MTF2 dimer within its DNA-binding regions. In vivo administration of the cuproptosis inhibitor tetrathiomolybdate (TTM), the mitochondrial antioxidant mitoTEMPO or the nonselective MTF2 inhibitor actinomycin D alleviates acrolein-evoked cardiomyocyte dysfunction (decreased PS, ±dL/dt, and prolonged TR90). These findings indicate that acrolein evoked cardiac functional anomalies possibly through MTF2-related control of cuproptosis.

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Pervasive environmental contaminant acrolein compromises myocardial geometry and function through the induction of cuproptosis

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Original ResearchVol. 58, Issue 3 • pp. 681-690DOI: 10.3724/abbs.2025228

SOX2 transactivates NRF2 to promote carboplatin resistance in lung squamous cell carcinoma

Authors: Hanfei Gao, Chaomei Li, Jie Sun, Liyuan Deng, Jia Li, Zhiqiang Wu, Hu Chen

Lung squamous cell carcinoma (LUSC) remains a major therapeutic challenge because of its pronounced resistance to chemotherapy, particularly carboplatin. In this study, we investigate the role of SOX2, a lineage-survival oncogene, in mediating carboplatin resistance in LUSC. We demonstrate that SOX2 is highly expressed in LUSC and is significantly associated with poor prognosis. Our results show that SOX2 directly transactivates the expression of NRF2, a master regulator of cellular redox homeostasis, thereby increasing glutathione (GSH) synthesis and protecting cells from carboplatin-induced oxidative stress. Pharmacological or genetic inhibition of NRF2 effectively abrogates SOX2-mediated carboplatin resistance both in vitro and in vivo, resensitizing LUSC cells to chemotherapy. These findings highlight SOX2 as a critical redox regulator that modulates NRF2 signaling to promote carboplatin resistance in LUSC. The identification of the SOX2-NRF2 axis as a potential therapeutic target suggests that NRF2 inhibition may represent a promising strategy to overcome chemoresistance in LUSC.

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SOX2 transactivates NRF2 to promote carboplatin resistance in lung squamous cell carcinoma

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Original ResearchVol. 58, Issue 2 • pp. 216-230DOI: 10.3724/abbs.2025123

Unveiling the multifaceted roles of extracellular vesicles in cancer: insights from molecular imaging and engineering strategies

Authors: Yuqin Teng, Gang Huang, Hao Yang

Extracellular vesicles (EVs), a class of nanoscale, membrane-bound vesicles secreted by various cell types, have emerged as rapidly advancing fields of research in recent years. This heterogeneous vesicle is a versatile carrier system for a variety of biomolecules, including proteins, nucleic acids, and metabolites. EVs play pivotal roles in intercellular communication, immune regulation, and disease pathogenesis, with particular implications for cancer biology. On the one hand, EVs promote tumor progression and metastasis by facilitating communication between cancer cells and their microenvironment. On the other hand, EVs carry noncoding RNAs, such as miRNAs and other regulatory RNAs, which directly modulate immune cell function or exert antitumor effects by influencing cancer cell proliferation and apoptosis. In addition to their biological roles, EVs show great potential as drug delivery systems because of their ability to be effectively taken up by target cells and stably deliver therapeutic payloads. In the context of cancer therapy, natural EVs demonstrate inherent therapeutic potential, particularly in targeting highly metabolically active organs. Furthermore, engineered EVs, which serve as both therapeutic vehicles and molecular imaging probes, have demonstrated significant potential for cancer theranostics. This review focuses on elucidating the dynamic changes and biological functions of EVs in vivo, with the aim of exploring the translational potential of EV-based molecular imaging and tracing technologies in cancer treatment. This work seeks to provide critical insights that may enhance the precision and efficacy of tumor therapies, offering a foundation for future clinical applications.

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Unveiling the multifaceted roles of extracellular vesicles in cancer: insights from molecular imaging and engineering strategies

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Original ResearchVol. 57, Issue 4 • pp. 676-678DOI: 10.3724/abbs.2025009

Head-to-head: IL-21 triumphs over IL-15 in NK cell therapy for glioblastoma

Authors: Jake C. Miller, Bihui Cao, Jia Shen

Glioblastoma (GBM) is the most aggressive primary brain tumor. Despite current treatment options, including surgery, radiotherapy, and temozolomide chemotherapy, patient outcomes remain poor, with a median survival of less than 15 months. This dire prognosis highlights an urgent need to develop more effective therapies. Natural Killer (NK) cells, a key component of the innate immune system, are being actively investigated as a potential treatment for GBM. NK cells continually surveil their environment for abnormal cells, including GBM stem cells (GSCs), which are central to GBM progression and recurrence. While NK cells exhibit some ability to target GSCs independently, their activity can be significantly amplified by inflammatory cytokines. One such cytokine, interleukin-15 (IL-15), is critical for NK cell survival and function, making it a focal point of research in GBM immunotherapy. However, IL-15 is not without complications; it has been associated with toxicity, and its overexpression has been shown to induce leukemia in mouse models, potentially due to heightened inflammatory responses. These issues make IL-15 overexpression a less-than-ideal strategy for enhancing NK cell anti-tumor activity. To address these limitations, Shanley and colleagues recently identified interleukin-21 (IL-21) as a promising alternative to IL-15 in their study published in Cancer Cell. Their findings revealed that IL-21 overexpression provides prolonged NK cell activity, even under repeated exposure to GSCs, and demonstrates efficacy both in vitro and in vivo. Importantly, IL-21-expressing NK cells showed no significant toxicity when injected into mouse brains. These results suggest that IL-21 could represent a safer and more effective cytokine for boosting NK cell-mediated GBM therapy.

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Head-to-head: IL-21 triumphs over IL-15 in NK cell therapy for glioblastoma

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Original ResearchVol. 58, Issue 2 • pp. 353-368DOI: 10.3724/abbs.2025108

METTL3-mediated m6A modification facilitates Nectin-4-induced VNN1 upregulation and promotion of ESCC progression

Authors: Yuanfeng Long, Hang Yang, Ruolan Zhang, Quanneng Zhao, Mi Yang, Guiqin Song, Kang Liu

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. N6-methyladenosine (m6A) RNA modification plays a role in tumorigenesis, but its contributions to ESCC and the regulation of cell adhesion molecules such as Nectin-4 are not fully elucidated. In this study, we investigate the role and the regulatory mechanisms of Nectin-4 in ESCC, particularly regarding the influence of m6A modification and its downstream metabolic effects. Our study demonstrates that methyltransferase-like protein 3 (METTL3) enhances Nectin-4 mRNA stability and expression through m6A methylation in ESCC, as validated by actinomycin D assay, MeRIP-qPCR, and dual-luciferase reporter assay. Both METTL3 and Nectin-4 are highly expressed in ESCC tissues and promote malignant phenotypes such as proliferation, migration, and invasion. Further analysis identifies pantothenate esterase 1 (VNN1) as a downstream target of Nectin-4, mediating the oncogenic effects of the METTL3/Nectin-4 axis and promoting the biosynthesis of pantothenic acid and coenzyme A, thus driving ESCC progression. By integrating transcriptomic data, this study elucidates a key pathogenic mechanism in which the METTL3/Nectin-4/VNN1 axis regulates metabolic reprogramming to promote ESCC development. These findings provide new insights into the molecular pathology of ESCC and offer potential biomarkers and therapeutic targets for early screening, prognosis, and precision treatment for ESSC.

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METTL3-mediated m6A modification facilitates Nectin-4-induced VNN1 upregulation and promotion of ESCC progression

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Original ResearchVol. 56, Issue 3 • pp. 356-365DOI: 10.3724/abbs.2023246

HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells

Authors: Xinxin Kou, Xiaoxia Yang, Zheng Zhao, Lei Li

This corrigendum corrects the affiliation of the authors in the original article. The affiliation has been changed from 'Cancer Hospital Affiliated to Zhengzhou University' to 'The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital'.

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HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells

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Original ResearchVol. 58, Issue 2 • pp. 437-452DOI: 10.3724/abbs.2025197

The prognostic marker NRIP1 is associated with tumor progression and immune infiltration in acute myeloid leukemia

Authors: Xunxun Zhu, Mingyan Zhang, Jingjing Zhang, Yanling Tao, Hao Zhang

Acute myeloid leukemia (AML) is a clinically aggressive hematologic malignancy characterized by high relapse rates and treatment resistance, highlighting the need for novel biomarkers to improve clinical outcomes. In this study, we explore the roles of nuclear receptor-interacting protein 1 (NRIP1) in AML, focusing on its associations with tumor progression and immune infiltration. Analysis of public AML gene expression datasets reveals that NRIP1 expression is significantly increased in AML patients. Those with high NRIP1 expression have markedly shorter overall survival than those with low expression. Furthermore, NRIP1 expression is significantly associated with the infiltration of diverse immune cells, including B cells, dendritic cells, T cells, mast cells, eosinophils, and T helper cells, suggesting that NRIP1 may be a regulator of immune cell infiltration. Functional enrichment analysis indicates that NRIP1 and its interacting partners are involved in tumorigenesis, immune microenvironment remodeling, and metabolic reprogramming. Survival analysis confirms the prognostic value of NRIP1. Importantly, functional validation in AML cell lines confirms that NRIP1 knockdown suppresses proliferation and induces apoptosis. Our study identifies NRIP1 as a multifaceted regulator that promotes AML by driving tumor progression, regulating immune cell infiltration, and modulating ferroptosis, highlighting its role as a novel prognostic biomarker.

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The prognostic marker NRIP1 is associated with tumor progression and immune infiltration in acute myeloid leukemia

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Original ResearchVol. 58, Issue 2 • pp. 258-274DOI: 10.3724/abbs.2025075

FGF8 promotes lipid droplet accumulation via the FGFR1/p-p38 axis in chondrocytes

Authors: Minglei Huang, Haoran Chen, Jieya Wei, Caixia Pi, Mengmeng Duan, Xiaohua Pu, Zhixing Niu, Siqun Xu, Shasha Tu, Sijun Liu, Jiazhou Li, Li Zhang, Yang Liu, Hao Chen, Chunming Xu, Jing Xie

Chondrocytes store lipids in the form of lipid droplets (LDs) and maintain cartilage lipid metabolic homeostasis by consuming or regenerating LDs. This modulation is largely mediated by a series of biochemical factors. Fibroblast growth factor 8 (FGF8) is one of the most important factors involved in the proliferation, differentiation, and migration of chondrocytes and has attracted increasing attention in the physiology and pathology of cartilage. However, the effect of FGF8 on LD accumulation in chondrocytes remains unclear. This study aims to elucidate the role of FGF8 in LDs and explore the underlying biomechanism involved. The results reveal that FGF8 promotes LD accumulation in chondrocytes by upregulating perilipin1 (Plin1) expression. FGF8 activates the cytoplasmic p-p38 signaling pathway via fibroblast growth factor receptor 1 (FGFR1) to increase LD accumulation in chondrocytes. Subsequent experiments with siRNAs and specific inhibitors further confirm the importance of the FGFR1/p38 axis for LD accumulation in chondrocytes exposed to FGF8. The results increase our understanding of the role of FGF8 in the lipid metabolic homeostasis of chondrocytes and provide insights into the physiology and pathology of cartilage.

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FGF8 promotes lipid droplet accumulation via the FGFR1/p-p38 axis in chondrocytes

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Original ResearchVol. xx, Issue xx • pp. xx–xxDOI: 10.3724/abbs.2026084

HDAC6 promotes osimertinib resistance evolution in non-small cell lung cancer by activating EGFR degradation through the ubiquitin-proteasome pathway

Authors: Cheng Yang, Danlei Xu, Zifang Zhu, Zhen Kang, Kangkang Ren, Yihan Yang, Ye Huang, Wei Zhang, Jun Che, Xinping Xu, Xiaolei Li

Osimertinib is the standard first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR-sensitive mutations. However, drug resistance inevitably develops, highlighting the critical need for strategies to overcome this resistance and prolong therapeutic efficacy. Understanding the mechanisms underlying drug resistance is essential, and drug-resistant cell models serve as valuable tools for investigating acquired resistance. In this study, we establish an osimertinib resistance evolution model in vitro by continuous high-dose drug induction and identify cell lines exhibiting “permanent” resistance to osimertinib (osimertinib resistant, OR). Transcriptome sequencing (RNA-seq), gain- and loss-of-function assay, including lentiviral-mediated overexpression and RNAi knockdown, pharmacological inhibition, and protein degradation analysis reveal significant alterations in genes associated with epigenetic regulation, notably a marked upregulation of histone deacetylase 6 (HDAC6) in OR cells. Knockdown of HDAC6 or pharmacological inhibition of HDAC6 restores the sensitivity of OR cells to osimertinib, whereas overexpression of HDAC6 in sensitive cells reduces drug efficacy and accelerates the onset of resistance. Furthermore, we find that HDAC6 upregulation promotes EGFR degradation, thereby contributing to resistance. Collectively, our findings demonstrate the utility of drug resistance evolution models in identifying key resistance factors. HDAC6 plays a pivotal role in osimertinib resistance, and targeting HDAC6 may represent a novel therapeutic strategy to overcome resistance and enhance treatment efficacy.

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HDAC6 promotes osimertinib resistance evolution in non-small cell lung cancer by activating EGFR degradation through the ubiquitin-proteasome pathway

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Original ResearchVol. 58, Issue 2 • pp. 396-405DOI: 10.3724/abbs.2025159

MSCs attenuate airway remodeling in HDM-induced asthma by inhibiting the Timp1-Wnt2b axis

Authors: Kai Yu, Xinyu Feng, Rong Zhang, Jian Fan, Jiaying Yuan, Yan Shang, Jiayi Zhao

MSCs have demonstrated their unique therapeutic potential in early clinical trials for a variety of respiratory diseases in recent years, but their use in the treatment of asthma has rarely been reported. In this study, a chronic murine asthma model that is more similar to clinical asthma is constructed via sustained HDM induction for 70 days, followed by treatment via tail vein injection of MSCs after modeling. The mechanism by which MSCs alleviate airway remodeling is investigated via RNA-seq. The airways on the day following treatment are used to screen for transcriptomic changes resulting from the MSC treatment under study, filtering for differentially expressed genes (DEGs), identifying their enrichment pathways, and finally confirming the DEGs gained via western blot analysis. After HDM treatment, airway remodeling is reversed, asthma and the HIF-1 signaling pathway are inhibited, and the expression levels of Timp1 and Wnt2b in the fibrosis pathway are also significantly decreased. STRING analysis reveals a reciprocal interaction in their expression, which is also confirmed by western blot analysis. To verify whether MSCs alleviate airway remodeling by inhibiting Timp1, we construct MSCs overexpressing Timp1 and evaluate their effects in vitro and in vivo. The ability of MSCs to alleviate airway remodeling is reversed after Timp1 is overexpressed. These findings demonstrate that MSCs alleviate asthma-induced airway remodeling by inhibiting the Timp1-Wnt2b axis.

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MSCs attenuate airway remodeling in HDM-induced asthma by inhibiting the Timp1-Wnt2b axis

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Original ResearchVol. 58, Issue 2 • pp. 231-244DOI: 10.3724/abbs.2025175

The dual role of whole-genome duplication: biological mechanisms, functional consequences, and detection advances

Authors: Yawei Song, Jiajie Yang, Shuheng Wu, Wei Wu

Whole-genome duplication (WGD) represents an evolutionarily conserved process occurring in prokaryotes, eukaryotes, and somatic mammalian tissues. While developmentally programmed WGD supports normal tissue regeneration, unscheduled WGD drives chromosomal instability and oncogenic progression in cancer. Recent studies have clarified dual roles of WGD across physiological homeostasis and disease pathogenesis. Here, we review the prevalence of WGD, the molecular mechanisms driving its major causes and its biological consequences. In addition, we highlight recent advancements in WGD detection, including both conventional cytogenetic techniques and newly developed high-throughput sequencing approaches. The integration of multi-omics and machine learning further improves ploidy analysis, particularly in cancer research. Together, these insights establish WGD as a critical regulator of development, regeneration, and disease and underscore the importance of emerging computational and sequencing tools for its precise characterization.

