Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy","authors":"Pandian Nagakannan ,&nbsp;Md Imamul Islam ,&nbsp;Shakila Sultana ,&nbsp;Soheila Karimi-Abdolrezaee ,&nbsp;Eftekhar Eftekharpour","doi":"10.1016/j.bbamcr.2025.120054","DOIUrl":"10.1016/j.bbamcr.2025.120054","url":null,"abstract":"<div><div>Ferroptosis is a recently discovered lytic form of cell death that is triggered by iron-driven excessive lipid peroxidation and depletion of glutathione and glutathione peroxidase-4 (GPX4). This form of cell death has been linked to a wide range of conditions from cancer to neurodegenerative diseases. Using murine hippocampal HT22 neurons, we aimed to investigate the underlying mechanisms of glutamate-mediated ferroptosis. A robust increase in Thioredoxin-Inhibiting Protein (TXNIP) prompted us to use genetic approaches and examine the role of this protein in ferroptosis in HT22 neurons, mouse embryonic fibroblasts, and Hela cells. Our results indicate that TXNIP is a key player in ferroptotic pathway, as its deletion conferred resistance to classic ferroptosis-inducing agents (erastin, RSL3, and ML210), while TXNIP overexpression increased their susceptibility to ferroptosis. Notably, TXNIP deletion protected cells from mitochondrial dysfunction induced by ferroptotic agents, independent of GSH and GPX4 levels. We further showed that TXNIP mediates ferroptosis through facilitating degradation of the iron-binding protein ferritin via NCOA4-mediated ferritinophagy. This resulted in elevated cytosolic labile iron levels, therefore amplifying lipid peroxidation, and promoting ferroptosis. Our findings suggest that TXNIP acts as a positive regulator of ferroptosis by modulating autophagy and iron availability. Targeting TXNIP might hold promise in developing drugs for diseases involving the ferroptotic pathway.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120054"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperosmolarity-induced activation of PIEZO1 engages detrimental calcium/oxidative stress signaling and adaptive catalase response in renal inner medullary collecting duct (mIMCD3) cells","authors":"Stephanie Probst ,&nbsp;Nadiya Romanova ,&nbsp;Robin Herbrechter ,&nbsp;Teresa Kern ,&nbsp;Marie Bergmeier ,&nbsp;Wing-Kee Lee ,&nbsp;Frank Thévenod","doi":"10.1016/j.bbamcr.2025.120041","DOIUrl":"10.1016/j.bbamcr.2025.120041","url":null,"abstract":"<div><div>The collecting duct (CD) is the final segment of the renal nephron and is involved in the fine regulation of osmotic and ionic homeostasis. Its medullary segment is continuously exposed to a wide spectrum of osmotic gradients and resultant osmotic stress. Strikingly, the expression of the mechanically activated non-selective cationic and Ca²⁺-permeable transduction ion channel PIEZO1 is most prominent in inner medullary CD (IMCD) cells, yet its functions there are still not well understood. We hypothesized increased PIEZO1 expression in the IMCD could be linked to its hyperosmotic stress environment. Using the mouse mIMCD₃ cell line, which has been used to characterize hyperosmotic stress-induced cell death, we demonstrate twice as much PIEZO1 expression compared to proximal tubule (WKPT-0293 Cl.2) or cortical CD (mCCD(cl.1)) cell lines. Hyperosmolarity/−tonicity by addition of NaCl ± urea to the culture medium (+ 100–300 mosmol/l) or PIEZO1 agonist Yoda1 (20 μmol/l) decreased mIMCD₃ cell viability assayed by MTT, which were antagonized by PIEZO1 inhibitors GsMTx4 (2.5 μmol/l) and salvianolic acid (SalB, 10 μmol/l). PIEZO1 activation by hyperosmolarity and agonists (Yoda1, Jedi1) increased Ca²⁺ influx, downstream reactive oxygen species (ROS), in particular mitochondrial superoxide (O₂^•-) formation, and subsequent adaptive ROS-decomposing catalase expression and activity that were sensitive to PIEZO1 antagonists (GsMTx4, SalB). Hence, the data demonstrate hyperosmolarity/−tonicity of the kidney elicits PIEZO1 activation, mitochondrial ROS formation