Key Takeaways & Executive Findings
- •• • LY96 overexpression in HCC tissues correlates with reduced overall survival (OS) in TCGA cohorts, establishing it as a prognostic biomarker with direct clinical utility for risk stratification. • • Mechanistic validation via GSEA and experimental assays confirms LY96-driven activation of TGF-β1/Smad2/3 signaling, a pathway amenable to pharmacological interruption with L6H21. • • Lipid-polymer hybrid nanoparticles achieve systemic delivery of L6H21, demonstrating significant suppression of HCC progression in both in vitro and in vivo models, with potential to overcome bioavailability barriers of small-molecule inhibitors. • • The integration of cancer-immunity cycle scoring with WGCNA provides a systems-level framework for target discovery, yielding LY96 as a node linking immunogenic cell death to oncogenic signaling.
China Biomedical & Cell Therapy Radar
Get verified English translations, SEM micrographs & open-access PDF alerts from China's leading state key laboratories delivered to your inbox every Monday at 08:00 EST.
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with advanced-stage disease characterized by limited therapeutic options and poor clinical outcomes. Lymphocyte antigen 96 (LY96) has been implicated in immunogenic cell death, yet its specific mechanistic contribution to HCC progression and its potential as a therapeutic target remain undefined. This study integrates cancer-immunity cycle scoring with weighted gene co-expression network analysis (WGCNA) and systems biology approaches to identify pivotal molecular drivers in HCC. LY96 expression was evaluated at transcriptomic and proteomic levels in HCC tissues, and its prognostic relevance was assessed using The Cancer Genome Atlas (TCGA) repository. Functional characterization of LY96 was performed through a panel of in vitro cellular assays and in vivo tumorigenesis models. Gene set enrichment analysis (GSEA) identified downstream signaling cascades, which were subsequently validated experimentally. A lipid-polymer hybrid nanoparticle (NP) platform was engineered for systemic delivery of the LY96 inhibitor L6H21. Clinically, marked LY96 overexpression was observed in HCC samples and correlated with reduced overall survival (OS). LY96 facilitated HCC progression via complementary in vitro and in vivo approaches. Mechanistically, LY96 induced activation of the TGF-β1/Smad2/3 signaling axis. The liposome-based nanoparticle system delivering L6H21 effectively suppressed HCC progression in both in vivo and in vitro studies. These findings identify LY96 as a promising diagnostic indicator and a viable therapeutic target for HCC intervention.
1. Introduction
Hepatocellular carcinoma (HCC) represents the predominant histological subtype of primary liver cancer and continues to pose a formidable global health challenge. Projections indicate that annual incidence will surpass one million cases worldwide by 2025. Despite advances in prevention and treatment, HCC remains among the foremost causes of cancer-associated deaths, driven by frequent recurrence and limited therapeutic efficacy. The 2022 Barcelona Clinic Liver Cancer (BCLC) guidelines position surgical resection and liver transplantation as central therapeutic modalities, complemented by transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and systemic therapies. However, advanced-stage disease exhibits scarce therapeutic options and poor clinical outcomes, underscoring the urgent need for novel molecular targets and intervention strategies.
Lymphocyte antigen 96 (LY96) has been associated with immunogenic cell death, yet its specific role in HCC progression and therapeutic potential remains unclear. This study addresses the bottleneck of target identification by integrating cancer-immunity cycle scoring with weighted gene co-expression network analysis (WGCNA) and systems biology methods. We systematically evaluate LY96 expression at transcriptomic and proteomic levels, assess its prognostic relevance using The Cancer Genome Atlas (TCGA) repository, and delineate its functional role through in vitro cellular assays and in vivo tumorigenesis models. Mechanistically, we identify LY96-mediated activation of the TGF-β1/Smad2/3 signaling axis. To translate these findings, we employ a lipid-polymer hybrid nanoparticle platform for systemic delivery of the LY96 inhibitor L6H21, demonstrating its potential as a newly proposed intervention strategy for HCC.
Loading authentic research manuscript (Pages 1–5)...
ZHANG Yixin, ZHENG Sui, SU Xiaoqing, LUO Wanrong, TANG Haifeng, XIONG Shiyu, TAN Min, LUO Baoming (2025). Ly96-mediated activation of TGF-β1/Smad2/3 signaling in hepatocellular carcinoma and its potential for nanoparticle-based therapy. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025128
Research & Educational Purpose Only: The translations, structured abstracts, analytical annotations, and data reports provided by SinoBioDataare intended exclusively for academic research, internal corporate R&D, and educational benchmarking. They do not constitute formal engineering, chemical safety, legal, or professional advice.
Copyright & Intellectual Property Notice: Original copyright of the underlying source articles and experimental data remains with the respective authors, institutions, and original publishing journals. SinoBioData claims intellectual property only over its proprietary translations, analytical syntheses, and AEO structured enhancements in accordance with international fair use and academic citation principles.
Frequently Asked Questions
What is the quantitative prognostic association between LY96 expression and overall survival in HCC patients?
Elevated LY96 expression is strongly associated with reduced overall survival (OS) among liver cancer patients, as demonstrated by analysis of The Cancer Genome Atlas (TCGA) repository. The study reports marked LY96 overexpression in HCC samples at both transcriptomic and proteomic levels, establishing a statistically significant correlation with poor clinical outcomes.
What is the specific molecular mechanism by which LY96 promotes HCC progression?
LY96 facilitates HCC progression via activation of the TGF-β1/Smad2/3 signaling axis. Gene set enrichment analysis (GSEA) identified this pathway, which was subsequently confirmed through experimental validation. Functional assays in vitro and in vivo demonstrated that LY96-mediated activation of TGF-β1/Smad2/3 drives oncogenic phenotypes.
What nanoparticle platform is used for delivery, and what is the therapeutic payload?
A lipid-polymer hybrid nanoparticle (NP) platform, specifically a liposome-based nanoparticle system, is employed for systemic delivery of the LY96 inhibitor L6H21. This approach effectively suppresses HCC progression in both in vivo and in vitro studies, addressing bioavailability and targeted delivery challenges associated with small-molecule inhibitors.
What methodological approach was used to identify LY96 as a therapeutic target?
The study combined cancer-immunity cycle scoring with weighted gene co-expression network analysis (WGCNA) and systems biology methods to identify pivotal molecular interactions. This integrative framework systematically pinpointed LY96 as a potential therapeutic target in HCC, linking immunogenic cell death pathways to oncogenic signaling.
What are the clinical implications of these findings for HCC treatment?
The observations identify LY96 as a promising diagnostic indicator and a viable intervention target for therapeutic modulation. The nanoparticle-based delivery of L6H21 offers a novel strategy to improve HCC treatment, particularly for advanced-stage disease where current therapeutic options are scarce and clinical outcomes remain poor.
Related Chinese Research & Cross-Citations
miR-199a-3p suppresses Vldlr expression to promote cardiomyocyte proliferation
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.
A positive feedback loop between FOSB and miR-133b controls colon cancer cell proliferation
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.
Reduced expression of the PER2 protein contributes to β1-AA-induced cardiac autophagy rhythm disorders
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.
A protein-RNA complex orchestrated by EMB1006, EMB1270, EMB976, and CFM2 facilitates clpP1 intron 2 splicing in Arabidopsis chloroplasts
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.
Tanshinones from Salvia miltiorrhiza alleviate ulcerative colitis via reprogramming the gut microbiota-metabolite axis
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.
Distinct miR319a identified from Persicaria chinensis mediates cross-kingdom suppression of cervical cancer by targeting ITGA3
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.