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The dual role of whole-genome duplication: biological mechanisms, functional consequences, and detection advances

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026049

circ_0006156 promotes esophageal squamous cell carcinoma progression via activation of the TGFβ/Smad pathway

Authors: Zhanpeng Tang, Jian Li, Rongyang Li, Luyuan Ma, Renchang Zhao, Zhenguo Sun, Hui Tian

Esophageal squamous cell carcinoma (ESCC) represents a common malignancy of the digestive system. Circular RNAs (circRNAs) are a distinct class of single-stranded non-coding RNAs that are essential in the progression of various tumors given that they can act as microRNA (miRNA) sponges in a manner similar to that of mRNAs. In this study, circ_0006156 is screened to be highly expressed in ESCC tissues through high-throughput sequencing and quantitative real-time polymerase chain reaction. Subsequent in vitro and in vivo experiments are conducted to validate its biological functions. Furthermore, the regulatory relationships among circ_0006156, miR-202-5p, and TGFBR1 are investigated using RNA antisense purification, miRNA sequencing, RNA immunoprecipitation, fluorescence in situ hybridization, dual-luciferase reporter assay, and bioinformatics analyses. The results show significant overexpression of circ_0006156 in ESCC tissues, with relatively shorter overall survival observed in patients with high circ_0006156 expression. circ_0006156 is further identified to directly bind to miR-202-5p. miR-202-5p inhibits the proliferation, migration, and invasion of ESCC cells in vitro and partially rescues the effects induced by circ_0006156. Consistent results are reported by subcutaneous xenograft tumor experiments in nude mice. In addition, circ_0006156 is confirmed to act as an endogenous sponge for miR-202-5p, which results in a relieved suppression of its target gene TGFβR1. In summary, circ_0006156 can regulate TGFβR1 expression by sponging miR-202-5p, which may further activate the TGFβ/Smad pathway and promote ESCC progression. Collectively, circ_0006156 functions as a novel oncogenic RNA in ESCC and may serve as a potential tumor marker.

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circ_0006156 promotes esophageal squamous cell carcinoma progression via activation of the TGFβ/Smad pathway

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Original ResearchVol. 58, Issue 2 • pp. 245-257DOI: 10.3724/abbs.2025086

Gankyrin-deficiency reprograms intrahepatic glucose and lipid metabolism to delay liver regeneration

Authors: Yitian Liu, Yiwei Sun, Lv Jin, Ying Xu, Bibo Wang, Ting Yu, Xiaofei Wei, Jing Xu, Yating Wei, Shuai Yang, Min Yu, Hongyang Wang, Yao Chen

Liver regeneration is a critical adaptive response to hepatic injury, requiring precise metabolic reprogramming to meet the energetic and biosynthetic demands of proliferating hepatocytes. While the oncoprotein Gankyrin is well-established as a promoter of liver fibrosis and hepatocarcinogenesis, its role in metabolic adaptations underlying liver regeneration remains unclear. In this study, we demonstrate that Gankyrin deficiency in the liver (Gank△Hep/Y) induces hepatic hypertrophy and aberrant glycogen accumulation. Gankyrin expression is significantly upregulated after partial hepatectomy (PHx), whereas Gank△Hep/Y -PHx mice exhibit impaired liver regeneration. This impairment is marked by a delayed restoration of the liver-to-body weight ratio, blunted glycogenolysis, and reduced fatty acid uptake. Mechanistically, Gankyrin activates Pygl and Cd36, key regulators of glycogenolysis and lipid uptake, respectively. Pharmacological inhibition of PYGL activity retards liver regeneration. Furthermore, we identify a novel interaction between Gankyrin and FOXO1, wherein Gankyrin promotes FOXO1 ubiquitination and subsequent proteasomal degradation. This Gankyrin-dependent suppression of FOXO1 leads to the transcriptional upregulation of Pygl and Cd36, thereby fueling hepatocyte proliferation. Collectively, our findings reveal Gankyrin as a master regulator of liver regeneration, integrating metabolic reprogramming with proliferative signaling through the FOXO1-PYGL/CD36 axis. These insights not only elucidate the mechanistic underpinnings of liver regeneration but also unveil the therapeutic potential of targeting the Gankyrin/FOXO1 pathway to mitigate hepatic insufficiency and enhance regenerative capacity in clinical settings.

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Gankyrin-deficiency reprograms intrahepatic glucose and lipid metabolism to delay liver regeneration

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Original ResearchVol. 58, Issue 2 • pp. 369-382DOI: 10.3724/abbs.2025103

IKZF3 promotes gastric cancer progression via Hedgehog signaling activation and is targetable by SANT-1

Authors: Muhammad Ali, Shantanu Baral, Jun Ren, Liuhua Wang, Bin Liu, Sen Wang, Daorong Wang

Elevated expression of Aiolos family zinc finger 3 (IKZF3), a transcription factor crucial for lymphocyte maturation, is observed in hematological cancers. However, its role in gastric cancer (GC) remains unclear. We detect the increased IKZF3 levels in GC tissues using immunohistochemical, qRT-PCR and western blot analysis. The function of IKZF3 in GC cells is further studied through CCK-8, Transwell, colony formation, scratch wound healing, and flow cytometry assays. IKZF3 overexpression significantly promotes GC cell invasion, migration, and proliferation, whereas IKZF3 knockdown induces cell cycle arrest at the G1/S phase. Flow cytometry confirms these alterations in cell cycle dynamics. Using the JASPAR database, we determine that IKZF3 binds to the SMO promoter region, thereby activating SMO expression. Notably, the SMO inhibitor SANT-1 effectively reverses IKZF3-mediated effects. Furthermore, IKZF3 promotes GC tumor growth in xenograft models. Our findings highlight the pivotal role of IKZF3 in GC progression by modulating SMO expression and activating the Hedgehog signaling pathway. Therapeutically, targeting IKZF3 with SANT-1 is promising for mitigating GC proliferation and invasion. This study provides insights into potential therapeutic approaches targeting IKZF3 for GC treatment.

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IKZF3 promotes gastric cancer progression via Hedgehog signaling activation and is targetable by SANT-1

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Original ResearchVol. 58, Issue 2 • pp. 458-462DOI: 10.3724/abbs.2025118

Zinc finger protein 154 inhibits the growth and metastasis of cervical cancer cells through inhibiting Wnt/β-catenin signaling by upregulating NLK

Authors: Chulan Yang, Hongyu Zhao, Jing Tuo, Wei Zhao, Zhiwei Zhang, Zemin Pan, Lianghai Wang, Haixuan Zhao, Songhua Zhao, Hongtao Li

Cervical cancer represents a significant global health concern affecting women. The global cancer burden data published by the World Health Organization’s International Agency for Research on Cancer (IARC) indicated that the incidence and mortality of cervical cancer were the fourth most common malignancy in females worldwide in 2022 [1]. DNA methylation is recognized as a pivotal epigenetic mechanism for gene silencing, which may accumulate with disease severity [2]. Hypermethylation has been discovered in several tumor suppressor gene (TSG) promoters in human cancers, and further understanding of gene silencing mechanisms has led more studies to consider epigenetic disruption as an important mechanism leading to the silencing of tumor suppressor genes in tumor development [3]. Recent studies have reported that methylation of the zinc finger protein 154 (ZNF154) gene plays an oncogenic role in the development of several cancers [4]. ZNF154 has been shown to inhibit tumor cell proliferation in nasopharyngeal carcinoma by altering the expression of E-cadherin through the Wnt/β-catenin pathway, thereby inhibiting epithelial-to-mesenchymal transition (EMT) [5]. He et al. [6] demonstrated that ZNF154 could transcriptionally regulate the expressions of tumor suppressor genes involved in the cell cycle, the p53 signaling pathway, and the Wnt/β-catenin signaling pathway in esophageal squamous cell carcinoma. Thus, ZNF154 can be considered a novel cancer biomarker of clinical significance. However, the role of ZNF154 in cervical cancer remains unclear. In the present study, we analyzed ZNF154 expression and its potential biological functions and molecular mechanisms in cervical cancer. ZNF154 was found to be downregulated by promoter methylation in cervical cancer tissue. Its overexpression in cervical cancer cells inhibited cell proliferation and migration. Mechanistically, ZNF154 inhibits the Wnt/β-catenin signaling pathway by directly targeting and positively modulating Nemo-like kinase (NLK) activity. Collectively, our findings indicate the crucial role of ZNF154 in the proliferation and migration of cervical cancer cells, indicating that ZNF154 may serve as a promising target for future therapeutic development.

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Zinc finger protein 154 inhibits the growth and metastasis of cervical cancer cells through inhibiting Wnt/β-catenin signaling by upregulating NLK

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Original ResearchVol. 58, Issue 2 • pp. 463-465DOI: 10.3724/abbs.2025140

ADD domain added new binding partners for the nuclear hub protein ATRX

Authors: Yan Chen, Yang Luo, Jielin Sun, Shouhua Wang, Bingbing Wan

ATRX is a large, multi-domain nuclear protein that functions as a crucial ATP-dependent chromatin remodeler, transcriptional regulator, and guardian of telomeric and genomic integrity. As a member of the SWI/SNF family of chromatin remodeling proteins, a primary and well-defined function of ATRX is to facilitate the replication-independent deposition of the histone variant H3.3 at specific genomic loci, predominantly repetitive sequences such as telomeres, pericentromeric heterochromatin, and ribosomal DNA (rDNA). Mutations in the ATRX gene are associated with a severe X-linked neurodevelopmental disorder and alpha-thalassemia. Moreover, ATRX dysfunction can lead to genomic instability, contributing to the development and progression of various cancers, including gliomas and pancreatic neuroendocrine tumors (PanNETs). ATRX orchestrates chromatin dynamics through its modular domains. Its N-terminal ADD domain and a PxVxL-like motif recognize histone H3K9me3 and interact with the heterochromatin-binding protein HP1α, respectively. Collaborating with the histone chaperone DAXX, ATRX then utilizes its C-terminal ATPase/Helicase domain to provide the energy needed to remodel chromatin and deposit the histone variant H3.3 into repetitive DNA regions. The Chen lab and other two groups previously elucidated the minimal elements for DAXX interaction, demonstrating that a short 1260‒1289 residues motif (DAXX-binding motif, DBM) of ATRX is solely responsible for ATRX-DAXX heterodimer formation. Beyond its role in chromatin remodeling, ATRX employs its RBR (RNA-binding region) to engage the telomeric long non-coding RNA (lncRNA) TERRA, thereby regulating TERRA-mediated R-loops and telomeric G-quadruplex (G4) structures. Interestingly, this same RBR also binds the muscle-specific lncRNA ChRO1 to coordinate constitutive heterochromatin reorganization and regulate cell differentiation. Notably, nearly half of the disease-causing mutations in ATRX, leading to a severe neurodevelopmental disorder, are clustered within the ADD domain, highlighting this relatively small domain’s critical functional importance and warranting more intense investigation. This Research Highlight discusses recent findings by Yan et al. that the histone variant macroH2A binds the ATRX ADD domain, expanding the known binding partners of this domain and providing structural insights into the interaction.

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ADD domain added new binding partners for the nuclear hub protein ATRX

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Original ResearchVol. 58, Issue 2 • pp. 201-215DOI: 10.3724/abbs.2025106

Energy stress and adaptation strategy of tumor cells in different microenvironments: from primary tumors to distant metastases

Authors: Mingzhe Xu, Junjie Fei, Zhi-Xiong Xiao, Yong Yi

Since the Warburg effect was first described in the 1920s, tumor energy metabolism has been a central focus of cancer research, emerging as a potential therapeutic target. The tumor microenvironment—including blood vessels, immune cells, stromal components, and other cell types—profoundly influences tumor cell metabolism. Variations in energy supply, oxygen availability, nutrient composition, and the accumulation of metabolic waste across different microenvironments challenge tumor cell survival and progression. In response, tumor cells adapt through flexible regulation and reprogramming of metabolic pathways. Although recent studies have explored metabolic adaptation mechanisms in various tumor microenvironments, the full spectrum from primary tumors to distant metastases remains unexplored. This review summarizes energy stress and adaptation maneuvers in tumor cells across different stages of tumor progression and offers a new perspective for comprehensive research to explore therapeutic strategies targeting tumor metabolism.

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Energy stress and adaptation strategy of tumor cells in different microenvironments: from primary tumors to distant metastases

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Original ResearchVol. 58, Issue 2 • pp. 303-310DOI: 10.3724/abbs.2025120

Structural insight into Vibrio cholerae EIIC sugar transporter dimer captured in a substrate-free inward-facing state

Authors: Hanhan Guo, Qiaoshuo Zhang, Zhao Wang, Kuo Zhang, Yang Fu

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a central pathway for carbohydrate transport in bacteria and plays a critical role in nutrient acquisition, metabolism, and virulence. In Vibrio cholerae, the glucose-specific EIIC transporter is a key component of the PTS system, mediating the transport of sugars into the bacterial cell, coupled with phosphorylation during translocation. Here, we present the 3.68 Å cryo-electron microscopy (cryo-EM) structure of the dimeric EIIC transporter from Vibrio cholerae in its inward-facing, substrate-free conformation. The structure reveals a detailed arrangement of the scaffold and transport domains, stabilized by extensive inter- and intraprotomer interactions. Comparative analysis with substrate-bound inward-facing structures of EIIC from E. coli highlights conformational changes, providing insights into substrate release and the structural transitions required for alternating access. Notably, the observed substrate-free inward-facing conformation features a larger substrate-binding pocket, which is consistent with a state poised for glucose release into the cytoplasm. The formation of a unique intraprotomer disulfide bond between residues C240 and C254 stabilizes the interface between the scaffold and transport domains, potentially regulating transporter dynamics. These findings elucidate the structural basis for substrate release in the PTS system and underscore the dynamic nature of EIIC-mediated sugar transport. Our study enhances the understanding of PTS system function in Vibrio cholerae and highlights the EIIC transporter as a promising target for antimicrobial drug development. Disruption of sugar transport in this essential pathway could impair bacterial growth and virulence, suggesting a novel therapeutic strategy against cholera. These results provide a foundation for future investigations into the structural and functional dynamics of bacterial sugar transporters.

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Structural insight into Vibrio cholerae EIIC sugar transporter dimer captured in a substrate-free inward-facing state

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2025251

Efficient production of recombinant mAbs mediated by a MAR-enhanced transposon vector combined with blasticidin selection in CHO cells

Authors: Xiaoyin Wang, Xuelian Han, Ting Liu, Shiqi Zhang, Zimeng Han, Ruoyuan Feng, Tianyun Wang

Recombinant antibodies, primarily produced in Chinese hamster ovary (CHO) cells, are widely used to treat various diseases. For industrial production, a rapid and efficient method to screen stable, high-expressing clones is essential. However, conventional screening based on random integration is often cumbersome and labor intensive. This study establishes a novel strategy for generating stable, high-yielding clones by combining a MAR-based piggyBac (PB) transposon semitargeted integration system with blasticidin (BSD) selection. Compared to the random integrated vector pMAR-mAb, the MAR-PB system increases the titers (3.95- to 5.61-fold) and specific protein productivity (Qp; 4.28- to 6.07-fold) of four monoclonal antibodies in stable cell pools. When compared to PB-only vectors, the MAR-PB transposon system enhances the titers (by up to 2.50-fold) and Qp (1.96- to 2.77-fold), respectively. The increased antibody production correlates with elevated mRNA expression. Furthermore, this approach increases the proportion of high-expressing clones by more than 10-fold and significantly improves volumetric yield. Importantly, this approach promotes the long-term stability of recombinant mAb expression for over 60 generations. Transcriptome analysis reveals that the system modulates genes involved in DNA binding, transcriptional regulation, and protein binding. In conclusion, the MAR-based PB transposon system combined with BSD selection presents a significant improvement for efficiently generating high-yielding and stable CHO cell clones, offering a valuable tool for recombinant antibody production.

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Efficient production of recombinant mAbs mediated by a MAR-enhanced transposon vector combined with blasticidin selection in CHO cells

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Original ResearchVol. 57, Issue 2 • pp. 325DOI: 10.3724/abbs.2024200

Corrigendum to: Downregulating integrin subunit alpha 7 (ITGA7) promotes proliferation, invasion, and migration of papillary thyroid carcinoma cells through regulating epithelial-to-mesenchymal transition

Authors: Yaoyao Guan, Adheesh Bhandari, Erjie Xia, Lingguo Kong, Xiaohua Zhang, Ouchen Wang

This is a corrigendum to the original article published in Acta Biochim Biophys Sin 2020, 52(2): 116–124. The authors correct an error in Figure 4 of the original manuscript. The correct figure is provided, and the authors apologize for the error.