and cell death that are partially countered by catalase-mediated stress adaptation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120041"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S100A16 knockdown reduces RPN2 expression and inhibits β-catenin/TCF signaling, leading to suppressed metastasis in cervical cancer cells","authors":"Min-Chieh Hsin ,&nbsp;Po-Hui Wang ,&nbsp;Pei-Ni Chen ,&nbsp;Yi-Hsien Hsieh ,&nbsp;Shun-Fa Yang ,&nbsp;Chung-Yuan Lee","doi":"10.1016/j.bbamcr.2025.120053","DOIUrl":"10.1016/j.bbamcr.2025.120053","url":null,"abstract":"<div><div>S100 calcium-binding protein A16 (S100A16), the most recently identified member of the S100 calcium-binding protein family, has been implicated in various cancers. However, its specific role in cervical cancer remains unclear. In this study, we demonstrated that silencing the S100A16 gene inhibits the migratory ability of HeLa and SiHa cells without affecting their viability. RNA sequencing analysis revealed that S100A16 significantly regulates ribophorin II (RPN2). Furthermore, RPN2 knockdown alone effectively suppressed cell migration and overexpression of S100A16 reversed the inhibition of migration caused by RPN2 silencing. Mechanistically, S100A16 was observed to regulate RPN2 through phosphorylated signal transducer and activator of transcription 3 (p-STAT3), which, in turn, modulated the downstream β-catenin/TCF pathway via phosphorylated GSK3β. An analysis of nuclear and cytosolic protein fractions further indicated that S100A16 silencing reduces the ability of β-catenin to translocate into the nucleus. In conclusion, our research revealed that S100A16 silencing downregulated RPN2 levels through p-STAT3, thereby inhibiting the p-GSK3β/β-catenin/TCF signaling pathway. These findings highlight S100A16 as a potential therapeutic target for cervical cancer.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120053"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple roles of EML1 in microtubule stabilization and vesicle transport in the nervous system","authors":"Yufang Zhang ,&nbsp;Jing Yu ,&nbsp;Yao Zhou ,&nbsp;Yan Yue ,&nbsp;Yan Liu","doi":"10.1016/j.bbamcr.2025.120048","DOIUrl":"10.1016/j.bbamcr.2025.120048","url":null,"abstract":"<div><div>Microtubule-associated protein EML1 is an important member of the EML family and plays a key role in cytoskeleton regulation and neural development. During neural development, EML1 expression is spatiotemporally specific, and its functional abnormalities are closely associated with neural developmental disorders such as subcortical band heterotopia. This article systematically reviews the structural characteristics and biological functions of EML1. Structural studies have shown that EML1 contains unique HELP-WD and TAPE domains, which underlie its binding to microtubules and functional performance. Functionally, EML1 regulates microtubule stability through multiple mechanisms. Moreover, EML1 is also involved in regulating intracellular material transport—maintaining the stability of transport tracks, coordinating the function of motor proteins, and regulating Golgi-related transport. These findings reveal the multiple roles of EML1 in cellular physiological processes and provide a new perspective for understanding the pathogenesis of related diseases. Future research should focus on elucidating the precise EML1 action mechanisms and its potential as a therapeutic target.