Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05080-8
Physiologically relevant liver models are essential for advancing hepatic disorder research, especially for disease modeling and drug development, yet current in vitro systems fail to adequately recapitulate the architecture and function of the liver. Owing to the accessibility, robust proliferation and multilineage differentiation potential of human induced pluripotent stem cells (iPSCs), liver organoids derived from iPSCs have emerged as a promising resource in hepatology. Despite this promise, the field still faces persistent bottlenecks including incomplete hepatic maturation, insufficient incorporation of non-parenchymal cells (notably immune and stromal populations), phenotypic instability, and a lack of consensus on standardized differentiation protocols. Therefore, this review systematically analyzes the challenges and strategies of iPSC differentiation into liver organoids and the related influencing factors by focusing on multidimensional regulation of hepatobiliary development as well as the effects of cellular origin, culture system and liver microenvironment on hepatic differentiation of iPSCs. Moving forward, priority should be given to the following directions: (1) Elucidating the self-assembly mechanism of liver organoids to enable precise control of hepatobiliary differentiation, thereby better governing organoid morphology and improving reproducibility; (2) Replacing exogenous cytokines with small-molecule compounds at different stages of iPSC differentiation to simplify and standardize differentiation protocols; (3) Advancing liver organoid transplantation as a means to validate physiological functionality and shift cell therapy from passive replacement toward active tissue reconstruction; (4) Integrating artificial intelligence to achieve intelligent and precise regulation of hepatic differentiation.
Stem Cell Research & Therapy•2024•DOI: 10.1186/s13287-024-03798-x
Background Development of hematopoietic stem and progenitor cells (HSPC) is a multi-staged complex process that conserved between zebrafish and mammals. Understanding the mechanism underlying HSPC development is a holy grail of hematopoietic biology, which is helpful for HSPC clinical application. Chromatin conformation plays important roles in transcriptional regulation and cell fate decision; however, its dynamic and role in HSPC development is poorly investigated. Methods We performed chromatin structure and multi-omics dissection across different stages of HSPC developmental trajectory in zebrafish for the first time, including Hi-C, RNA-seq, ATAC-seq, H3K4me3 and H3K27ac ChIP-seq. Results The chromatin organization of zebrafish HSPC resemble mammalian cells with similar hierarchical structure. We revealed the multi-scale reorganization of chromatin structure and its influence on transcriptional regulation and transition of cell fate during HSPC development. Nascent HSPC is featured by loose conformation with obscure structure at all layers. Notably, PU.1 was identified as a potential factor mediating formation of promoter-involved loops and regulating gene expression of HSPC. Conclusions Our results provided a global view of chromatin structure dynamics associated with development of zebrafish HSPC and discovered key transcription factors involved in HSPC chromatin interactions, which will provide new insights into the epigenetic regulatory mechanisms underlying vertebrate HSPC fate decision.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024230
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.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2025146
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.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025080
Macrophages are key players in the pathology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Existing studies and our previous studies have documented the role of CD206-positive M2 macrophages in the inflammatory process of AAV. Inflammasome activation is a critical pathway through which macrophages release inflammatory factors. In this study, we investigate the role of the inflammasome in macrophages in AAV and explore the role of CD206 in this process. We recruit newly diagnosed AAV patients and disease controls from our department. The expression and localization of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) and CD206 in the kidney are determined via immunofluorescence experiments. Myeloperoxidase (MPO)-ANCA immunoglobulin G (MPO-ANCA IgG) is purified from new-onset AAV patients with MPO-ANCA and used to treat lipopolysaccharide (LPS)-primed macrophages in vitro. Our findings reveal that NLRP3 expression is significantly elevated in the kidneys of active AAV patients, accompanied by increased cleaved caspase-1 and N-terminal gasdermin-D (GSDMD) levels in peripheral blood mononuclear cells (PBMCs). In vitro, MPO-ANCA IgG induces NLRP3 inflammasome activation and interleukin (IL)-1β production in macrophages, which is associated with increased MPO expression and JNK signaling pathway activation. Immunofluorescence analysis demonstrates partial colocalization of CD206 and NLRP3 in AAV kidneys. Furthermore, silencing of MRC1 gene, which encodes CD206, reduces inflammasome activation induced by MPO-ANCA IgG. In conclusion, our study provides evidence that MPO-ANCA IgG contributes to NLRP3 inflammasome activation and macrophage pyroptosis, with CD206 playing a critical role in this process. These findings elucidate the mechanisms underlying inflammation in AAV and suggest potential therapeutic targets.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025076