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Corrigendum to: Downregulating integrin subunit alpha 7 (ITGA7) promotes proliferation, invasion, and migration of papillary thyroid carcinoma cells through regulating epithelial-to-mesenchymal transition

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Original ResearchVol. 58, Issue 1 • pp. 1-2DOI: 10.3724/abbs.2025247

Special issue: advances in immunology and its applications

Authors: Mingshun Han, Hongyan Wang

Innate immunity and adaptive immunity play crucial roles in regulating inflammation-related diseases such as tumors, infections, and autoimmune diseases. The interplay between innate immunity and adaptive immunity ensures the maintenance of tissue homeostasis and effective clearance of invading pathogens or tumor cells. However, dysregulation in each type of immune cells or their communications leads to pathological conditions, ranging from chronic inflammation to malignant progression. In recent years, the field of immunology has witnessed a paradigm shift, moving from merely describing immune cell signaling or phenotypes to actively exploring strategies that reshape immune functions for therapeutic benefit. Exploring effectors or strategies to reshape T cell function for the improved anti-tumor and anti-infection efficacy has emerged as a critical research direction. This includes the development and optimization of chimeric antigen receptor T-cell (CAR-T) therapies for clinical applications. While CAR-T therapy has revolutionized the treatment of hematologic malignancies, its success in solid tumors remains limited. Chen et al. [1] dissect the distinct signaling mechanisms of chimeric antigen receptors (CARs) compared to T cell receptors (TCRs). They elucidate how CAR-T cells, despite overcoming MHC restrictions, encounter significant hurdles such as inefficient tumor infiltration and the hostility of the immunosuppressive tumor microenvironment (TME). To address these challenges, the authors underscore several innovative strategies, such as optimizing receptor clustering to facilitate immune synapse formation and integrating novel co-stimulatory domains to augment therapeutic efficacy in solid tumors. Moving beyond engineering, fundamental insights into microenvironmental stress and T cell intrinsic signaling are pivotal. While oxidative stress is a well-established concept in the TME, Ji and Xiao [2] draw attention to the phenomenon of “reductive stress”. They explain how a surplus of intracellular reducing agents disrupts redox balance, creating a reductive environment that significantly influences immune cell differentiation and tumor survival. In a complementary study, Shi et al. [3] investigate the intrinsic role of pattern recognition receptor (PRR) signaling within T cells. Although PRRs are historically classified as innate sensors, this review highlights their critical function in adaptive immunity, discussing how T cells utilize PRRs to interpret endogenous danger signals and microbial cues to regulate cytokine release and proliferation. Additionally, Ma et al. [4] provide a comprehensive update on T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), an important immune checkpoint. By detailing its expression profile across T cells, NK cells, and myeloid lineages, they propose that rational combination therapies targeting TIM-3 alongside other checkpoints offer a promising avenue to surmount current resistance mechanisms. This issue also highlights the regulation of immunity by neurotransmitters and biological rhythms, illustrating the profound integration of the immune system with physiological networks. Fan and Zhao [5] summarize the neurotransmitter-receptor landscape in T cell tumor immunology. They elaborate on how specific neurotransmitters, including glutamate, acetylcholine, GABA, and serotonin, could dictate T cell activation and differentiation within the TME. The authors advocate for targeting these neuro-immune axes, such as through β-blockers or glutamate receptor inhibitors, as a new frontier for enhancing cancer immunotherapy. From a different perspective, Sun et al. [6] assess the influence of circadian rhythms on the TME and immunotherapy outcomes. They present evidence indicating that the efficacy of treatments like immune checkpoint blockade depends on administration timing, suggesting that future clinical protocols should incorporate chronobiology to maximize patient benefit. Further exploring this dimension, Zhao et al. [7] examine the bidirectional circadian dialogue between the host and the gut microbiota. They describe how modern lifestyle factors, such as shift work and irregular dietary habits, disrupt this synchronization, resulting in compromised barrier integrity and systemic metabolic disorders. This issue also focuses on the function of various innate immune cells, including ILCs, macrophages, and dendritic cells (DCs), as well as their crosstalk with T cells in maintaining homeostasis across lung, gut, and aging contexts. Chen et al. [8] concentrate on Group 2 innate lymphoid cells (ILC2s), which functionally mirror Th2 cells. They underscore the context-specific roles of ILC2s in pulmonary diseases, explaining how these cells react to environmental alarmins such as IL-33 and thymic stromal lymphopoietin (TSLP). The review also discusses targeting ILC2 plasticity as a potential therapeutic intervention for lung inflammation. Recent findings suggest lipid metabolism as a crucial determinant of innate immune function. Huang et al. [9] offer an updated survey of lipid-regulated immunobiology in macrophages, examining how

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Special issue: advances in immunology and its applications

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026087

A bifunctional aptamer-siRNA chimera targeting ACE2 for the inhibition of SARS-CoV-2 S pseudovirus entry and replication

Authors: Tao Jiang, Zhiqiang Chen, Wei Li, Xiaohua Ni, Wen Pan, Qihan Wu

The relentless evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of immune-evasive variants underscore an urgent need for novel therapeutic strategies that are resilient to viral mutations. Targeting conserved host factors essential for viral entry represents a promising approach to overcome this challenge. Here, we report the development of a bifunctional therapeutic platform targeting the primary human receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Using systematic evolution of ligands by exponential enrichment (SELEX), we isolate a high-affinity DNA aptamer, designated AA2, that binds to human ACE2 with a dissociation constant (Kd) of 5.41 ± 1.23 nM. Molecular docking and competitive binding assays confirm that AA2 sterically hinders the interaction between the viral spike receptor-binding domain (RBD) and ACE2. Consequently, AA2 demonstrates potent neutralization of SARS-CoV-2 S pseudovirus entry into host cells. To achieve a synergistic antiviral effect, we engineer an aptamer-siRNA chimera (AsiC) by conjugating AA2 to a short interfering RNA (siRNA) targeting the GFP coding region of the pseudovirus genome. This AsiC construct significantly represses viral replication compared to aptamer or siRNA treatment alone, validating a dual mechanism of action that combines receptor blockade with targeted gene silencing. This study establishes a robust proof-of-concept for an ACE2-targeted AsiC, representing a new class of dual-function antiviral therapeutics with the potential to effectively combat current and future ACE2-dependent coronaviruses.

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A bifunctional aptamer-siRNA chimera targeting ACE2 for the inhibition of SARS-CoV-2 S pseudovirus entry and replication

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Original ResearchVol. 58, Issue 1 • pp. 49-66DOI: 10.3724/abbs.2025235

Immune checkpoint TIM-3 in tumor immunotherapy

Authors: Shuaiya Ma, Mengyao Zhu, Chunhong Ma, Chunyang Li

Over the past decade, immunotherapy has emerged as a pivotal therapeutic strategy in cancer treatment. Immune checkpoint inhibitors (ICIs), such as CTLA-4 and PD-1 monoclonal antibodies, have demonstrated remarkable clinical efficacy in different types of cancer. However, the overall success rate of immune checkpoint therapies remains low. Investigating alternative immune checkpoint molecules is imperative. T-cell immunoglobulin and mucin-containing molecule-3 (TIM-3), which is expressed in T cells, natural killer (NK) cells, macrophages, and dendritic cells, has gained recognition as a promising candidate for tumor immunotherapy. Targeting TIM-3 represents a promising approach for cancer immunotherapy, particularly through the rational design of novel combination therapies with other ICIs. In this review, we present a comprehensive summary of the research advancements concerning the role of TIM-3 in regulating immune responses in different cell types and explore theoretical frameworks for targeting TIM-3 to achieve more effective immunotherapeutic breakthroughs.

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Immune checkpoint TIM-3 in tumor immunotherapy

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Original ResearchVol. 57, Issue 1 • pp. 1-2DOI: 10.3724/abbs.2024234

Safari in the RNA world: a special issue focused on RNA biogenesis, functions, and technologies

Authors: Ya-Nan Chang, Hong Cheng

RNA is one of the most essential biopolymers in cells. According to the central dogma, messenger RNAs (mRNAs) transmit genetic information from DNA to proteins through a complex process, facilitated by key non-coding RNAs (ncRNAs) such as ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs). In addition to these essential RNAs, a wide variety of ncRNAs have been discovered, each playing key roles in gene regulation and contributing to the complexity of the RNA landscape. All RNAs undergo intricate processing and modifications before maturation and transport to their respective cellular compartments, where they perform their functions. Regulation of these processes often results in the generation of multiple isoforms from a single gene, further diversifying the RNA landscape. Understanding the mechanisms of RNA biogenesis and the functional roles of RNAs in both physiological and pathological contexts is essential for unraveling how cells respond to developmental and environmental cues, with profound implications for biomedicine. This special issue features 12 expert reviews in RNA research, each offering a comprehensive summary of the latest advances in RNA biology from their respective perspectives.

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Safari in the RNA world: a special issue focused on RNA biogenesis, functions, and technologies

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Original ResearchVol. 58, Issue 1 • pp. 137-155DOI: 10.3724/abbs.2025239

An updated overview of lipid-regulated immunobiology in macrophages

Authors: Ziyang Huang, He Xu, Han Lin, Quan D. Zhou

Macrophages are well known for their widespread distribution, diverse roles, and involvement in multiple pathophysiological contexts, thereby constructing an immunological front line. Meanwhile, constant efforts over the past few decades have unveiled diverse reprogramming patterns of lipid metabolism as crucial, response- and context-specific drivers of macrophage functions and fate. Here, we take a bird’s-eye view of major fields across the research landscape of lipid-regulated macrophages; review the latest advances in understanding how alterations in several lipid subclasses, especially their fatty acyl composition and oxidative status, direct macrophage-mediated responses and pathology outcomes; and summarize representative insights that have deciphered the lipidome composition of macrophages or profiled specific lipid species under different scenarios. We hope that this review provides readers with a handy grip to learn and explore the field of lipid-regulated immunobiology, exemplified by but not limited to macrophages.

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An updated overview of lipid-regulated immunobiology in macrophages

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Original ResearchVol. 58, Issue 1 • pp. 39-48DOI: 10.3724/abbs.2025227

T cell-intrinsic PRR signaling in immunity and pathology

Authors: Yixuan Shi, Meng Wang, Baodi Dai, Xinliang Lu, Sirui Li

The immune system orchestrates a delicate balance between robust defense against pathogens and restraint to prevent tissue damage, with T cells serving as central mediators of adaptive immunity. The canonical pathway for T-cell activation hinges on the precise recognition of peptide antigens presented by major histocompatibility complex (MHC) molecules via the T-cell receptor (TCR), which is complemented by essential co-stimulatory signals. However, this model alone cannot fully explain the nuanced contextualization of immune responses, particularly how T cells integrate signals related to the nature of the threat. Pattern recognition receptors (PRRs), which are traditionally studied in innate immune cells, are recognized as critical regulators of T cell function, challenging the conventional dichotomy between innate and adaptive immunity. T cell-intrinsic PRR signaling integrates endogenous danger signals and microbes to modulate critical processes, including cytokine production, proliferation, and polarization, thereby shaping immune responses and disease outcomes in contexts ranging from viral infections to chronic inflammation and cancer. However, the molecular mechanisms underlying PRR-mediated T cell regulation and their contributions to immune homeostasis or pathology remain incompletely understood. This study investigates the role of T cell-intrinsic PRR signaling in shaping immune responses and its implications for disease. By elucidating key signaling pathways and their impact on T cell function, we aim to offer novel insights into the complex regulation of T cell-mediated immunity and uncover an underappreciated paradigm for immune-related disorders, providing new insights into the pathogenesis of inflammatory and neoplastic diseases.

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T cell-intrinsic PRR signaling in immunity and pathology

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Original ResearchVol. 58, Issue 1 • pp. 90-105DOI: 10.3724/abbs.2025203

Circadian rhythm in immunotherapy and cellular therapy: impacts on the tumor microenvironment

Authors: Xiaoyang Sun, Lulu Qin, Xinghua Liang, Dongrui Wang

Immunotherapy, including cellular therapy, has emerged as a crucial pillar in cancer treatment, complementing established modalities such as surgery, chemotherapy and radiotherapy. The clinical observation that immunotherapy is effective in only a limited proportion of patients inspires mechanistic research on the complicated regulatory network within the tumor microenvironment (TME). Circadian regulation significantly affects immune cell behavior, including the activity of immune cells and cytokine production, and emerging evidence suggests the key role of circadian regulation in the TME, which subsequently affects the effectiveness of immunotherapy. Results from preclinical and clinical studies indicate that appropriate timing of adoptive cellular therapy and immune checkpoint blockade therapy improves their efficacy. Therefore, understanding the molecular mechanism of the circadian rhythm together with its role in immunotherapy is essential for optimizing cellular function, proliferation and persistence in the TME. Here, we review how circadian rhythms influence immunotherapy and the TME across different stages of tumor progression. Future clinical protocols may integrate concepts of circadian rhythm and immunotherapy to enhance treatment response.

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Circadian rhythm in immunotherapy and cellular therapy: impacts on the tumor microenvironment

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Original ResearchVol. 58, Issue 1 • pp. 120-136DOI: 10.3724/abbs.2025243

The context-dependent role of group 2 innate lymphoid cells in lung diseases

Authors: Yue Chen, Xiaojuan Ji, Jinxin Qiu, Ju Qiu

Group 2 innate lymphoid cells (ILC2s), a subset of innate lymphoid cells (ILCs) lacking antigen-specific receptors and functionally mirroring T helper 2 (Th2) cells, are indispensable components of the innate immune system that lack antigen-specific receptors but phenotypically and functionally mirror T helper 2 (Th2) cells, particularly in their expression of the transcription factor GATA3 and the secretion of type 2 cytokines for mediating type 2 immune responses. ILC2s are tissue-resident cells in mucosal tissues, including the lung, where they play crucial roles in maintaining tissue homeostasis and regulating immune responses. ILC2s are poised to respond to environmental signals such as IL-25, IL-33, and TSLP, which activate and expand ILC2s. Their functions are highly context-dependent and influenced by interactions with other immune cells. In this review, we summarize recent findings on the roles of ILC2s in lung diseases, highlighting their typical characteristics and their responsiveness to environmental signals in the context of pulmonary pathology. We also discuss potential therapeutic strategies targeting ILC2s, which may offer new avenues for the treatment of inflammatory lung diseases. Understanding the mechanisms by which ILC2s contribute to lung disease progression will provide valuable insights for the development of novel diagnostic (e.g., ILC2 phenotypic markers) and therapeutic approaches (e.g., targeting ILC2 plasticity or alarmin-ILC2 signaling axes).

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The context-dependent role of group 2 innate lymphoid cells in lung diseases

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2025237

Altered gut microbial dynamics and the antivascular remodeling effect of carnosine in hypobaric hypoxic pulmonary hypertension rats

Authors: Huaying Wei, Shikun Guo, Wenjing Ding, Yifan Yang, Xinyu Hu, Ailifeila Aili, Xiaolan Chen, Xinying Xue, Lei Pan

Exposure to chronic hypobaric hypoxia provokes marked alterations in the gut microbiota and its metabolome, yet the functional significance of histidine-derived metabolites in hypobaric hypoxic pulmonary hypertension (PH) remains underexplored. Here, we employ 16S rDNA, metagenomic, and untargeted metabolomic sequencing to characterize longitudinal shifts in the fecal microbiota and metabolites during hypobaric hypoxic PH development in Sprague-Dawley rats. Fecal carnosine levels and the abundance of its producer, Ruminococcus bromii, both decrease significantly over 28 days of hypobaric hypoxia (P < 0.05). Spearman correlation shows that carnosine is inversely correlated with the percentage of pulmonary arteriole media thickness (MT%; r = –0.8741, P < 0.001). Therapeutic supplementation with carnosine restores systemic and pulmonary antioxidant defenses and attenuates vascular remodeling without altering right ventricular pressures. In vitro, carnosine inhibits hypoxia-induced pulmonary artery smooth muscle cell (PASMC) proliferation and migration and suppresses nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation. These findings reveal dynamic gut-lung crosstalk in hypobaric hypoxic PH and nominate carnosine as a metabolite-based intervention to mitigate hypoxia-driven pulmonary vascular remodeling.

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Altered gut microbial dynamics and the antivascular remodeling effect of carnosine in hypobaric hypoxic pulmonary hypertension rats

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Original ResearchVol. xx, Issue xx • pp. xx–xxDOI: 10.3724/abbs.2025245

SPP1 facilitates sorafenib resistance in hepatocellular carcinoma by upregulating aerobic glycolysis in endothelial cells

Authors: Wufei Ye, Tao Chen, Yueran Li, Jiajie Luan, Kui Yang, Sheng Wang

The occurrence of resistance to sorafenib, a first-line treatment for hepatocellular carcinoma (HCC), significantly limits its clinical efficacy. Therefore, investigating the potential mechanism of sorafenib resistance in HCC is highly important for developing HCC treatment strategies. In the present study, we identify that SPP1 (encoding osteopontin; OPN) is significantly elevated in sorafenib-resistant HCC. Furthermore, the upregulation of SPP1 is related to vascular invasion, advanced disease stage and poor prognosis in HCC patients. As the IC50 value of sorafenib increases in HepG2 cells, the SPP1 protein secreted by the cells is significantly upregulated, which subsequently facilitates the proliferation of human umbilical vein endothelial cells (HUVECs) and resistance to sorafenib. Further studies reveal that SPP1 induces resistance to sorafenib in HepG2 cells by upregulating glycolysis in HUVECs and further producing lactate. Mechanistically, SPP1 increases the expressions of the glucose transporter GLUT1 and the key glycolytic enzymes PFK1 and PKM2 in HUVECs, resulting in lactate accumulation, which in turn promotes the phosphorylation levels of BRAF and ERK as well as HIF-1α expression in HepG2 cells, leading to sorafenib resistance in HCC. Notably, SPP1 silencing can inhibit the proliferation and invasion of sorafenib-resistant HepG2 cells both in vitro and in vivo. Importantly, lactate derived from HUVECs plays a more dominant role in sorafenib resistance than does SPP1 in HepG2 cells. In summary, SPP1 enhances sorafenib resistance in HepG2 cells through promoting aerobic glycolysis in HUVECs, suggesting that the SPP1-aerobic glycolysis axis might be a prognostic biomarker as well as a potential therapeutic target for sorafenib-resistant HCC.