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120048"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RIPK3 activation promotes peritoneal dialysis-related peritoneal fibrosis via NLRP3/Caspase-1/IL-1β pathway","authors":"Zhiyong Xie ,&nbsp;Rong Wei ,&nbsp;Wenying Zhang ,&nbsp;Xiaodong Tang ,&nbsp;Hang Chen ,&nbsp;Qilan Nie ,&nbsp;Xinying Zhang ,&nbsp;Yilin Chen ,&nbsp;Zhuohan Li ,&nbsp;Ziqing Tan ,&nbsp;Minwei Du ,&nbsp;Yuyao Zhang ,&nbsp;Xuan Peng ,&nbsp;Hui Di ,&nbsp;Yueqiang Wen ,&nbsp;Ying Huang ,&nbsp;Long Xiao ,&nbsp;Jianbo Liang ,&nbsp;Dezhu Chen ,&nbsp;Zebin Wang ,&nbsp;Ying Zhang","doi":"10.1016/j.bbamcr.2025.120060","DOIUrl":"10.1016/j.bbamcr.2025.120060","url":null,"abstract":"<div><div>Peritoneal fibrosis is one of the leading causes for withdraw of peritoneal dialysis (PD) but there is no available effective therapy strategy. As an essential role in regulating TNF-induced necroptosis, receptor interacting protein kinase-3 (RIPK3) participated in the progression of multiple organ fibrosis. Here, we investigated the role and the possible mechanism of RIPK3 in PD-associated peritoneal fibrosis in PD patients, a mouse peritoneal dialysis model and in vitro peritoneal mesothelial cells. We found that phosphorylated-RIPK3 (p-RIPK3) were markedly elevated in PD fluids and peritoneal tissue from PD patients, a mouse PD model and in peritoneal mesothelial cells induced by TGFβ and high glucose PD fluids. And activated RIPK3 recruits its substrate protein, MLKL, and promotes its phosphorylation. RIPK3 kinase inhibition using GSK’872 compound could attenuate high glucose PD fluid-induced peritoneal fibrosis in a mouse PD model. In vitro peritoneal mesothelial cells, RIPK3 kinase inhibition or siRNA transfection target on RIPK3 attenuate TGFβ or high glucose PD fluid-induced fibrotic progress. Meanwhile, GSK’872 intervention could inhibit the NLRP3/Caspase-1/IL-1β pathway in PD mouse model and in vitro peritoneal mesothelial cells, inhibiting RIPK3 kinase activity or siRNA silencing RIPK3 expression could block NLRP3/Caspase-1/IL-1β pathway. Moreover, Co-immunoprecipitation (Co-IP) experiment and immunofluorescence indicated that p-RIPK3 could combinate with NLRP3 and TGFβ intervention could promote this interaction, while RIPK3 kinase inhibitor could avianize their combination. These findings implicate that RIPK3 activation may be a crucial mediator in PD associated peritoneal fibrosis and targeting RIPK3 activation may be a novel therapeutic strategy to attenuate PD-related peritoneal fibrosis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120060"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated fibroblasts secreting IL-6 inhibit the cisplatin and docetaxel killing effect in lung squamous cell carcinoma.","authors":"Xu Zhu, Long Li, Xuanyin Wang, Ying Zhang, Zeyang Yang, Jiaming Ren, Lu Wang, Xianling Zeng, Jing Xiao, Siyu Wang, Peiying Pan, Jian Zhang, Xiaojun Du, Tao Wang, Langbo Liu, Xiaolin Shu, Qiaoling Zhang, Jiangwei Wu, Siyuan Yang, Xinlei Liu, Zhu Zeng, Jieheng Wu","doi":"10.1016/j.bbamcr.2025.120029","DOIUrl":"10.1016/j.bbamcr.2025.120029","url":null,"abstract":"<p><p>Chemoresistance remains a major obstacle in the treatment of lung squamous cell carcinoma (LUSC), often leading to suboptimal clinical outcomes. Among the key contributors to this resistance are cancer-associated fibroblasts (CAFs), which are increasingly recognized for their tumor-supportive roles. Despite this, the molecular pathways through which CAFs promote chemoresistance in LUSC are not fully elucidated. This study found that CAFs-derived interleukin-6 (IL-6) upregulated the expression of Specificity Protein 1 (SP1) and the ATP-binding cassette transporter B7 (ABCB7) in LUSC cells exposed to cisplatin and docetaxel. In vitro assays showed a marked decrease in apoptosis in tumor cells co-cultured with CAFs. Consistent with these findings, in vivo xenograft models demonstrated that IL-6-producing CAFs reduced the antitumor efficacy of both chemotherapeutic agents. Elevated serum IL-6 levels also emerged as a potential indicator of poor response to chemotherapy. Our findings suggest that IL-6 secreted by CAFs impairs the cytotoxic effects of cisplatin and docetaxel in LUSC, partly through activation of the PI3K/AKT/NF-κB signaling axis. Targeting this IL-6-mediated pathway may offer a promising strategy to overcome chemoresistance and enhance therapeutic outcomes in patients with LUSC.