EGFR-tyrosine kinase inhibitor (TKI) therapy is the most effective targeted therapy for non-small cell lung cancer (NSCLC). However, drug resistance remains a significant factor in the failure of lung cancer therapy. In the present study, we utilize network pharmacology, molecular docking, in vitro and in vivo experiments to explore the targets and biological mechanisms of CP, a novel curcumin-piperlongumine hybrid molecule, in EGFR-TKI-resistant NSCLC cells. The results reveal that CP exhibits enhanced biological activity compared to its parent compounds. CP can effectively inhibit cell proliferation by arresting cell cycle in the G2/M phase and inducing apoptosis. Mechanistically, CP-induced apoptosis is partially mediated by PI3K/AKT signaling pathway. These findings highlight the potential of CP as a promising therapeutic agent for EGFR-TKI-resistant lung cancer therapy.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024166
EGFR protein trafficking is critical for regulating multiple biological processes, including cell growth and survival. However, how EGFR protein homeostasis is maintained remains unclear. In this study, we show that a reduction in plasma membrane-associated EGFR triggers EGFR transcription by promoting pSTAT3 nuclear localization. Nucleus-localized pSTAT3 binds to the EGFR gene promoter to transactivate EGFR. Moreover, erlotinib, an EGFR tyrosine kinase inhibitor (TKI), can also increase pSTAT3 nuclear accumulation, resulting in increased EGFR transcription and erlotinib resistance. Importantly, pharmacological inhibition of pSTAT3 can significantly overcome the resistance of cancer cells to erlotinib. Together, these findings demonstrate that pSTAT3 is pivotal for maintaining EGFR protein homeostasis and suggest that activation of the pSTAT3-EGFR axis contributes to EGFR-TKI resistance.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-05080-8
Physiologically relevant liver models are essential for advancing hepatic disorder research, particularly for disease modeling and drug development, yet current in vitro systems inadequately recapitulate liver architecture and function. Human induced pluripotent stem cells (iPSCs) offer accessibility, robust proliferation, and multilineage differentiation potential, making iPSC-derived liver organoids a promising resource in hepatology. However, persistent bottlenecks include incomplete hepatic maturation, insufficient incorporation of non-parenchymal cells (notably immune and stromal populations), phenotypic instability, and lack of standardized differentiation protocols. This review systematically analyzes challenges and strategies in iPSC differentiation into liver organoids, focusing on multidimensional regulation of hepatobiliary development and the effects of cellular origin, culture system, and liver microenvironment. Future priorities include: (1) elucidating self-assembly mechanisms to enable precise control of hepatobiliary differentiation, improving organoid morphology and reproducibility; (2) replacing exogenous cytokines with small-molecule compounds at different stages to simplify and standardize protocols; (3) advancing liver organoid transplantation to validate physiological functionality and shift cell therapy from passive replacement toward active tissue reconstruction; (4) integrating artificial intelligence for intelligent and precise regulation of hepatic differentiation.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21256
BACKGROUND: Intervertebral disc degeneration is a chronic spinal disease characterized by accelerated apoptosis of nucleus pulposus cells and decomposition of the extracellular matrix, which often leads to low back pain and spinal dysfunction. The molecular mechanism has not been fully understood, hindering the development of precision treatment strategies. Transcriptomics technology can be used to deeply analyze gene expression patterns, and proteomics technology can be used to identify protein function dynamics. The combined application of these two technologies provides an important means to elucidate the pathological mechanism of intervertebral disc degeneration. OBJECTIVE: To review the research progress of transcriptomics and proteomics technologies in intervertebral disc degeneration, and discuss the key roles of these two omics technologies in analyzing molecular mechanisms, screening diagnostic markers, and exploring therapeutic targets. METHODS: A computerized search of relevant literature published from January 1995 to April 2025 in PubMed, Web of Science, CNKI, and Sinomed databases was performed. Chinese search terms were "transcriptomics, ribonucleic acid sequencing, proteomics, intervertebral disc degeneration, nucleus pulposus, annulus fibrosus, cartilage endplate" and English search terms were "transcriptomics, ribonucleic acid sequencing, proteomics, intervertebral disc degeneration, nucleus pulposus, annulus fibrosus, cartilage endplate". After excluding duplicate and irrelevant literature, 24 articles were included for review. RESULTS AND CONCLUSION: Transcriptomics studies have elucidated the dynamic evolution of gene expression in intervertebral disc degeneration, revealing key regulatory networks involved in apoptosis, inflammatory response, and matrix degradation. Proteomics has deeply analyzed the dynamic changes in protein composition in the nucleus pulposus and annulus fibrosus, emphasizing the key functions of matrix metalloproteinases and cytokines in matrix degradation. The combination of the two provides a multi-dimensional perspective on the molecular mechanisms of intervertebral disc degeneration, enhancing the depth of mechanistic research. Comprehensive analysis indicates that the synergistic application of transcriptomics and proteomics shows significant potential in revealing the molecular mechanisms and potential therapeutic targets of intervertebral disc degeneration.