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SPP1 facilitates sorafenib resistance in hepatocellular carcinoma by upregulating aerobic glycolysis in endothelial cells

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Original ResearchVol. 58, Issue 1 • pp. 183-200DOI: 10.3724/abbs.2025157

Intestinal aging-related immune dysfunction: mechanisms and interventions

Authors: Xin Shen, Xianzhi Gao, Lie Wang

Intestinal immunosenescence, a hallmark of organismal aging, has emerged as a critical biological process impacting the health of elderly individuals. This review systematically examines the core mechanisms underlying intestinal immunosenescence, including immune cell dysfunction, imbalances in immune-microbiota interactions, and impaired barrier function. We analyze its associations with infectious diseases, chronic inflammation, and neurodegenerative disorders, summarizing recent advances in dietary interventions, microecological therapy, and other emerging strategies. By integrating cutting-edge technologies, we prospect the development of precision interventions aimed at delaying intestinal immunosenescence, thereby providing a theoretical basis for improving the healthspan of the aging population.

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Intestinal aging-related immune dysfunction: mechanisms and interventions

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Original ResearchVol. 58, Issue 1 • pp. 156-168DOI: 10.3724/abbs.2025231

Metabolic crosstalk between intestinal microbiota and dendritic cells: from homeostasis to inflammation

Authors: Mengjie Wang, Haibi Su, Juan Liu

The intestinal microbiota plays critical roles in regulating immunity and inflammation through intricate interactions between microbial metabolites and diverse immune cells. Dendritic cells (DCs), the most potent professional antigen-presenting cells, are essential for sensing the complicated microbiota environment and subsequently initiating and regulating adaptive immune responses. While the commensal microbiota typically mediates DC-triggered immune tolerance and thus the maintenance of intestinal homeostasis, epithelial injury or pathogenic infection generally drives the proinflammatory function of DCs, contributing to harmful inflammation and intestinal disorders. Various microbiota metabolites (such as short-chain fatty acids, bile acids, and tryptophan derivatives) play critical roles in modulating the developmental and functional diversity of DCs through metabolic, epigenetic, or signaling reprogramming. In this review, we discuss the metabolic crosstalk between the intestinal microbiota and DCs and its pivotal function in orchestrating the balance between intestinal homeostasis and pathogenic inflammation. We also discuss future directions to better elucidate the microbiota-DC dialog in intestinal immunity and develop therapeutic approaches for manipulating the microbiota-DC axis against inflammatory disorders.

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Metabolic crosstalk between intestinal microbiota and dendritic cells: from homeostasis to inflammation

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Original ResearchVol. 58, Issue 1 • pp. 169-182DOI: 10.3724/abbs.2025192

Dysregulated immunometabolism in gut inflammation

Authors: Mengqi Zheng, Qiuheng Tian, Jing Shen, Shiyang Li

Gut inflammatory diseases, including inflammatory bowel disease (IBD), infectious enteritis, and other inflammatory conditions, are among the most common non-neoplastic intestinal disorders. Their pathogenesis is often driven by an imbalance between pro-inflammatory and anti-inflammatory signals, with immune cells playing pivotal roles in maintaining this equilibrium. Immune cells in the gut exhibit complex, multifaceted functions: they eliminate pathogens, promote tissue repair, and counteract tumors, but excessive immune activation can exacerbate tissue damage and disease progression. Notably, metabolic reprogramming in inflammatory contexts serves as a key regulator of immune cell function and phenotypic switching. This includes alterations in cellular energy metabolism (e.g., macrophage polarization via disrupted glycolysis or fatty acid oxidation) and the modulation of immune responses by microenvironmental metabolites (e.g., bile acid-mediated Th17/Treg balance). While alterations in immune cell function and composition within the inflammatory milieu are well-established, the significance of disease-associated metabolic reprogramming—specifically how metabolism regulates immune cell function—has garnered increasing attention. This review explores how cellular metabolic reprogramming, changes in the metabolic microenvironment, and gut dysbiosis collectively influence the differentiation, proliferation, and function of immune cells in various intestinal inflammatory diseases, as well as their impact on disease progression.

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Dysregulated immunometabolism in gut inflammation

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026043

Development of a colloidal gold immunochromatographic strip based on GAPDH for Pentatrichomonas hominis in dogs

Authors: Qian Zhai, Xuejiao Chen, Xichen Zhang, Jianhua Li, Pengtao Gong, Xiaocen Wang, Xin Li, Xu Zhang, Nan Zhang

Pentatrichomonas hominis is a zoonotic protozoan belonging to the family Trichomonadidae that primarily inhabits the cecum and colon. Although traditionally regarded as an opportunistic pathogen, P. hominis is increasingly recognized for its pathogenic potential, including roles in animal diarrheal disease and the induction of intestinal epithelial damage and chronic inflammation in mice. A previous study further identified a significant correlation between P. hominis infection and colorectal cancer, underscoring its growing clinical and public health significance. This parasite infects a wide range of hosts, among which dogs, displaying infection rates as high as 47.4%, are regarded as a potential zoonotic reservoir because of their close contact with humans. Consequently, establishing reliable detection methods for P. hominis in dogs is essential for veterinary practice and public health surveillance. Current methods for detecting P. hominis infections in dogs mainly include direct smear microscopy and polymerase chain reaction (PCR)-based techniques. Although direct smear microscopy is straightforward, it frequently exhibits low sensitivity. In comparison, PCR demonstrates high sensitivity and specificity, yet it relies on specialized equipment, trained operators, and extended processing time. Recently, reported nucleic acid detection approaches, such as recombinase polymerase amplification coupled with lateral flow dipstick (RPA-LFD) and RPA-CRISPR/Cas12a assays, have enhanced the efficiency and accessibility of molecular detection for P. hominis. However, these methods still necessitate nucleic acid extraction, controlled temperature conditions, and operational complexity. In addition, some emerging detection technologies, such as microfluidic chips and nanozyme-based detection systems, offer advantages of high throughput and sensitivity but have not yet been widely applied in the field of detection of parasitic infection. Although immunoassays, including enzyme-linked immunosorbent assay (ELISA) and colloidal gold immunochromatographic strips, have been successfully used for the detection of infections of some intestinal protozoans, such as Giardia, there have been no reports on their application for detecting P. hominis infections, primarily due to the lack of specific detection antigens. To address the detection need, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used as the primary discovery tool to identify specific detected antigens. Using this targeted proteomics approach, we precisely identified immunoreactive proteins and selected glyceraldehyde 3 phosphate dehydrogenase (GAPDH), an immunogenic and species-specific antigen in related parasites, as the candidate antigen. Based on this identified antigen, we subsequently developed and evaluated the detection performance in both indirect ELISA and colloidal gold immunochromatographic strips using recombinant GAPDH. This study aimed to identify novel antigens for immunodetection of P. hominis and to establish a practical, on-site method for detecting dog infections, thereby facilitating further epidemiological and clinical research.

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Development of a colloidal gold immunochromatographic strip based on GAPDH for Pentatrichomonas hominis in dogs

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026104

Phillyrin protects against myocardial ischemia/reperfusion injury by promoting KNL1 K605 acetylation to inhibit the p53/p21 pathway

Authors: Dongsheng He, Zhipeng Ren, Shangxuan Li, Ziqiang Dai, Gen Zhang, Huan Wang, Guanzheng Cui, Dianyuan Li

Reperfusion therapy is critical for acute myocardial infarction but is often accompanied by myocardial ischemia/reperfusion injury (MIRI). Phillyrin, a natural lignan from Forsythia suspensa, exerts anti-inflammatory and antioxidant effects; however, its role and mechanism in MIRI remain unclear. In this study, HL-1 cardiomyocytes are subjected to oxygen-glucose deprivation/reperfusion (OGD/R). Cell viability, apoptosis, oxidative stress, and inflammation are measured after phillyrin treatment. Multiomics (mRNA-seq, proteomics, and acetylproteomics) is used to identify key targets and pathways. Molecular docking, co-immunoprecipitation, site-directed mutagenesis, and western blot analysis are used to validate posttranslational regulation. A mouse MIRI model is established to confirm the in vivo cardioprotective effects of phillyrin. Phillyrin preserves cell viability and reduces apoptosis, oxidative stress, and inflammation in OGD/R-injured HL-1 cells. Multiomics integration reveals that phillyrin acts primarily through posttranslational regulation and highlights kinetochore scaffold 1 (KNL1) as the only protein that is both upregulated and hyperacetylated at lysine 605 (K605). Mechanistically, phillyrin may bind to the KNL1 C-terminus and enhance the interaction between KNL1 and acetyltransferase p300/CBP. KNL1 K605R mutation and Knl1 knockdown reduce KNL1 protein expression and reverse the inhibitory effects of phillyrin on p53 pathway-mediated apoptosis, oxidative stress, and inflammation. In mouse MIRI models, phillyrin reduces infarct size, myocardial damage, and cardiomyocyte apoptosis; these effects are abolished by knockdown of Knl1. Therefore, phillyrin promotes KNL1 acetylation at K605 to increase KNL1 protein expression, thereby inhibiting p53 signaling and alleviating apoptosis, oxidative stress, and inflammation in MIRI. This study identifies KNL1 acetylation at K605 as a novel posttranslational modification target for cardioprotection.

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Phillyrin protects against myocardial ischemia/reperfusion injury by promoting KNL1 K605 acetylation to inhibit the p53/p21 pathway

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026102

Integrating genetically encoded fluorescent sensors to elucidate the spatiotemporal choreography of necrosis by sodium overload

Authors: Yike Song, Yale Xia, Yin Fu, Jing Yao, Lian Zeng, Yuxi Duan, Ni Su, Xie Li, Xiawei Cheng, Yuzheng Zhao, Yi Yang, Yejun Zou

Necrosis by sodium overload (NECSO) is a distinct cell death modality induced by the chemical regulator necrocide 1 (NC1), which targets the transient receptor potential melastatin 4 (TRPM4) channel to drive excessive sodium influx and potassium efflux. This unique necrosis is characterized by the exchange of monovalent ions, a restrained ATP supply, redox disorder and a final membrane rupture as main features. Real-time monitoring of metabolic and redox causality during the whole process in living cells has been technically challenging. To bridge this gap, we integrate an advanced toolset of genetically encoded fluorescent sensors to monitor monovalent ions, energy metabolites, and redox equivalents with high spatiotemporal resolution. By directing these sensors to specific subcellular compartments, we successfully capture the real-time choreography of potassium loss specifically induced by NC1 via TRPM4. Furthermore, we establish a precise detection paradigm for evaluating energy currency by integrating sensors for NADH and ATP that are capable of subcellular imaging. We observe general and rapid NADH accumulation along with an ATP shortage in the mitochondria and cytosol. A concomitant reduction in mitochondrial oxidative stress is observed. This study not only elucidates the metabolic progression of a peculiar type of necrosis but also establishes a robust methodological framework for applying genetically encoded sensors to broader physiological and toxicological research.

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Integrating genetically encoded fluorescent sensors to elucidate the spatiotemporal choreography of necrosis by sodium overload

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Original ResearchVol. 56, Issue 12 • pp. 1733-1747DOI: 10.3724/abbs.2024130

EEPD1 attenuates radiation-induced cardiac hypertrophy and apoptosis by degrading FOXO3A in cardiomyocytes

Authors: Kaiwen Yu, Xi Su, Tongfang Zhou, Xuwei Cai, Min Zhang

Radiation-induced heart disease (RIHD) is a severe delayed complication of thoracic irradiation (IR). Endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1) plays an important role in DNA damage repair, but its role in RIHD is less known. In this study, EEPD1 global knockout mice, C57BL/6J mice, and C57BL/6J mice overexpressing EEPD1 are treated with radiation at a total dose of 20 Gy or 0 Gy. After 9 weeks, echocardiography is used to assess cardiac hypertrophy and apoptosis. The results show that EEPD1 deletion exacerbates radiation-induced cardiac hypertrophy and apoptosis, while EEPD1 overexpression has the opposite effect. Further mechanistic investigations reveal that EEPD1 interacts with FOXO3A and destabilizes it by catalyzing its deubiquitination. Inhibition of FOXO3A ameliorates cardiac hypertrophy and apoptosis after EEPD1 knockdown. Thus, EEPD1 protects against radiation-induced cardiac hypertrophy and apoptosis via destabilization of FOXO3A, which may offer new insight into therapeutic strategies for RIHD.

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EEPD1 attenuates radiation-induced cardiac hypertrophy and apoptosis by degrading FOXO3A in cardiomyocytes

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026081

PPIA as a central regulator in a novel cell death pathway activated by iron homeostasis and redox disruption in multiple myeloma

Authors: Zhiming Wang, Chuan He, Qi Li, Xinyun Zhang, Si Chen, Lexin He, Yali Chai, Meifang Zhao, Linlin Qin, Menglu Chen, Hongxia Cui, Hao Xu, Yuchen Zhang, Bingzong Li, Wenzhuo Zhuang

Multiple myeloma (MM) patients frequently experience relapse, disease progression, and drug resistance, necessitating novel therapeutic strategies. This study investigates the role of peptidylprolyl isomerase A (PPIA) in mediating dihydroartemisinin (DHA)-induced ferroptosis in MM. Building on our previous work establishing the prognostic relevance of ferroptosis in MM, we elucidate the mechanism by which DHA triggers this form of cell death through the disruption of iron metabolism and redox homeostasis. DHA significantly reduces the viability of MM cell lines and primary CD138+ cells derived from patient bone marrow samples and attenuates tumor burden in orthotopic MM models. Mechanistically, DHA upregulates the iron-regulatory genes transferrin receptor 1 (TFRC) and heme oxygenase-1 (HMOX1), thereby perturbing iron homeostasis and promoting ferroptosis. Crucially, DHA targets the oxidized form of PPIA, a redox-sensitive chaperone, binding to it and preventing its reduction, which elevates intracellular reactive oxygen species (ROS). Combined treatment with DHA and erastin, which concurrently disrupt iron and amino acid metabolism, exerts synergistic cytotoxicity and enhances MM inhibition. Furthermore, in a syngeneic mouse model, DHA promotes T-cell activation and augments tumor suppression. Collectively, these findings underscore PPIA’s pivotal role in a novel ferroptotic cell death pathway and reveal new therapeutic opportunities for MM.

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PPIA as a central regulator in a novel cell death pathway activated by iron homeostasis and redox disruption in multiple myeloma

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Original ResearchVol. xx, Issue xx • pp. xx–xxDOI: 10.3724/abbs.2026025

Sanguinarine exerts anti-hepatocellular carcinoma activity by targeting FDX1 to induce FDX1/LIAS/DLAT/HSP70 axis-dependent cuproptosis

Authors: Xiaoyan Hao, Yiqiao Qiu, Ling Li, Siqi Chen, Yuxuan Gao, Ketao Ma, Lili Wei, Qiang Zhang, Liang Zhang

Hepatocellular carcinoma (HCC), the predominant type of primary liver cancer, represents an extremely aggressive malignancy. The induction of cuproptosis has developed into a favorable therapeutic direction for HCC, considering its strong association with HCC. Sanguinarine (San), a benzophenanthridine alkaloid derived from traditional herbs such as Chelidonium majus L., demonstrates broad-spectrum anticancer activities against various cancer cell types. However, the precise molecular mechanisms underlying its effects in the treatment of HCC remain largely undefined. This investigation seeks to examine the anti-HCC effects of San and to explore the mechanisms underlying these effects through the induction of cuproptosis. In vitro experiments demonstrate that San markedly inhibits the proliferation, movement, and epithelial-mesenchymal transition of HCC cells while enhancing their apoptosis. In vivo, San notably impedes tumor growth and upregulates the cuproptosis signature markers ferredoxin 1 (FDX1), oligomeric dihydrolipoamide S-acetyltransferase (DLAT), and heat shock protein 70 (HSP70) in HCC xenograft tumor models. Mechanistically, San induces proteotoxic stress and cuproptosis in HCC cells by increasing copper concentration, upregulating the expression of FDX1, lipoic acid synthetase (LIAS), HSP70, and lipoylated DLAT aggregation, and simultaneously reducing mitochondrial membrane potential and intracellular glutathione and pyruvate levels. Moreover, the combination of San with copper ionophores (Elesclomol-CuCl2) exhibits synergistic effects in promoting cuproptosis. FDX1 silencing markedly diminishes San-induced suppression of cell proliferation and FDX1 and HSP70 levels in HCC cells. Additionally, molecular docking analysis predicts that San exhibits the highest potential for binding with FDX1. Surface plasmon resonance experiments and cellular thermal shift assay confirm that San strongly interacts with FDX1 and markedly enhances the thermostability of FDX1. In conclusion, our findings indicate that San substantially inhibits the progression of HCC by targeting FDX1/LIAS/DLAT/HSP70 axis-dependent cuproptosis.