</p>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":" ","pages":"120029"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ESCO2 drives breast cancer proliferation and metastasis through PI3K/AKT/mTOR phosphorylation: A potential therapeutic target","authors":"Pingchuan Li ,&nbsp;Lineng Wei ,&nbsp;Meng Li ,&nbsp;Huawei Yang","doi":"10.1016/j.bbamcr.2025.120043","DOIUrl":"10.1016/j.bbamcr.2025.120043","url":null,"abstract":"<div><div>Breast cancer remains a major global health threat to women, underscoring the urgent need for novel therapeutic targets. While ESCO2, an essential cell cycle regulator, has been implicated in cancer progression, its precise role and molecular mechanisms in breast cancer remain poorly understood. In this study, we first demonstrated significant upregulation of ESCO2 in breast cancer through analysis of TCGA and GEO datasets, which was further validated in clinical specimens and cell lines, with its expression correlating with advanced T-stage, aggressive molecular subtypes and poor prognosis. Functional studies in MDA-MB-231 and MDA-MB-468 cells revealed that ESCO2 overexpression promoted cell proliferation, migration and invasion, while its knockdown exerted opposite effects. Mechanistic investigations uncovered that ESCO2 depletion reduced phosphorylation of PI3K/AKT/mTOR pathway components, and co-immunoprecipitation assays confirmed direct interaction between ESCO2 and PI3K. Importantly, the tumor-suppressive effects of ESCO2 knockdown could be rescued by SC79-mediated AKT activation. In vivo experiments using xenograft mouse models consistently showed that ESCO2 silencing significantly inhibited tumor growth, increased apoptosis and necrosis, and reduced metastasis. Collectively, our findings establish ESCO2 as a novel oncogene driving breast cancer progression through PI3K/AKT/mTOR pathway activation, highlighting its potential as a promising therapeutic target for breast cancer intervention.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120043"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prolyl isomerase Pin4 impacts estrogen receptor transactivation by enhancing phosphorylation and consequently promotes the proliferation of breast cancer cells","authors":"Masa-Ki Inoue ,&nbsp;Rena Ueda ,&nbsp;Mikako Nakanishi ,&nbsp;Machi Kanna ,&nbsp;Yasuka Matsunaga ,&nbsp;Tomoichiro Asano ,&nbsp;Yusuke Nakatsu","doi":"10.1016/j.bbamcr.2025.120044","DOIUrl":"10.1016/j.bbamcr.2025.120044","url":null,"abstract":"<div><div>Breast cancer is the most common tumor in women, and approximately 70 % of cases are diagnosed to be estrogen receptor α (ERα)-positive. Estradiol (E2)-ERα signaling is undoubtedly involved in the development of breast cancer, and the upregulation of this pathway is linked to tamoxifen resistance. However, ERα regulation is complex, and the underlying mechanisms have not been comprehensively elucidated.</div><div>Pin4 is a prolyl isomerase that promotes cis-trans isomerization of proline residues. Although its role remains unclear, an analysis of public databases reveals that Pin4 expression in breast cancer tissues is higher than that in normal tissues.</div><div>Here, we reveal that Pin4 regulates ERα transcriptional activity and is essential for the proliferation of ERα-positive breast cancer cells. In MCF7 and T47D cells, Pin4 knockdown drastically decreased cell proliferation by inducing cell cycle arrest. In addition, the silencing of Pin4 impaired the expression of E2-induced genes, including E2F1. We also found that Pin4 interacted with ERα and affected its transcriptional activity by promoting phosphorylation at Ser167, which was involved in the recruitment of steroid receptor coactivator-3 (SRC-3) into ERα. Importantly, the silence of Pin4 gene in T47D cells attenuated the interaction between SRC-3 and ERα.</div><div>Collectively, the study findings show that Pin4 is a critical factor in the development of ERα-positive breast cancers and the identification of Pin4 inhibitors could be a promising therapeutic strategy.