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21397
BACKGROUND: In patients with severe medial compartment osteoarthritis of the knee combined with moderate lateral compartment osteoarthritis, it is controversial whether medial monondylar replacement alone can achieve satisfactory clinical benefit. OBJECTIVE: To compare and analyze the difference in clinical outcomes of unicompartmental knee arthroplasty and total knee arthroplasty in patients with heterogeneous degenerative changes of the knee (medial compartment Kellgren-Lawrence grade III-IV combined with lateral compartment Kellgren-Lawrence grade II). METHODS: Knee arthroplasty patients with severe medial ventricular osteoarthritis combined with mild and moderate lateral ventricular osteoarthritis shown by preoperative knee X-ray were selected and divided into unicompartmental knee arthroplasty group and total knee arthroplasty group according to different operation methods, and 50 patients were included in each group according to 1:1 pairing. Western Ontario and McMaster University Osteoarthritis Index (WOMAC), American Knee Association Score, joint amnesia score, postoperative gait parameters, and complications were collected at 3, 6 months, 1 and 2 years after surgery, and the relevant data were statistically analyzed to compare the differences in postoperative efficacy between the two groups. RESULTS AND CONCLUSION: (1) The American Knee Association Score and WOMAC scores of the unicompartmental knee arthroplasty group were better than those of the total knee arthroplasty group at 3, 6 months and 1 year after surgery (P < 0.05). Two years after surgery, American Knee Association Score and WOMAC score were not significantly different between two groups (P > 0.05). (2) There was no significant difference in joint amnesia score between the two groups at 3 months postoperatively (P > 0.05), but at 6 months, 1 year, and 2 years postoperatively, the unicompartmental knee arthroplasty group was higher than the total knee arthroplasty group (P < 0.05). (3) At 1 year postoperatively, the unicompartmental knee arthroplasty group had better gait speed and stride length than the total knee arthroplasty group (P < 0.05), while there was no significant difference in cadence between the two groups (P > 0.05). (4) No complications occurred in either group within 2 years postoperatively. (5) Follow-up confirmed that in patients with severe medial compartment osteoarthritis (Kellgren-Lawrence grade III-IV) combined with moderate lateral compartment degeneration (Kellgren-Lawrence grade II), unicompartmental knee arthroplasty had equivalent clinical efficacy to total knee arthroplasty at 2 years postoperatively, and the biomechanical advantages of unicompartmental knee arthroplasty were significant within 1 year postoperatively. During the follow-up period, no obvious progression of lateral compartment osteoarthritis (increase in Kellgren-Lawrence grade) was found, but long-term observation is needed. Before making a decision, clinicians should establish a multidimensional evaluation framework (including patient age, exercise load expectation, surgeon's unicompartmental knee arthroplasty volume, etc.), and fully inform patients of the risk of lateral compartment progression, and comprehensively evaluate whether to perform unicompartmental knee arthroplasty.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21583
BACKGROUND: Hydrogel cardiac patches, with their excellent biocompatibility and tunable mechanical properties, demonstrate significant potential in treating acute myocardial infarction, especially when combined with stem cell technology. Hydrogels modified with active components of traditional Chinese medicine (TCM) can promote the proliferation, differentiation, migration, and homing of stem cells. This synergistic effect provides a new approach for stem cell transplantation therapy based on hydrogel cardiac patches.
OBJECTIVE: To focus on the application scenarios of novel biomaterial hydrogel cardiac patches combined with TCM in the treatment of myocardial infarction, and to discuss their development prospects.
METHODS: PubMed and CNKI databases were searched for literature on TCM combined with hydrogel cardiac patches for the treatment of acute myocardial infarction from January 2010 to January 2025. English search terms included "hydrogel, cardiac patch, myocardial infarction, Chinese medicine, stem cell, drug delivery system"; Chinese search terms included "水凝胶, 心脏贴片, 心肌梗死, 中药, 干细胞, 递药系统". According to inclusion and exclusion criteria, 99 articles were finally included for review.