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Sanguinarine exerts anti-hepatocellular carcinoma activity by targeting FDX1 to induce FDX1/LIAS/DLAT/HSP70 axis-dependent cuproptosis

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Original ResearchVol. xx, Issue xx • pp. xx–xxDOI: 10.3724/abbs.2025196

OAZ1/CASP8AP2 double knockout enhances recombinant protein production in HEK293 cells through metabolic reprogramming and antiapoptotic effects

Authors: Junhe Zhang, Liao Zhang, Lu Hou, Weidong Li, Shaolei Geng, Xiaoyin Wang, Tianyun Wang

Human embryonic kidney (HEK) 293 cells are widely used for recombinant protein production because of their efficient posttranslational modification capabilities. However, their large-scale culture is often limited by metabolic stress and early apoptosis, leading to insufficient protein yields. In this study, we aim to increase protein expression through the coordinated modulation of metabolic and apoptotic pathways. Using CRISPR/Cas9 technology, we target and knockout the genes of ornithine decarboxylase antizyme 1 (OAZ1), which regulates polyamine metabolism, and caspase 8-associated protein 2 (CASP8AP2), an apoptosis-related protein. We successfully construct an OAZ1/CASP8AP2 double-knockout HEK293 cell line. Following transfection with the knockout vector and screening of single-cell clones, multiple levels of validation confirm the successful gene knockout. The results show that the double-knockout cells exhibit significantly reduced apoptosis rates. Furthermore, the production of recombinant secreted alkaline phosphatase (SEAP) and vitronectin (VN) increases by 2.1 folds and 2.9 folds, respectively, compared with those in wild-type cells. Metabolic profiling reveals that the cell cycle is arrested in the G1/G0 phase, accompanied by increased specific consumption and production rates of key metabolites. This study demonstrates that concurrent inhibition of apoptosis and optimization of metabolism effectively enhances recombinant protein production in HEK293 cells, suggesting a novel strategy for improving HEK293 cell-based expression.

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OAZ1/CASP8AP2 double knockout enhances recombinant protein production in HEK293 cells through metabolic reprogramming and antiapoptotic effects

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Original ResearchVol. 56, Issue 12 • pp. 1860-1874DOI: 10.3724/abbs.2024141

Vaccarin suppresses diabetic nephropathy through inhibiting the EGFR/ERK1/2 signaling pathway

Authors: Xuexue Zhu, Xinyu Meng, Xinyao Du, Chenyang Zhao, Xinyu Ma, Yuanyuan Wen, Shijie Zhang, Bao Hou, Weiwei Cai, Bin Du, Zhijun Han, Fei Xu, Liying Qiu, Haijian Sun

Diabetic nephropathy (DN) is recognized as one of the primary causes of chronic kidney disease and end-stage renal disease. Vaccarin (VAC) confers favorable effects on cardiovascular and metabolic diseases, including type 2 diabetes mellitus (T2DM). Nonetheless, the potential role and mechanism of VAC in the etiology of DN have yet to be completely elucidated. In this study, a classical mouse model of T2DM is experimentally induced via a high-fat diet (HFD)/streptozocin (STZ) regimen. Renal histological changes are assessed via H&E staining. Masson staining and immunohistochemistry (IHC) are employed to assess renal fibrosis. RT-PCR is utilized to quantify the mRNA levels of renal fibrosis, oxidative stress and inflammation markers. The levels of malondialdehyde (MDA) and reactive oxygen species (ROS), as well as the content of glutathione peroxidase (GSH-Px), are measured. The protein expressions of collagen I, TGF-β1, α-SMA, E-cadherin, Nrf2, catalase, SOD3, SOD2, SOD1, p-ERK, p-EGFR (Y845), p-EGFR (Y1173), p-NFκB P65, t-ERK, t-EGFR and t-NFκB P65 are detected by western blot analysis. Our results reveal that VAC has a beneficial effect on DN mice by improving renal function and mitigating histological damage. This is achieved through its inhibition of renal fibrosis, inflammatory cytokine overproduction, and ROS generation. Moreover, VAC treatment effectively suppresses the process of epithelial-mesenchymal transition (EMT), a crucial characteristic of renal fibrosis, in high glucose (HG)-induced HK-2 cells. Network pharmacology analysis and molecular docking identify epidermal growth factor receptor (EGFR) as a potential target for VAC. Amino acid site mutations reveal that Lys-879, Ile-918, and Ala-920 of EGFR may mediate the direct binding of VAC to EGFR. In support of these findings, VAC reduces the phosphorylation levels of both EGFR and its downstream mediator, extracellular signal-regulated kinase 1/2 (ERK1/2), in diabetic kidneys and HG-treated HK-2 cells. Notably, blocking either EGFR or ERK1/2 yields renal benefits similar to those observed with VAC treatment. Therefore, this study reveals that VAC attenuates renal damage via inactivation of the EGFR/ERK1/2 signaling axis in T2DM patients.

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Vaccarin suppresses diabetic nephropathy through inhibiting the EGFR/ERK1/2 signaling pathway

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Original ResearchVol. 56, Issue 12 • pp. 1886-1890DOI: 10.3724/abbs.2024088

A PCR-independent, annealing-free cloning method for the insertion of short DNA fragments

Authors: Linbo Li, Jin Yan, Yuan Qi, Zhenglong Xiang, Na Jiang, Tongkang Yuan, Zhenyi Wang, Yuan Wang, Huaizhe Zhan, Shiyi Liu, Li Zhao, Jing Xu, Xiaowei Lei, Yuxuan Liu, Gui Wang, Jiayang Xie, Zhenming Guo, Chunhai Cai, Shan Bian

Cloning short DNA fragments, such as shRNA and sgRNA, is a routine but time-consuming task in molecular biology. Traditional methods require annealing of complementary oligos or PCR amplification, which are labor-intensive and time-consuming. Here, we report a novel PCR-independent, annealing-free cloning method that enables the insertion of short DNA fragments using a single oligo. The method relies on T4 DNA ligase for ligation and host cell DNA polymerase for complementary strand synthesis. We demonstrate that adding T4 DNA polymerase and dNTPs to the ligation mixture significantly improves cloning efficiency. This approach simplifies the cloning process, reduces time to less than 1 hour, and is compatible with standard laboratory reagents. Our method provides a rapid and efficient alternative for cloning short DNA fragments, with broad applications in gene knockdown and genome editing.

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A PCR-independent, annealing-free cloning method for the insertion of short DNA fragments

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026027

PCIF1 modulates glioblastoma cell migration and invasion by altering PI(3,4)P2 levels through the PI5-phosphatase INPP5B

Authors: Preethi Priyanka Musunuru, Yihan Li, Yu Zhou, Gai Liu, Zhuang Sha, Zhiyuan Hu, Junbo Zhou, Naveena Konduru, Qingming Meng, Shangfeng Gao, Rutong Yu

Phosphorylated CTD Interacting Factor 1 (PCIF1) is the exclusive methyltransferase responsible for the N6,2-O-dimethyladenosine (m6Am) modification in mammalian mRNA. Our previous research identified PCIF1 as a potent tumor suppressor in glioma, demonstrating its ability to impair cell proliferation, induce G2/M phase arrest, and promote apoptosis. However, its role in glioma cell migration and invasion remains unclear. In this study, we investigate how PCIF1 regulates glioma cell migration and invasion. Overexpression of PCIF1 inhibits migration and invasion, whereas PCIF1 knockdown enhances these behaviors. Corresponding changes are observed in mesenchymal markers (Vimentin, β-catenin, Snail, Slug) and the epithelial marker T-cadherin, indicating that PCIF1 suppresses epithelial-to-mesenchymal transition (EMT)-mediated glioma invasion. Mechanistically, PCIF1 modulates the AKT pathway by promoting proteasomal degradation of AKT while increasing phosphorylated AKT (p-AKT) levels, revealing a complex regulatory mechanism. PCIF1 knockdown upregulates INPP5B, a lipid phosphatase, causing accumulation of PI(3,4)P2 and enhanced AKT activation. Conversely, PCIF1 overexpression increases PI(3,4,5)P3 production, elevating p-AKT levels. This bidirectional regulation suggests that PCIF1 influences phosphoinositide signaling and AKT activation. Our findings highlight PCIF1 as a key modulator of glioblastoma cell migration and invasion through phosphoinositide signaling, positioning it as a potential biomarker and therapeutic target in glioma.

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PCIF1 modulates glioblastoma cell migration and invasion by altering PI(3,4)P2 levels through the PI5-phosphatase INPP5B

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Original ResearchVol. 58, Issue 4 • pp. 854-864DOI: 10.3724/abbs.2026015

P300-mediated H3K18 acetylation triggers necroptosis via modulation of KRT18 transcription in diabetic nephropathy

Authors: Qiao Zhao, Qinqin Cai, Aynigar Nizam, Qingxia Yang, Xu Liu, Fufen Meng, Zhipeng Meng

Diabetic nephropathy (DN) is a major cause of end-stage renal disease. While glomerular damage is a known aspect of its pathology, tubular epithelial cell necroptosis also plays a crucial role in disease progression. Epigenetic modifications, particularly histone acetylation, have garnered attention for their role in the regulation of kidney damage-related gene expression. This study explores whether the histone acetyltransferase P300 regulates KRT18 expression via histone H3 lysine 18 acetylation (H3K18ac), driving tubular epithelial cell necroptosis and accelerating DN progression. We establish an STZ-induced diabetic nephropathy mouse model and a high glucose-treated HK-2 cell model. Western blot analysis, qPCR, immunohistochemistry, and AO/PI staining are employed to assess the expression levels of P300, H3K18ac, KRT18, and necroptosis-related proteins (RIPK1 and MLKL). Functional validation of the P300-KRT18 axis is performed using shRNA interference, overexpression, and the small molecule inhibitor C646. Both in vivo and in vitro models show significant upregulation of P300, H3K18ac, and KRT18, coupled with RIPK1/MLKL pathway activation and increased cell death. P300 knockdown or C646 treatment effectively inhibits H3K18ac and KRT18 expression, reducing necroptosis; KRT18 knockdown also alleviates P300 overexpression-induced cell death. Co-transfection with P300 overexpression and KRT18 interference demonstrates that KRT18 is a key downstream effector of P300-mediated necroptosis. In conclusion, P300 upregulates KRT18 expression through H3K18 acetylation, subsequently activating the RIPK1/MLKL pathway and promoting tubular epithelial cell necroptosis. The P300-KRT18 axis may serve as a novel epigenetic therapeutic target for DN, suggesting that epigenetic regulation could be a viable intervention strategy to delay DN progression.

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P300-mediated H3K18 acetylation triggers necroptosis via modulation of KRT18 transcription in diabetic nephropathy

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Original ResearchVol. 56, Issue 11 • pp. 1573-1583DOI: 10.3724/abbs.2024149

Integrins and NAFLD-associated liver diseases: clinical associations, pathophysiological mechanisms and pharmacological implications

Authors: Yangyue Ni, Mengwen Huang, Shiyang Chen, Shihui Wang, Jianfeng Chen

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and poses a substantial health burden with increasing incidence globally. NAFLD encompasses a spectrum extending from hepatic steatosis to nonalcoholic steatohepatitis (NASH), with the possibility of progressing to cirrhosis or, in severe instances, hepatocellular carcinoma (HCC). NAFLD extends beyond simple metabolic disruption and involves multiple immune cell-mediated inflammatory processes. Integrins are a family of heterodimeric transmembrane cell adhesion receptors that regulate various aspects of NAFLD onset and progression, including hepatocellular steatosis, hepatic stellate cell (HSC) activation and immune cell infiltration. In this review, we comprehensively summarize the involvement of integrins in NAFLD, as well as the downstream signal transduction mediated by these receptors. Furthermore, we present the latest clinical and preclinical findings on drugs that target integrins for steatosis, inflammation, fibrosis and NAFLD-related HCC treatment.

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Integrins and NAFLD-associated liver diseases: clinical associations, pathophysiological mechanisms and pharmacological implications

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Original ResearchVol. 56, Issue 11 • pp. 1644-1658DOI: 10.3724/abbs.2024102

Acetyl-11-keto-β-boswellic acid restrains the progression of synovitis in osteoarthritis via the Nrf2/HO-1 pathway

Authors: Jing Zhou, Xueyan Li, Zeyu Han, Yinhua Qian, Lang Bai, Qibin Han, Maofeng Gao, Yi Xue, Dechun Geng, Xing Yang, Yuefeng Hao

Synovial inflammation plays a key role in osteoarthritis (OA) pathogenesis. Fibroblast-like synoviocytes (FLSs) represent a distinct cell subpopulation within the synovium, and their unique phenotypic alterations are considered significant contributors to inflammation and fibrotic responses. The underlying mechanism by which acetyl-11-keto-β-boswellic acid (AKBA) modulates FLS activation remains unclear. This study aims to assess the beneficial effects of AKBA through both in vitro and in vivo investigations. Network pharmacology evaluation is used to identify potential targets of AKBA in OA. We evaluate the effects of AKBA on FLSs activation in vitro and the regulatory role of AKBA on the Nrf2/HO-1 signaling pathway. ML385 (an Nrf2 inhibitor) is used to verify the binding of AKBA to its target in FLSs. We validate the in vivo efficacy of AKBA in alleviating OA using anterior cruciate ligament transection and destabilization of the medial meniscus (ACLT+DMM) in a rat model. Network pharmacological analysis reveals the potential effect of AKBA on OA. AKBA effectively attenuates lipopolysaccharide (LPS)-induced abnormal migration and invasion and the production of inflammatory mediators, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS) in FLSs, contributing to the restoration of the synovial microenvironment. After treatment with ML385, the effect of AKBA on FLSs is reversed. In vivo studies demonstrate that AKBA mitigates synovial inflammation and fibrotic responses induced by ACLT+DMM in rats via activation of the Nrf2/HO-1 axis. AKBA exhibits theoretical potential for alleviating OA progression through the Nrf2/HO-1 pathway and represents a viable therapeutic candidate for this patient population.

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Acetyl-11-keto-β-boswellic acid restrains the progression of synovitis in osteoarthritis via the Nrf2/HO-1 pathway

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026074

Tryptophan-substituted antimicrobial peptide temporin-1CEb: in vitro and in vivo antibacterial activity against clinically isolated multidrug-resistant Klebsiella pneumonia

Authors: Fengquan Jiang, Yanjun Ma, Yunfei Zhang, Dejing Shang, Weibing Dong

Tryptophan (Trp)-substituted antimicrobial peptides (AMPs) exhibit enhanced interactions with bacterial cell membranes, potentially improving their antimicrobial efficacy. Klebsiella pneumoniae (20.59% of 2054 ICU isolates) is resistant to multiple clinically used antibiotics and presents significant treatment challenges. In the present study, three Trp-modified peptides (I4W, L12W, and I1WL5W) are generated by substituting Ile or Leu residues in temporin-1CEb, a peptide derived from frog skin, with Trp at various sites to assess their antibacterial effects and mechanisms against K. pneumoniae. Compared with L12W, both I4W and I1WL5W display superior antimicrobial activity and lower cytotoxicity. Mechanistic studies reveal that AMPs exert antibacterial and bactericidal effects through bacterial surface charge neutralization, insertion into bacterial cell membranes, increase permeability of both the inner and outer membranes, and disruption of membrane integrity. Notably, I1WL5W exhibit the most potent membrane-disrupting activity. Assessment of the impact of Trp-containing peptides on bacterial biofilms reveals that these peptides not only inhibit exopolysaccharide production and biofilm formation but also degrade preformed biofilms. A murine lung infection model is established to investigate the therapeutic efficacy of I1WL5W against MDRKP 1203-induced lung infection in mice. Compared with the control treatment, treatment with I1WL5W results in reduced bacterial counts and levels of IL-6 and TNF-α in both the blood and lung tissues of MDRKP 1203-infected mice, and treatment with I1WL5W improves lung tissue structure. The present study provides valuable insights for designing Trp-containing peptides with potent antimicrobial properties by facilitating their penetration across bacterial membranes.