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120044"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CHIP modulates Wnt/β-catenin signalling in colorectal cancer through proteasomal degradation of DDX17","authors":"Sunny Kumar ,&nbsp;Sayani Ghosh ,&nbsp;Malini Basu ,&nbsp;Mrinal K. Ghosh","doi":"10.1016/j.bbamcr.2025.120049","DOIUrl":"10.1016/j.bbamcr.2025.120049","url":null,"abstract":"<div><div>The C-terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, plays a pivotal role in cellular protein homeostasis by targeting client proteins for proteasomal degradation. DEAD-box RNA helicase DDX17 is a key regulator of RNA metabolism and has been implicated in various cancer-related processes, including Wnt/β-catenin signalling and EMT. In this study, we uncover a novel regulatory axis involving CHIP and DDX17 responsible for modulation of Wnt/β-catenin signalling in colorectal cancer (CRC). Bioinformatic analyses of CPTAC database and immunohistochemical analysis of clinical samples revealed a significant negative correlation between CHIP and DDX17. By using immunoprecipitation-mass spectrometry we have identified DDX17 as a high-confidence interacting partner of CHIP, which was validated through co-immunoprecipitation, domain-mapping, immunocytochemistry, and molecular docking studies, pinpointing the TPR domain of CHIP is essential for this interaction. Mechanistically, CHIP overexpression led to accelerated degradation of DDX17, resulting in reduced β-catenin mRNA stability, leading to the suppression of Wnt/β-catenin signalling that results in G1 arrest and decreasing proliferation and EMT. Conversely, CHIP knockdown stabilized DDX17, hence promoting β-catenin signalling that leads to oncogenic phenotype. Our results suggest that CHIP exerts a tumor-suppressive phenotype in CRC by destruction of DDX17, thereby attenuating β-catenin-driven oncogenic processes. Altogether, this study identifies a novel “CHIP–DDX17–β-catenin” axis as a critical regulatory mechanism in CRC.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120049"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGB1 activates caspase-1 and induces hepatic stellate cell activation via GABPA-ASC","authors":"Mengjia Jing ,&nbsp;Yixing Luo ,&nbsp;Lumiao Zhang ,&nbsp;Yu Fu ,&nbsp;Wei Yan","doi":"10.1016/j.bbamcr.2025.120032","DOIUrl":"10.1016/j.bbamcr.2025.120032","url":null,"abstract":"<div><div>In the intricate process leading to liver fibrosis, which frequently correlates with inflammation, the activation of hepatic stellate cells (HSCs) is critical. High mobility group box 1(HMGB1), as endogenous danger signal in the extracellular environment, governs the activation of caspase-1 and hepatic stellate cell. Constructing a liver fibrosis model via intraperitoneal thioacetamide (TAA) administration unveiled excessive HMGB1 expression and serum release during the TAA-induced fibrosis progression. Intraperitoneal injection of ethyl pyruvate (EP, which inhibits the release of HMGB1) or AAV-shHMGB1 can significantly reverse the progression of liver fibrosis induced by TAA. Recombinant HMGB1 (rHMGB1) and <em>Z</em>-YVAD-FMK (Caspase-1 inhibitor) were used to treat HSCs. It was found that HMGB1 could activate caspase-1, while Z-YVAD-FMK could prevent HMGB1-induced activation of HSCs. Through immunofluorescence, immunoblotting, lentiviral transfection, luciferase reporter assay and chromatin immunoprecipitation assay, it was found that HMGB1 activated caspase-1 through GABPA-regulated ASC transcription, which not only participates in the activation of caspase-1, but also promotes the process of liver fibrosis. Taken together, HMGB1 significantly drives HSC activation. It boosts ASC transcriptional activity via GABPA leading to caspase-1 activation and fostering liver fibrosis development.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120032"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}