RESULTS AND CONCLUSION: Hydrogel cardiac patches, with their excellent biocompatibility, tunable mechanical properties, and drug-loading capacity, provide ideal mechanical support and microenvironment for myocardial repair. As a hydrophilic polymer biomaterial, the three-dimensional network structure of hydrogel cardiac patches can highly mimic the physical properties of the natural cardiac extracellular matrix, providing a microenvironment for loaded biological cells to proliferate or maintain activity, and helping cell migration, adhesion, spreading, differentiation, and intercellular connection formation. Hydrogels modified with TCM can load stem cells, fully induce and regulate them, and more effectively perform cell regeneration therapy in the myocardial infarction area to achieve better repair. Therefore, the combined application of TCM and hydrogel cardiac patches has great development potential and prospects. Currently, the combined application mainly focuses on the following aspects: precise sustained-release therapy of TCM active ingredients via hydrogel cardiac patch loading; cell regeneration therapy via induced pluripotent stem cells delivered by TCM-modified hydrogel patches; and repair of cardiac electrophysiological function via TCM combined with conductive hydrogels. In future research, it is necessary to deeply understand the characteristics of hydrogels made from different materials and methods, and the therapeutic effects and mechanisms of TCM monomers and compound extracts, to achieve more combined applications of TCM and hydrogel cardiac patches.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026078
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated clinical benefits in heart failure with preserved ejection fraction (HFpEF), yet the underlying mechanisms remain poorly defined. Given that mitochondrial dysfunction represents a central feature of HFpEF pathophysiology, we investigate whether modulation of mitochondrial homeostasis contributes to the cardioprotective effects of dapagliflozin. Using a Dahl salt-sensitive rat model of HFpEF, we find that dapagliflozin markedly improves diastolic function and attenuates cardiac hypertrophy, fibrosis, and apoptosis. These beneficial effects are accompanied by significant restoration of mitochondrial structure and function. Consistently, in an in vitro HFpEF model, dapagliflozin enhances mitochondrial respiratory capacity in cardiomyocytes, indicating a direct mitochondrial regulatory effect. Mechanistically, integrative transcriptomic and experimental analyses identify the SIRT1/PGC-1α/Mitofusin-2 (Mfn-2) signaling axis as a critical pathway suppressed in HFpEF but reactivated following dapagliflozin treatment. Activation of this pathway promotes mitochondrial biogenesis and improves mitochondrial dynamics, thereby preserving cardiomyocyte homeostasis. Collectively, our findings reveal that dapagliflozin exerts cardioprotective effects in HFpEF by restoring mitochondrial homeostasis through the SIRT1/PGC-1α/Mfn-2 axis, providing mechanistic insight into SGLT2i-mediated benefits and highlighting mitochondrial regulation as a potential therapeutic strategy for HFpEF.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025076
Acquired resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib (AZD9291) remains an unresolved clinical bottleneck in non-small cell lung cancer (NSCLC), with median progression-free survival plateauing at 18.9 months. This study evaluates CP, a novel curcumin-piperlongumine hybrid molecule, against AZD9291-resistant NSCLC using network pharmacology, molecular docking, and in vitro/in vivo validation. PPI network analysis of intersecting targets identified EGFR, SRC, PIK3R, PIK3CA, KDR, MET, GRB2, PIK3CB, HSP90AA1, and ITGB1 as core nodes, with KEGG enrichment converging on the PI3K/AKT signaling axis. Molecular docking confirmed hydrogen-bond-mediated binding between CP and these targets. Western blot analysis demonstrated that CP markedly suppressed phosphorylation of EGFR, PI3K, AKT, and GSK-3β. Functionally, CP arrested the cell cycle at G2/M and induced apoptosis in drug-resistant NSCLC cells, with enhanced potency relative to parent compounds curcumin and piperlongumine. In vivo xenograft experiments corroborated growth inhibition. The data position CP as a dual-pathway inhibitor targeting both EGFR and PI3K/AKT cascades, providing a mechanistic rationale for its development as a therapeutic candidate in EGFR-TKI-resistant advanced NSCLC. The unresolved question of whether GSK-3β inhibition operates independently of EGFR-AKT signaling warrants further investigation.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025080
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening systemic autoimmune disease characterized by necrotizing small vessel vasculitis, with pauci-immune glomerulonephritis being the most severe manifestation. Macrophages, particularly CD206-positive M2 subsets, are central to AAV pathology, yet the mechanistic link between inflammasome activation and CD206 remains undefined. This study investigates NLRP3 inflammasome activity and pyroptosis in CD206+ macrophages exposed to myeloperoxidase (MPO)-ANCA immunoglobulin G (IgG). Newly diagnosed AAV patients and disease controls were recruited; renal NLRP3 and CD206 expression were assessed by immunofluorescence. MPO-ANCA IgG was purified from new-onset AAV patients and applied to lipopolysaccharide (LPS)-primed macrophages in vitro. Results demonstrate significantly elevated NLRP3 expression in active AAV kidneys, accompanied by increased cleaved caspase-1 and N-terminal gasdermin-D (GSDMD) in peripheral blood mononuclear cells (PBMCs). In vitro, MPO-ANCA IgG induces NLRP3 inflammasome activation and interleukin (IL)-1β production, associated with increased MPO expression and JNK signaling pathway activation. Immunofluorescence reveals partial colocalization of CD206 and NLRP3 in AAV kidneys. Silencing of MRC1, encoding CD206, reduces inflammasome activation induced by MPO-ANCA IgG. These findings establish that MPO-ANCA IgG contributes to NLRP3 inflammasome activation and macrophage pyroptosis, with CD206 playing a critical role. The study elucidates mechanisms underlying AAV inflammation and suggests potential therapeutic targets.