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Tryptophan-substituted antimicrobial peptide temporin-1CEb: in vitro and in vivo antibacterial activity against clinically isolated multidrug-resistant Klebsiella pneumonia

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Original ResearchVol. 56, Issue 11 • pp. 1633-1643DOI: 10.3724/abbs.2024148

UHRF1 knockdown induces cell cycle arrest and apoptosis in breast cancer cells through the ZBTB16/ANXA7/Cyclin B1 axis

Authors: Di Liu, Qin Du, Yuxuan Zhu, Yize Guo, Ya Guo

Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is involved in tumorigenicity through DNA methylation in various cancers, including breast cancer. This study aims to investigate the regulatory mechanisms of UHRF1 in breast cancer progression. Herein, we show that UHRF1 is upregulated in breast cancer tissues and cell lines as measured by western blot analysis and immunohistochemistry. Breast cancer cells are transfected with a UHRF1 overexpression plasmid (pcDNA-UHRF1) or short hairpin RNA targeting UHRF1 (sh-UHRF1), followed by detection of cell proliferation, invasion, apoptosis, and cell cycle. UHRF1 overexpression promotes proliferation and invasion and attenuates cell cycle arrest and apoptosis in breast cancer cells, while UHRF1 knockdown shows the opposite effect. Moreover, methylation-specific PCR and ChIP assays indicate that UHRF1 inhibits zinc finger and BTB domain containing 16 (ZBTB16) expression by promoting ZBTB16 promoter methylation via the recruitment of DNA methyltransferase 1 (DNMT1). Then, a co-IP assay is used to verify the interaction between ZBTB16 and the annexin A7 (ANXA7) protein. ZBTB16 promotes ANXA7 expression and subsequently inhibits Cyclin B1 expression. Rescue experiments reveal that ZBTB16 knockdown reverses the inhibitory effects of UHRF1 knockdown on breast cancer cell malignancies and that ANXA7 knockdown abolishes the inhibitory effects of ZBTB16 overexpression on breast cancer cell malignancies. Additionally, UHRF1 knockdown significantly inhibits xenograft tumor growth in vivo. In conclusion, UHRF1 knockdown inhibits proliferation and invasion, induces cell cycle arrest and apoptosis in breast cancer cells via the ZBTB16/ANXA7/Cyclin B1 axis, and reduces xenograft tumor growth in vivo.

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UHRF1 knockdown induces cell cycle arrest and apoptosis in breast cancer cells through the ZBTB16/ANXA7/Cyclin B1 axis

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Original ResearchVol. 56, Issue 11 • pp. 1673-1686DOI: 10.3724/abbs.2024134

SUN5, a testis-specific nuclear membrane protein, participates in recruitment and export of nuclear mRNA in spermatogenesis

Authors: Xiyi He, Yunfei Zhang, Zenghui Mao, Gang Liu, Lihua Huang, Xiaowen Liu, Yuyan Su, Xiaowei Xing

SUN5, a testis-specific gene, is associated with acephalic spermatozoa syndrome (ASS). Here, we demonstrate that SUN5 is involved in mRNA export. In Sun5-knockout mice (Sun5–/–), poly(A)+ RNA accumulates in the nuclei of germ cells, leading to reduced sperm counts, decreased sperm motility and disrupted sperm head-to-tail junctions. Additionally, in the GC-2 germ cell line with RNA interference of Sun5, heterogeneous nuclear ribonucleoproteins (hnRNPs) and poly (A)+ RNA (mainly mRNA) are retained in the nucleus. Further mechanistic studies reveal that SUN5 interacts with Nxf1 (nuclear RNA export factor 1) and nucleoporin 93 (Nup93). Interference with Nup93 inhibits mRNA export. Treatment with leptomycin B to block the CRM1 pathway indicates that Sun5 regulates mRNA export through an Nxf1-dependent pathway. In Sun5–/– mice, the binding of Nxf1 and Nup93 decreases due to loss of Sun5 function, and the process of submitting Nxf1-binding mRNPs to Nup93 is inhibited, resulting in abnormal spermatogenesis. Together, these data may elucidate a novel pathway for mRNA export in male germ cells.

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SUN5, a testis-specific nuclear membrane protein, participates in recruitment and export of nuclear mRNA in spermatogenesis

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Original ResearchVol. 56, Issue 10 • pp. 1509-1520DOI: 10.3724/abbs.2024098

FTO-mediated m6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis

Authors: Tingjuan Huang, Chunhong Zhang, Junjie Ren, Qizhi Shuai, Xiaonan Li, Xuewei Li, Jun Xie, Jun Xu

The activation of hepatic stellate cells (HSCs) is central to the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSC activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals, and N6-methyladenosine (m6A) modification is closely related to autophagy. In this study, we find that the m6A demethylase fat mass and obesity-associated protein (FTO), which is the m6A methylase with the most significant difference in expression, is upregulated during HSC activation and bile duct ligation (BDL)-induced hepatic fibrosis. Importantly, we identify that FTO overexpression aggravates HSC activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is a target of FTO because FTO mainly mediates the m6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and the activation of HSCs. Notably, the m6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level by recognizing the m6A binding site and ultimately inhibiting autophagy and HSC activation. Taken together, our findings highlight m6A-dependent ULK1 as an essential regulator of HSC autophagy and reveal that ULK1 is a novel potential therapeutic target for hepatic fibrosis treatment.

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FTO-mediated m6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis

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Original ResearchVol. 56, Issue 10 • pp. 1483-1497DOI: 10.3724/abbs.2024078

Up-regulation of miR-10a-5p expression inhibits the proliferation and differentiation of neural stem cells by targeting Chl1

Authors: Juan Zhang, Lihong Yang, Yuqing Sun, Li Zhang, Yufei Wang, Ming Liu, Xiujuan Li, Yuxiang Liang, Hong Zhao, Zhizhen Liu, Zhiyong Qiu, Ting Zhang, Jun Xie

Neural tube defects (NTDs) are characterized by the failure of neural tube closure during embryogenesis and are considered the most common and severe central nervous system anomalies during early development. Recent microRNA (miRNA) expression profiling studies have revealed that the dysregulation of several miRNAs plays an important role in retinoic acid (RA)-induced NTDs. However, the molecular functions of these miRNAs in NTDs remain largely unidentified. Here, we show that miR-10a-5p is significantly upregulated in RA-induced NTDs and results in reduced cell growth due to cell cycle arrest and dysregulation of cell differentiation. Moreover, the cell adhesion molecule L1-like (Chl1) is identified as a direct target of miR-10a-5p in neural stem cells (NSCs) in vitro, and its expression is reduced in RA-induced NTDs. siRNA-mediated knockdown of intracellular Chl1 affects cell proliferation and differentiation similar to those of miR-10a-5p overexpression, which further leads to the inhibition of the expressions of downstream ERK1/2 MAPK signaling pathway proteins. These cellular responses are abrogated by either increased expression of the direct target of miR-10a-5p (Chl1) or an ERK agonist such as honokiol. Overall, our study demonstrates that miR-10a-5p plays a major role in the process of NSC growth and differentiation by directly targeting Chl1, which in turn induces the downregulation of the ERK1/2 cascade, suggesting that miR-10a-5p and Chl1 are critical for NTD formation in the development of embryos.

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Up-regulation of miR-10a-5p expression inhibits the proliferation and differentiation of neural stem cells by targeting Chl1

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Original ResearchVol. 56, Issue 10 • pp. 1498-1508DOI: 10.3724/abbs.2024090

miR-373-3p promotes aerobic glycolysis in colon cancer cells by targeting MFN2

Authors: Yu Wang, Jie Lun, Yuying Zhang, Mengchao Yu, Xingqian Liu, Jing Guo, Hongwei Zhang, Wensheng Qiu, Jing Fang

MicroRNAs (miRNAs) are implicated in the development of cancers and may serve as potential targets for therapy. However, the functions and underlying mechanisms of miRNAs in cancers are not well understood. This work aims to study the role of miR-373-3p in colon cancer cells. We find that the expression of miR-373-3p mimics promotes and the miR-373-3p inhibitor suppresses aerobic glycolysis and proliferation of colon cancer cells. Mechanistically, miR-373-3p inhibits the expression of MFN2, a gene that is known to suppress glycolysis, which leads to the activation of glycolysis and eventually the proliferation of cells. In a nude mouse tumor model, the expression of miR-373-3p in colon cancer cells promotes tumor growth by enhancing lactate formation, which is inhibited by the co-expression of MFN2 in the cells. Administration of the miR-373-3p antagomir blunts in vivo tumor growth by decreasing lactate production. In addition, in human colon cancers, the expression levels of miR-373-3p are increased, while those of MFN2 mRNA are decreased, and the increase of miR-373-3p is associated with the decrease of MFN2 mRNA. Our results reveal a previously unknown function and underlying mechanism of miR-373-3p in the regulation of glycolysis and proliferation in cancer cells and underscore the potential of targeting miR-373-3p for colon cancer treatment.

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miR-373-3p promotes aerobic glycolysis in colon cancer cells by targeting MFN2

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Original ResearchVol. 56, Issue 10 • pp. 1425-1436DOI: 10.3724/abbs.2024073

Identification of RACK1 as a novel regulator of non-structural protein 4 of chikungunya virus

Authors: Yao Yan, Fengyuan Zhang, Meng Zou, Hongyu Chen, Jingwen Xu, Shuaiyao Lu, Hongqi Liu

Chikungunya virus (CHIKV) is a neglected arthropod-borne and anthropogenic alphavirus. Over the past two decades, the CHIKV distribution has undergone significant changes worldwide, from the original tropics and subtropics regions to temperate regions, which has attracted global attention. However, the interactions between CHIKV and its host remain insufficiently understood, which dampens the need for the development of an anti-CHIKV strategy. In this study, on the basis of the optimal overexpression of non-structural protein 4 (nsP4), we explore host interactions of CHIKV nsP4 using mass spectrometry-based protein-protein interaction approaches. The results reveal that some cellular proteins that interact with nsP4 are enriched in the ubiquitin-proteasome pathway. Specifically, the scaffold protein receptor for activated C kinase 1 (RACK1) is identified as a novel host interactor and regulator of CHIKV nsP4. The inhibition of the interaction between RACK1 and nsP4 by harringtonolide results in the reduction of nsP4, which is caused by the promotion of degradation but not the inhibition of nsP4 translation. Furthermore, the decrease in nsP4 triggered by the RACK1 inhibitor can be reversed by the proteasome inhibitor MG132, suggesting that RACK1 can protect nsP4 from degradation through the ubiquitin-proteasome pathway. This study reveals a novel mechanism by which the host factor RACK1 regulates CHIKV nsP4, which could be a potential target for developing drugs against CHIKV.

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Identification of RACK1 as a novel regulator of non-structural protein 4 of chikungunya virus

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Original ResearchVol. 56, Issue 10 • pp. 1566-1570DOI: 10.3724/abbs.2024114

Exploring the mechanism of Panax notoginseng saponin in inhibiting the inflammatory response of microglia in cerebral ischemia based on network pharmacology

Authors: Zhaoda Duan, Wenji Jia, Jianxiang Wang, Dongyao Xu, Yujia Yang, Zhi Qi, Li Yang, Chunyun Wu

With the increasing global population and aging demographic, the incidence of stroke is rising. Among these, ischemic stroke (IS), also known as cerebral ischemia, constitutes over 80% of all stroke cases. This condition is characterized by an acute cerebrovascular disease caused by the blockage and interruption of the brain's blood supply, resulting in localized tissue ischemia, oxygen, and glucose deficiency, ultimately leading to the death of nerve cells and tissue necrosis [1,2]. "Vascular recanalization and the restoration of cerebral blood flow" are the primary clinical treatment objectives and are achieved through the intravenous administration of drugs such as tissue plasminogen activator or through surgical thrombectomy. These interventions not only restore the delivery of oxygen and glucose to the affected cerebral area but also help prevent the expansion of the infarcted region. However, the restoration of reperfusion cerebral blood flow similarly exposes the infarct area to peripheral immune cells, triggering the activation of the immune response and inflammation-induced injury [3]. Research indicates that IS elicits a robust inflammatory response, with neuroinflammation playing a crucial role in the secondary neurodegeneration process following stroke. Neuroinflammatory responses are initiated and perpetuated through injury cascades that include the release of inflammatory mediators, the migration and recruitment of white blood cells across the blood-brain barrier, and the impairment of endothelial nitric oxide synthase. These mechanisms collectively promote the activation of pro-inflammatory genes, which in turn activate microglia (MG) and exacerbate ischemic damage and neurological dysfunction [4]. MG are resident immune cells of the central nervous system (CNS). Its function is akin to that of macrophages, serving as the first line of defense against injuries within the central nervous system. Under typical conditions, brain microglia participate in immune surveillance and defense against infectious agents. However, in the pathogenesis of neurodegenerative diseases such as IS, MG are activated by various stimuli. Once activated, MG are known to release numerous proinflammatory or cytotoxic factors, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and reactive oxygen species (ROS). These factors initiate the neuroinflammatory response, exacerbate inflammation, intensify damage to brain tissue and neurons, and significantly hinder the repair of brain injuries and neurogenesis [5,6]. Therefore, inhibiting the activation of microglia and reducing the inflammatory response in the central nervous system are crucial for minimizing brain damage caused by IS and are vital for developing effective prevention and treatment strategies. In recent years, certain natural compounds extracted from traditional drug formulations have shown high therapeutic potential in protecting the brain from cerebral ischemic injury. These compounds reduce the neuroinflammatory response and apoptosis following stroke. Traditional Chinese herbal medicine (TCHM) and its constituent herbs feature a multiplicity of components, targets, and pathways owing to their complex formulations and therapeutic principles, making them promising sources for developing effective treatments for IS. Panax notoginseng saponin (PNS), as the principal bioactive component of Panax notoginseng, is extensively utilized in the prevention and treatment of cardiovascular and cerebrovascular diseases. Its pharmacological benefits include dissipating blood stasis, promoting hemostasis, alleviating swelling and pain, regulating energy metabolism disorders, balancing ion metabolism, and reducing and accelerating the clearance of free radicals [7]. Research indicates that PNS mitigates apoptosis by maintaining mitochondrial homeostasis, enhancing the integrity of the blood‒brain barrier (BBB), augmenting cerebral blood supply, and fostering the differentiation of neural stem cells and proliferation of hippocampal neurons. In addition, PNS offers neuroprotection against focal cerebral I/R injury in rats by reducing brain edema, upregulating the expression of the heat shock protein HSP70, and downregulating the expression of transferrin [8,9]. Additionally, PNS has been reported to enhance the recovery of neurogenesis and neurological function in cerebral embolism induced by microspheres and to reduce sepsis-induced acute kidney injury by suppressing inflammation [10]. However, the mechanism by which PNS targets IS has not been fully elucidated. In this study, we investigated the anti-inflammatory effects of PNS on IS and identified potential target pathways that could inhibit microglia-mediated inflammatory response.

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Exploring the mechanism of Panax notoginseng saponin in inhibiting the inflammatory response of microglia in cerebral ischemia based on network pharmacology

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Original ResearchVol. 56, Issue 10 • pp. 1415-1424DOI: 10.3724/abbs.2024085

Posttranslational regulatory mechanism of PD-L1 in cancers and associated opportunities for novel small-molecule therapeutics

Authors: Minchen Cai, Mengting Xu, Dianping Yu, Qun Wang, Sanhong Liu

Despite the tremendous progress in cancer research over the past few decades, effective therapeutic strategies are still urgently needed. Accumulating evidence suggests that immune checkpoints are the cause of tumor immune escape. PD-1/PD-L1 are among them. Posttranslational modification is the most critical step for protein function, and the regulation of PD-L1 by small molecules through posttranslational modification is highly valuable. In this review, we discuss the mechanisms of tumor cell immune escape and several posttranslational modifications associated with PD-L1 and describe examples in which small molecules can regulate PD-L1 through posttranslational modifications. Herein, we propose that the use of small molecule compounds that act by inhibiting PD-L1 through posttranslational modifications is a promising therapeutic approach with the potential to improve clinical outcomes for cancer patients.

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Posttranslational regulatory mechanism of PD-L1 in cancers and associated opportunities for novel small-molecule therapeutics

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Original ResearchVol. xx, Issue xx • pp. xx-xxDOI: 10.3724/abbs.2026065

Ginsenoside Rh2 alleviates osteoporosis by attenuating oxidative stress-induced osteoblast dysfunction via the FoxO1/β-catenin pathway

Authors: Wenqi Jin, Yujing Tan, Xuenan Chen, Zehan Guo, Jixiang Ren, Liwei Sun

The degree of oxidative stress decreases osteoblast function with age, which leads to a decline in bone compressive capacity. Ginsenoside Rh2 is a known clinical or adjuvant therapy for various tissues. In this study, we investigate the pharmacological effects of Rh2 against oxidative stress-induced osteoblasts. Osteoblasts are pretreated with Rh2 for 48 h and then exposed to hydrogen peroxide (H2O2), which results in significantly decreased ROS levels, increased antioxidant enzyme activity, and enhanced mitochondrial function. Functionally, Rh2 increases alkaline phosphatase (ALP) expression, together with enhanced mineralization and expression of osteogenesis-associated genes. Rh2 also promotes the nuclear translocation of FoxO1 and β-catenin, whereas it does not reverse reduced mineralization caused by decreased FoxO1 or β-catenin activity, indicating that its effect is mediated through the functional interaction between FoxO1 and β-catenin. In a mouse model of lipopolysaccharide (LPS)-induced bone loss, Rh2 administration improves trabecular microstructure, increases osteoblast numbers, and upregulates serum metabolites associated with bone formation. Immunofluorescence analysis further reveals that Rh2 promotes the nuclear co-localization of FoxO1 and β-catenin in femurs, indicating their coordinated action within this signaling axis. These findings indicate that Rh2 mitigates oxidative stress-induced osteoblast dysfunction via the FoxO1/β-catenin pathway, highlighting the pivotal role of redox balance in bone remodeling and suggesting a promising therapeutic strategy for osteoporosis.

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Ginsenoside Rh2 alleviates osteoporosis by attenuating oxidative stress-induced osteoblast dysfunction via the FoxO1/β-catenin pathway

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Original ResearchVol. 56, Issue 9 • pp. 1256-1266DOI: 10.3724/abbs.2024105

Molecular insight into the potential functional role of pseudoenzyme GFOD1 via interaction with NKIRAS2

Authors: Jiawen Shi, Xinyi Guo, Chan Liu, Yilun Wang, Xiaobao Chen, Guihua Wu, Jianping Ding, Tianlong Zhang

The glucose-fructose oxidoreductase/inositol dehydrogenase/rhizopine catabolism protein (Gfo/Idh/MocA) family includes a variety of oxidoreductases with a wide range of substrates that utilize NAD or NADP as redox cofactor. Human contains two members of this family, namely glucose-fructose oxidoreductase domain-containing protein 1 and 2 (GFOD1 and GFOD2). While GFOD1 exhibits low tissue specificity, it is notably expressed in the brain, potentially linked to psychiatric disorders and severe diseases. Nevertheless, the specific function, cofactor preference, and enzymatic activity of GFOD1 remain largely unknown. In this work, we find that GFOD1 does not bind to either NAD or NADP. Crystal structure analysis unveils that GFOD1 exists as a typical homodimer resembling other family members, but lacks essential residues required for cofactor binding, suggesting that it may function as a pseudoenzyme. Exploration of GFOD1-interacting partners in proteomic database identifies NF-κB inhibitor-interacting Ras-like 2 (NKIRAS2) as one potential candidate. Co-immunoprecipitation (co-IP) analysis indicates that GFOD1 interacts with both GTP- and GDP-bound forms of NKIRAS2. The predicted structural model of the GFOD1-NKIRAS2 complex is validated in cells using point mutants and shows that GFOD1 selectively recognizes the interswitch region of NKIRAS2. These findings reveal the distinct structural properties of GFOD1 and shed light on its potential functional role in cellular processes.

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Molecular insight into the potential functional role of pseudoenzyme GFOD1 via interaction with NKIRAS2

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Original ResearchVol. 56, Issue 9 • pp. 1373-1386DOI: 10.3724/abbs.2024111

Lactate activates CCL18 expression via H3K18 lactylation in macrophages to promote tumorigenesis of ovarian cancer

Authors: Jinrui Sun, Qinmei Feng, Yue He, Ming Wang, Yumei Wu

This study investigates the role of lactate in the genesis and progression of ovarian cancer (OV) and explores the underlying mechanisms. Serum lactate levels show a positive correlation with tumor grade and poor prognosis in patients with OV. Bioinformatics analysis identifies CCL18 as a lactate-related gene in OV. CCL18 is up-regulated in cancerous tissues and positively related to serum lactate levels in OV patients. THP-1 cells are exposed to phorbol-12-myristate-13-acetate for M0 macrophage induction. The results of RT-qPCR and ELISA for M1/M2 macrophage-related markers and inflammatory cytokines show that the exposure of lactate to macrophages induces M2 polarization. Based on the coculture of OV cells with macrophages, lactate-treated macrophages induces a significant increase in the proliferation and migration of OV cells. However, these effects can be reversed by silencing of Gpr132 in macrophages or treatment with anti-CCL18 antibody. Experiments using the xenograft model verify that the oncogenic role of lactate in tumor growth and metastasis relies on Gpr132 and CCL18. ChIP-qPCR and luciferase reporter assays reveal that lactate regulates CCL18 expression via H3K18 lactylation. In conclusion, lactate is a potential therapeutic target for OV. It is involved in tumorigenesis by activating CCL18 expression via H3K18 lactylation in macrophages.

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Lactate activates CCL18 expression via H3K18 lactylation in macrophages to promote tumorigenesis of ovarian cancer

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Original ResearchVol. 56, Issue 9 • pp. 1289-1299DOI: 10.3724/abbs.2024084

FOXM1 mediates methotrexate resistance in osteosarcoma cells by promoting autophagy

Authors: Luoyang Wang, Dongchang Zhai, Lei Tang, Hui Zhang, Xinlong Wang, Ning Ma, Xiaoyue Zhang, Mingguo Cheng, Ruowu Shen

Osteosarcoma (OS) is a primary bone cancer mostly found in adolescents and elderly individuals. The treatment of OS is still largely dependent on traditional chemotherapy. However, the high incidence of drug resistance remains one of the greatest impediments to limiting improvements in OS treatment. Recent findings have indicated that the transcription factor FOXM1 plays an important role in various cancer-related events, especially drug resistance. However, the possible role of FOXM1 in the resistance of OS to methotrexate (MTX) remains to be explored. Here, we find that FOXM1, which confers resistance to MTX, is highly expressed in OS tissues and MTX-resistant cells. FOXM1 overexpression promotes MTX resistance by enhancing autophagy in an HMMR/ATG7-dependent manner. Importantly, silencing of FOXM1 or inhibiting autophagy reverses drug resistance. These findings demonstrate a new mechanism for FOXM1-induced MTX resistance and provide a promising target for improving OS chemotherapy outcomes.

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FOXM1 mediates methotrexate resistance in osteosarcoma cells by promoting autophagy

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Original ResearchVol. 56, Issue 9 • pp. 1311-1322DOI: 10.3724/abbs.2024049

Aminophylline suppresses chronic renal failure progression by activating SIRT1/AMPK/mTOR-dependent autophagy

Authors: Xin Liao, Jieyi Lu, Zhifeng Huang, Jinai Lin, Miao Zhang, Huanru Chen, Xiaoqing Lin, Xia Gao, Sitang Gong

Chronic renal failure (CRF) is a severe syndrome affecting the urinary system for which there are no effective therapeutics. In this study, we investigate the effects and mechanisms of aminophylline in preventing CRF development. A rat model of chronic renal failure is established by 5/6 nephrectomy. The levels of serum creatinine (SCR), urinary protein (UPR), and blood urea nitrogen (BUN) are detected by ELISA. Histological evaluations of renal tissues are performed by H&E, Masson staining, and PAS staining. Functional protein expression is detected by western blot analysis or immunofluorescence microscopy. Glomerular cell apoptosis is determined using the TUNEL method. Results show that Aminophylline significantly reduces the levels of SCR, UPR, and BUN in the CRF model rats. Histological analyses show that aminophylline effectively alleviates renal tissue injuries in CRF rats. The protein expression levels of nephrin, podocin, SIRT1, p-AMPK, and p-ULK1 are greatly increased, while p-mTOR protein expression is markedly decreased by aminophylline treatment. Additionally, the protein level of LC3B in CRF rats is significantly increased by aminophylline. Moreover, aminophylline alleviates apoptosis in the glomerular tissues of CRF rats. Furthermore, resveratrol promotes SIRT1, p-AMPK, and p-ULK1 protein expressions and reduces p-mTOR and LC3B protein expressions in CRF rats. Selisistat (a SIRT1 inhibitor) mitigates the changes in SIRT1, p-AMPK, p-ULK1, p-mTOR, and LC3B expressions induced by aminophylline. Finally, RAPA alleviates renal injury and apoptosis in CRF rats, and 3-MA eliminates the aminophylline-induced inhibition of renal injury and apoptosis in CRF rats. Aminophylline suppresses chronic renal failure progression by modulating the SIRT1/AMPK/mTOR-mediated autophagy process.

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Aminophylline suppresses chronic renal failure progression by activating SIRT1/AMPK/mTOR-dependent autophagy

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Original ResearchVol. 56, Issue 9 • pp. 1365-1372DOI: 10.3724/abbs.2024091

Hepatitis E virus infection upregulates ING5 expression in vitro and in vivo

Authors: Wanqiu Zhao, Yueping Xia, Tengyuan Li, Huichan Liu, Guo Zhong, Dongxue Chen, Wenhai Yu, Yunlong Li, Fen Huang

Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individuals infected by HEV are prone to chronic hepatitis and increase the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor that is expressed at low levels in cancer tumors or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study, acute and chronic HEV animal models are used to explore the interaction between ING5 and HEV. Notably, the expression of ING5 is significantly increased in both the livers of acute HEV-infected BALB/c mice and chronic HEV-infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression is further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulates ING5 expression both in vivo and in vitro, which has significant implications for further understanding the pathogenic mechanism of HEV infection.

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Hepatitis E virus infection upregulates ING5 expression in vitro and in vivo

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Original ResearchVol. 56, Issue 9 • pp. 1340-1351DOI: 10.3724/abbs.2024050

GroEL triggers NLRP3 inflammasome activation through the TLR/NF-κB p-p65 axis in human periodontal ligament stem cells

Authors: Li Zhang, Mengmeng Duan, Xiaohua Pu, Huiling Zheng, Xinjie Ning, Ying Tu, Chunming Xu, Demao Zhang, Chengcheng Liu, Jing Xie

The interaction between bacteria and the host plays a vital role in the initiation and progression of systemic diseases, including gastrointestinal and oral diseases, due to the secretion of various virulence factors from these pathogens. GroEL, a potent virulence factor secreted by multiple oral pathogenic bacteria, is implicated in the damage of gingival epithelium, periodontal ligament, alveolar bone and other peripheral tissues. However, the underlying biomechanism is still largely unknown. In the present study, we verify that GroEL can trigger the activation of NLRP3 inflammasome and its downstream effector molecules, IL-1β and IL-18, in human periodontal ligament stem cells (hPDLSCs) and resultantly induce high activation of gelatinases (MMP-2 and MMP-9) to promote the degradation of extracellular matrix (ECM). GroEL-mediated activation of the NLRP3 inflammasome requires the participation of Toll-like receptors (TLR2 and TLR4). High upregulation of TLR2 and TLR4 induces the enhancement of NF-κB (p-p65) signaling and promotes its nuclear accumulation, thus activating the NLRP3 inflammasome. These results are verified in a rat model with direct injection of GroEL. Collectively, this study provides insight into the role of virulence factors in bacteria-induced host immune response and may also provide a new clue for the prevention of periodontitis.

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GroEL triggers NLRP3 inflammasome activation through the TLR/NF-κB p-p65 axis in human periodontal ligament stem cells

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Original ResearchVol. 56, Issue 9 • pp. 1406-1409DOI: 10.3724/abbs.2024115

Identification and validation of disease severity-related circular RNA in acute pancreatitis

Authors: Jiarong Li, Zefang Sun, Caihong Ning, Chiayen Lin, Dingcheng Shen, Gengwen Huang, Shuai Zhu, Lu Chen

Acute pancreatitis arises from the activation of digestive enzymes in pancreatic acinar cells, leading to autodigestion of the pancreas and surrounding tissues. It is a common digestive tract emergency which requires hospitalization, and its incidence is increasing worldwide. In the past decade, several advances have been made in the treatment of acute pancreatitis. However, there is still a lack of efficacious drugs for clinical practice, and the limited value of existing biomarkers for early warning of the severity of acute pancreatitis is a major obstacle. Thus, there is an urgent need to gain a better understanding of the molecular mechanisms of acute pancreatitis. Circular RNAs (circRNAs) are a unique class of RNA molecules that are covalently closed. Ongoing investigations have provided evidence that circRNAs govern downstream target expression by acting as miRNA sponges, functioning as transcription factors, interacting with RNA-binding proteins, and regulating alternative splicing. These mechanisms support the pivotal role of circRNAs in a wide variety of physiological and pathological conditions, such as innate immunity, inflammation, neuronal function, and tumorigenesis. To explore the role of circular RNA in acute pancreatitis, we employed circRNA microarray technology (Arraystar Human circRNA Array V2) to examine the circRNA expression profile in the blood of three acute pancreatitis patients and three healthy controls. Clinical acute pancreatitis samples were obtained from Xiangya Hospital, Central South University. This study was approved by the Ethics Committee of Xiangya hospital (No. 2019010008). Normal control patients were recruited from among individuals who had visited Xiangya Hospital for a routine checkup. Written informed consent was obtained from all participants or their legal representatives for publication of data. The diagnosis and severity classification of acute pancreatitis were performed according to the American Gastroenterological Association guidelines and the Revised Atlanta Classification (RAC). circRNAs with a fold change ≥1.5 and a P value<0.05 were considered to be differentially expressed. As shown in Figure 1A, the two groups presented different expression profiles. We found that 91 circRNAs were significantly differentially expressed in the blood of acute pancreatitis patients, with 10 circRNAs exhibiting increased expression and 81 exhibiting decreased expression (Figure 1B,C). Among the differentially expressed circRNAs in acute pancreatitis, downregulated circRNAs are more prevalent than upregulated circRNAs, and the differential expression is more significant. Therefore, the present study focused on downregulated circRNAs. We selected circRNAs that are downregulated at least 2.5-fold and excluded those with fewer than 1000 bases to ensure the accuracy of qPCR. Based on these criteria, we identified nine circRNAs (circ_0006554, circ_0007798, circRNA_405815, circ_0001847, circ_0069748, circ_0001850, circ_0008417, circ_0002560, and circ_0000008) for validation by qPCR (Applied Biosystems, Foster City, USA) in blood samples from 30 acute pancreatitis patients (10 patients each with mild acute pancreatitis, moderate severe acute pancreatitis, and severe acute pancreatitis) and 15 healthy individuals. The levels of circ_0007798, circ_0001847, and circ_0069748 were significantly lower in acute pancreatitis patients than in normal controls, while the remaining circRNAs were not significantly differentially expressed (Figure 1D). In addition, the levels of circ_0007798 increased gradually with the severity of acute pancreatitis, suggesting that circ_0007798 is associated with the clinical severity of the disease (Figure 1E). Differential circRNAs have been studied for the diagnosis of pancreatic diseases. The expression level of circ_0007798 can be used to grade the severity of acute pancreatitis and provide individualized treatment. Furthermore, homology analysis (NCBI blast) revealed that circ_0007798 has a high degree of conservation between rats and humans according to the basic local alignment search tool. In conclusion, according to the

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Identification and validation of disease severity-related circular RNA in acute pancreatitis

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Original ResearchVol. 56, Issue 9 • pp. 1352-1364DOI: 10.3724/abbs.2024024

The mechanism by which piR-000699 targets SLC39A14 regulates ferroptosis in aging myocardial ischemia/reperfusion injury

Authors: Hongyang Chi, Yue’e Chai, Lingju Ma, Yichen Wang, Qianqian Wu, Lexin Wang, Junjie Zhai, Fufun Ma, Yancheng Tian, Ning Qi, Jianhong Peng, Youjuan Fu, Xiaoling Yang, Hui Huang, Shengchao Ma

Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to different types of cell death. The degree of irreversible myocardial damage is closely related to age, and ferroptosis is involved in cardiomyocyte damage. However, the mechanisms underlying ferroptosis regulation in aging myocardial I/R injury are still unclear. The present study aims to explore the underlying mechanism of piRNA regulation in ferroptosis. Using left anterior descending coronary artery ligation in an aging rat model and a D-galactose-induced rat cardiomyocyte line (H9C2) to construct an aging cardiomyocyte model, we investigate whether ferroptosis occurs after reperfusion injury in vitro and in vivo. This study focuses on the upregulation of piR-000699 after hypoxia/reoxygenation treatment in aging cardiomyocytes by observing hypoxia/reoxygenation (H/R) injury indicators and ferroptosis-related indicators and clarifying the role of piR-000699 in H/R injury caused by ferroptosis in aging cardiomyocytes. Bioinformatics analysis reveals that SLC39A14 is a gene that binds to piR-000699. Our data show that ferroptosis plays an important role in I/R injury both in vivo and in vitro. Furthermore, the results show the potential role of piR-000699 in regulating SLC39A14 in ferroptosis in aging cardiomyocytes under hypoxia/reoxygenation conditions. Together, our results reveal that the mechanism by which piR-000699 binds to SLC39A14 regulates ferroptosis in aging myocardial I/R injury.

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The mechanism by which piR-000699 targets SLC39A14 regulates ferroptosis in aging myocardial ischemia/reperfusion injury

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Original ResearchVol. 56, Issue 9 • pp. 1267-1277DOI: 10.3724/abbs.2024010

TRMT13 inhibits the growth of papillary thyroid cancer by targeting ANAPC4

Authors: Lianyong Liu, Yan Wang, Mei Zou, Shiwei Chen, Fengying Wu, Xiangqi Li

The recently discovered gene TRMT13 encodes a type of RNA methylase and is a member of the CCDC family (also called CCDC76). Here, we delineate its role in papillary thyroid cancer (PTC). Bioinformatics analysis shows significant TRMT13 and ANAPC4 downregulation in PTC and reveals that the expression levels of both genes are linearly correlated. Subsequent analyses confirm that both TRMT13 and ANAPC4 expressions are downregulated in PTC tissues and that this change in expression has a significant impact on cancer diagnosis. We conduct assays on PTC cells subjected to TRMT13 and ANAPC4 silencing or overexpression to assess the biological effects of these genes. We also perform rescue experiments to validate the regulatory effects of TRMT13 on ANAPC4. A nude mouse tumor model is used to evaluate the effects of TRMT13 and ANAPC4 on PTC tumorigenesis. TRMT13 expression is decreased in PTC tissues and cell lines and is positively correlated with that of ANAPC4. Cell assays reveal that TRMT13/ANAPC4 attenuates the malignancy of PTC cells by restraining cell proliferation, migration and invasion, while rescue experiments corroborate that ANAPC4 is a downstream target of TRMT13. In the nude mouse xenograft model, both TRMT13 and ANAPC4 inhibit tumor growth, and TRMT13 and ANAPC4 expression levels are significantly associated with survival. Taken together, these findings lead to the conclusion that TRMT13 inhibits PTC growth via ANAPC4, indicating a new role of TRMT13 and providing insights into the tRNA methyltransferase and coiled-coil domain-containing protein families.

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TRMT13 inhibits the growth of papillary thyroid cancer by targeting ANAPC4

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Original ResearchVol. 56, Issue 9 • pp. 1300-1310DOI: 10.3724/abbs.2024042

Proanthocyanidins isolated from lotus seed skin mitigate glycolipid metabolism disorder through the p38/Nrf2/NF-κB signaling pathway

Authors: Yuhang Yi, Tao Li, Chenghao lv, Wenjiang He, Wenzhi Li, Xixin Zhou, Si Qin

Lotus seed skin extract is rich in flavonoids, making it a promising candidate for developing health products. In a previous study, we found that proanthocyanidins from lotus seed skin, particularly proanthocyanidin B1 (PB1), can indirectly activate the Nrf2 signaling pathway, exerting an antioxidant effect. In this study, we isolate proanthocyanidins from lotus seed skin (PLS) using ethanol extraction and RP-HPLC identification, and investigate its effects on glycolipid metabolism both in vivo and in vitro. Our results demonstrate that PLS reduces body weight in high-fat diet (HFD) mice by decreasing feed efficiency. PLS also normalizes serum glucose, insulin secretion, glycosylated hemoglobin (HbA1c), and intraperitoneal glucose tolerance (IPGTT). Furthermore, PLS significantly improves blood lipid parameters and inhibits the expressions of six proinflammatory factors, including IL-1α, IL-1β, IL-3, IL-6, IFN-γ and TNF-α in HFD mice. Additionally, analysis of fresh liver tissues reveals that PLS and PB1 induce the expressions of antioxidant proteins such as HO-1 and NQO1 by activating the p38-Nrf2 signaling pathway and inhibiting the NF-κB signaling pathway. In conclusion, proanthocyanidins from lotus seed skin regulate glycolipid metabolism disorders by targeting the p38/Nrf2/NF-κB signaling pathway. Our study offers a new approach for the high-value comprehensive utilization of lotus seed skin by-products and precise dietary intervention for metabolic syndrome.

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Proanthocyanidins isolated from lotus seed skin mitigate glycolipid metabolism disorder through the p38/Nrf2/NF-κB signaling pathway

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Original ResearchVol. 56, Issue 9 • pp. 1278-1288DOI: 10.3724/abbs.2024066

The rod cell, a small form of Candida albicans, possesses superior fitness to the host gut and adaptation to commensalism

Authors: Yinxing Xu, Wencheng Zhu, Baodi Dai, Hui Xiao, Jiangye Chen

Candida albicans deploys various morphological forms through complex switching mechanisms, ensuring its survival and thriving as a commensal or pathogen in vastly different human niches. In this study, we demonstrate that a novel ''rod'' morphological form of C. albicans coexists and is interchangeable with previously reported white, gray, and opaque forms, constituting a tetra-stable phenotypic switching system. Rod cells arise from the efg1 mutant of SC5314 cells or from the clinical BJ1097 strain cultured under glucose-free conditions. They are characterized by a distinct gene expression profile and can be stably maintained through in vitro passaging or in vivo inhabitation of the gastrointestinal (GI) tract of mice. Remarkably, the majority of the efg1 mutant cells become rod cells in N-acetylglucosamine (GlcNAc)-containing medium, and the GlcNAc sensor Ngs1 is instrumental in converting the white or gray cells to the rod cells. Conversely, glucose inhibits rod cells through Cph1; consequently, the loss of Cph1 in the efg1 mutant cells permits their conversion to rod cells in glucose-replete media. Notably, rod cells of the efg1/cph1 mutant display superior adaptation and longer persistence in the murine GI environment than wild-type white cells. Taken together, these findings establish rod cells as a previously unappreciated form that is not only morphologically and transcriptionally distinguishable but also defined by specific genetic and environmental determinants, shedding light on complex fungus-host interactions.

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The rod cell, a small form of Candida albicans, possesses superior fitness to the host gut and adaptation to commensalism

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Original ResearchVol. 56, Issue 8 • pp. 1118-1129DOI: 10.3724/abbs.2024127

O-glycosylation of SARS-CoV-2 spike protein by host O-glycosyltransferase strengthens its trimeric structure

Authors: Zhijue Xu, Han Zhang, Jiaqi Tian, Xin Ku, Rumeng Wei, Jingli Hou, Can Zhang, Fang Yang, Xia Zou, Yang Li, Hiroyuki Kaji, Sheng-Ce Tao, Atsushi Kuno, Wei Yan, Lin-Tai Da, Yan Zhang

Protein O-glycosylation, also known as mucin-type O-glycosylation, is one of the most abundant glycosylation in mammalian cells. It is initially catalyzed by a family of polypeptide GalNAc transferases (ppGalNAc-Ts). The trimeric spike protein (S) of SARS-CoV-2 is highly glycosylated and facilitates the virus’s entry into host cells and membrane fusion of the virus. However, the functions and relationship between host ppGalNAc-Ts and O-glycosylation on the S protein remain unclear. Herein, we identify 15 O-glycosites and 10 distinct O-glycan structures on the S protein using an HCD-product-dependent triggered ETD mass spectrometric analysis. We observe that the isoenzyme T6 of ppGalNAc-Ts (ppGalNAc-T6) exhibits high O-glycosylation activity for the S protein, as demonstrated by an on-chip catalytic assay. Overexpression of ppGalNAc-T6 in HEK293 cells significantly enhances the O-glycosylation level of the S protein, not only by adding new O-glycosites but also by increasing O-glycan heterogeneity. Molecular dynamics simulations reveal that O-glycosylation on the protomer-interface regions, modified by ppGalNAc-T6, potentially stabilizes the trimeric S protein structure by establishing hydrogen bonds and non-polar interactions between adjacent protomers. Furthermore, mutation frequency analysis indicates that most O-glycosites of the S protein are conserved during the evolution of SARS-CoV-2 variants. Taken together, our finding demonstrate that host O-glycosyltransferases dynamically regulate the O-glycosylation of the S protein, which may influence the trimeric structural stability of the protein. This work provides structural insights into the functional role of specific host O-glycosyltransferases in regulating the O-glycosylation of viral envelope proteins.

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O-glycosylation of SARS-CoV-2 spike protein by host O-glycosyltransferase strengthens its trimeric structure

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Original ResearchVol. 56, Issue 8 • pp. 1130-1144DOI: 10.3724/abbs.2024100

Macrophages exploit the mannose receptor and JAK-STAT1-MHC-II pathway to drive antigen presentation and the antimycobacterial immune response after BCG vaccination

Authors: Ying Zhang, Dandan Xu, Qi Nie, Jing Wang, Dan Fang, Yan Xie, Huang Xiong, Qin Pan, Xiao-Lian Zhang

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains one of the leading causes of fatal infectious diseases worldwide. The only licensed vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), has variable efficacy against TB in adults. Insufficiency of immune cell function diminishes the protective effects of the BCG vaccine. It is critical to clarify the mechanism underlying the antimycobacterial immune response during BCG vaccination. Macrophage mannose receptor (MR) is important for enhancing the uptake and processing of glycoconjugated antigens from pathogens for presentation to T cells, but the roles of macrophage MR in the BCG-induced immune response against M.tb are not yet clear. Here, we discover that macrophage MR deficiency impairs the antimycobacterial immune response in BCG-vaccinated mice. Mechanistically, macrophage MR triggers JAK-STAT1 signaling, which promotes antigen presentation via upregulated MHC-II and induces IL-12 production by macrophages, contributing to CD4+ T cell activation and IFN-γ production. MR deficiency in macrophages reduces the vaccine efficacy of BCG and increases susceptibility to M.tb H37Ra challenge in mice. Our results suggest that MR is critical for macrophage antigen presentation and the antimycobacterial immune response to BCG vaccination and offer valuable guidance for the preventive strategy of BCG immunization.

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Macrophages exploit the mannose receptor and JAK-STAT1-MHC-II pathway to drive antigen presentation and the antimycobacterial immune response after BCG vaccination

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Original ResearchVol. 57, Issue 8 • pp. 1252-1259DOI: 10.3724/abbs.2024229

CD40 ligation-induced ERK activation leads to enhanced radiosensitivity in cervical carcinoma cells via promoting autophagy

Authors: Baocai Liu, Yadong Zhang, Quan Wang, Qian Wang, Zhixin Wang, Li Feng

CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, plays an important role not only in the immune system but also in tumor progression. CD40 ligation reportedly promotes autophagy in immune cells. However, the effects of CD40 ligation on autophagy and its mechanism in solid tumor cells are still unclear. In this study, we find that CD40 ligation promotes autophagosome formation and consequently promotes autophagic flux in cervical cancer cells. Mechanistically, this effect relies on ERK contributing to CD40 ligation-induced ATG13 upregulation by p53. Furthermore, we demonstrate that CD40 ligation-induced autophagy increases the radiosensitivity of cervical cancer cells. Taken together, our results provide new evidence for the involvement of the CD40 pathway in autophagy and radiotherapy in cervical cancer cells.

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CD40 ligation-induced ERK activation leads to enhanced radiosensitivity in cervical carcinoma cells via promoting autophagy

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Original ResearchVol. 57, Issue 12 • pp. 1999-2010DOI: 10.3724/abbs.2025066

Crystal structures of Kif2A complexed with WDR5 reveal the structural plasticity of WIN-S7 sites

Authors: Yang Yang, Shuting Zhang, Zhangyu Wu, Wenwen Li, Xuefang Sun, Yumi Xuan, Tianrong Hang, Li Xu, Xuemin Chen

Chromosome congression and spindle assembly are essential for genomic stability and proper cell division, with deficiencies in these processes linked to tumorigenesis. WD repeat-containing protein 5 (WDR5), a core component of the mixed lineage leukemia (MLL) methyltransferase complex, directly binds to kinesin family member 2A (Kif2A) to regulate these mitotic events. Despite the importance of this interaction, its structural basis for Kif2A recognition by WDR5 remains unclear. Here, we determine the crystal structure of WDR5 in complex with a Kif2A-derived peptide (residues 114–122) at a resolution of 1.85 Å. Structural analysis reveals that Kif2A engages both the WIN and S7 sites of WDR5 via Arg117 and Ser121, with Ser121 forming hydrogen bonds with WDR5 Tyr191 and Lys259, driving Tyr191 rotation and opening the S7 pocket. Additional structures of WDR5 complexed with truncated or mutated Kif2A peptides and a WDR5 Y191F variant highlight the dynamic nature of Tyr191. Notably, anti-WDR5 compounds exhibit a similar binding mode at the WDR5 WIN-S7 site. The results of mutagenesis combined with isothermal titration calorimetry (ITC) assays underscore the critical roles of Arg117 and Ser121 in mediating the binding of Kif2A to WDR5. In summary, our findings provide atomic-level insights into the molecular mechanisms underlying the non-canonical mitotic function of the MLL/WDR5 complex and highlight WIN-S7 sites as promising therapeutic targets for diseases associated with chromosomal instability, such as cancers.

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Crystal structures of Kif2A complexed with WDR5 reveal the structural plasticity of WIN-S7 sites

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Original ResearchVol. 56, Issue 12 • pp. 2022-2033DOI: 10.3724/abbs.2025021

Pyruvate dehydrogenase alleviates macrophage autophagy in Hcy-induced ApoE–/– mice

Authors: Qiujun Liu, Feng Li, Shutong Hu, Ning Ding, Fang Ma, Yinju Hao, Guizhong Li, Jiantuan Xiong, Huiping Zhang, Yideng Jiang

Macrophages play a protective role in atherosclerosis, whereas homocysteine (Hcy) is recognized as an independent risk factor for atherosclerosis. Defects in macrophage autophagy contribute to the formation of atherosclerotic plaques, and dysregulated energy metabolism is closely linked to the process of autophagy. However, the regulation of macrophage autophagy by pyruvate dehydrogenase (PDH), a key component of the PDH complex involved in energy and metabolic homeostasis, remains poorly understood in the context of atherosclerosis induced by Hcy. In our study, proteomic profiling identifies 748 upregulated proteins and 760 downregulated proteins in Hcy-treated macrophages. KEGG pathway analysis reveals significant enrichment of differentially expressed proteins in metabolism-related pathways, including those related to the biosynthesis of amino acids, carbon metabolism, and glycolysis/gluconeogenesis. Additionally, we explore the role of PDH in mediating Hcy-induced atherosclerosis in ApoE–/– mice. The results show a marked reduction in PDH expression and activity in Hcy-treated macrophages, leading to impaired autophagy. Notably, PDH activation enhances the assembly of the autophagy initiator ULK1-FIP200-Atg13 complex through the modulation of the AMPK/mTOR signaling pathway, suggesting a potential therapeutic target for Hcy-induced atherosclerosis.

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Pyruvate dehydrogenase alleviates macrophage autophagy in Hcy-induced ApoE–/– mice

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Original ResearchVol. 56, Issue 8 • pp. 1145-1155DOI: 10.3724/abbs.2024123

Deciphering disease through glycan codes: leveraging lectin microarrays for clinical insights

Authors: Hangzhou Yang, Zihan Lin, Bo Wu, Jun Xu, Sheng-Ce Tao, Shumin Zhou

Glycosylation, a crucial posttranslational modification, plays a significant role in numerous physiological and pathological processes. Lectin microarrays, which leverage the high specificity of lectins for sugar binding, are ideally suited for profiling the glycan spectra of diverse and complex biological samples. In this review, we explore the evolution of lectin detection technologies, as well as the applications and challenges of lectin microarrays in analyzing the glycome profiles of various clinical samples, including serum, saliva, tissues, sperm, and urine. This review not only emphasizes significant advancements in the high-throughput analysis of polysaccharides but also provides insight into the potential of lectin microarrays for diagnosing and managing diseases such as tumors, autoimmune diseases, and chronic inflammation. We aim to provide a clear, concise, and comprehensive overview of the use of lectin microarrays in clinical settings, thereby assisting researchers in conducting clinical studies in glycobiology.

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Deciphering disease through glycan codes: leveraging lectin microarrays for clinical insights

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