Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Differentiation-inducing factor-1 ameliorates liver fibrosis through the reversion of activated hepatic stellate cells","authors":"Akira Ooka ,&nbsp;Momoka Yamaguchi ,&nbsp;Kensuke Suzuki ,&nbsp;Shin-ya Saito ,&nbsp;Yukiko K. Kaneko ,&nbsp;Toshihide Kimura ,&nbsp;Tomohisa Ishikawa","doi":"10.1016/j.bbadis.2025.167802","DOIUrl":"10.1016/j.bbadis.2025.167802","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>DIF-1 derived from <em>Dictyostelium discoideum</em> ameliorates liver fibrosis (LF) in mice.</div></span></li><li><span>•</span><span><div>When the LF mouse model was orally administered with DIF-1, decreased expression of <em>Acta2</em>, <em>Col1a1</em>, <em>Pdgfrb</em>, and <em>Timp1</em>, markers of activated hepatic stellate cells (HSCs) and genes related to LF, and increased expression of <em>Lrat</em>, a marker of quiescent HSCs, were observed in the liver tissue.</div></span></li><li><span>•</span><span><div>The treatment of primary cultured mouse activated HSCs with DIF-1 reverted the cell morphology to a quiescent HSC-like shape and significantly reduced the expression of α-smooth muscle actin, a marker of activated HSCs.</div></span></li></ul></div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167802"},"PeriodicalIF":4.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632062","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":"Electrical stimulation promotes peripheral nerve regeneration by upregulating glycolysis and oxidative phosphorylation","authors":"Nannan Zhang ,&nbsp;Xiaoying Yao ,&nbsp;Qingqing Zhang ,&nbsp;Chuanji Zhang ,&nbsp;Qian Zheng ,&nbsp;Yuzhong Wang ,&nbsp;Fangzhen Shan","doi":"10.1016/j.bbadis.2025.167804","DOIUrl":"10.1016/j.bbadis.2025.167804","url":null,"abstract":"<div><div>Peripheral nerve injury (PNI) frequently results in motor and sensory dysfunction due to the limited regenerative capacity of axonal neurons and Schwann cells. Electrical stimulation (ES) has emerged as a promising strategy to enhance nerve regeneration; however, the underlying mechanisms, particularly those related to energy metabolism, remain poorly understood. This study aimed to investigate whether ES could promote nerve regeneration in a mouse model of PNI by modulating energy metabolism. ES was applied to the gastrocnemius and posterior thigh muscles post-sciatic nerve injury. Motor functional recovery was evaluated using gait analysis and electrophysiological test. Molecular and cellular changes in the distal nerve stumps were evaluated through Western blot and immunofluorescence staining. Nerve regeneration was assessed by neurostructural protein staining and nerve ultrastructure visualized by transmission electron microscopy. Our findings indicate that ES significantly accelerated both morphological and functional recovery following PNI. Specifically, ES upregulated energy metabolism in the sciatic nerve post-PNI by enhancing glucose uptake, glycolysis, and oxidative phosphorylation. Furthermore, ES increased the expression of neurotrophic factors and modulated the AMPK/mTOR/p70S6K signaling pathway, which are crucial for cellular metabolism and nerve regeneration. Collectively, these findings underscore the critical role of ES in modulating energy metabolism to support nerve regeneration, highlighting its potential as a clinical strategy for treating peripheral neuropathy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167804"},"PeriodicalIF":4.2,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632061","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":"Keloid vasculature reacts to intralesional injection therapies but does not predict the response to treatment: Biopsies from double-blinded, randomized, controlled trial","authors":"Tuomas Komulainen ,&nbsp;Kristiina E. Hietanen ,&nbsp;Teemu Tolonen ,&nbsp;Seppo Parkkila ,&nbsp;Ilkka S. Kaartinen ,&nbsp;Tero A.H. Järvinen","doi":"10.1016/j.bbadis.2025.167790","DOIUrl":"10.1016/j.bbadis.2025.167790","url":null,"abstract":"<div><div>Keloids are benign fibroproliferative skin scars that expand beyond the original wound site. Hypoxia and angiogenesis are thought to drive pathological scar formation in keloids. We utilized biopsies collected before, during and after the double-blinded randomized controlled trial (RCT) comparing the intralesional treatments of 5-fluorouracil and triamcinolone injections in 48 human keloids. We could not detect any cells expressing the hypoxia markers (carbonic anhydrase 9 and hypoxia-inducible factor 1α) in the three distinct regions of keloid dermis. The amount of epidermal hypoxia could not predict the response to treatment. The middle dermis of the patients obtaining a clinical response to the intralesional injections showed significant increase in mature blood vessels and in lymphatics after the treatment. Our study does not support hypoxia being the driver behind keloid formation but demonstrates that the patients obtaining a response to intralesional therapies develop more blood vessels and lymphatics in the middle dermis of the keloids during the treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167790"},"PeriodicalIF":4.2,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation, interaction and intimation of Nrf2 pathway and their mutational studies causing Nrf2 associated cancer","authors":"Mridul Sahu,&nbsp;Utkarsh Jain","doi":"10.1016/j.bbadis.2025.167764","DOIUrl":"10.1016/j.bbadis.2025.167764","url":null,"abstract":"<div><div>Responses against infection trigger several signaling pathways that lead to the production of cytokines, these cytokines release ROS and RNS, damaging DNA and proteins turn into various diseases including cancer. To combat these harmful cytokines, the Nrf2 pathway is activated. The gene NFE2L2 encodes Nrf2, which is divided into seven conserved domains (Neh1–7). The DLG and ETGE motifs, conserved sequences of amino acid in the Neh2 domain of Nrf2, bind to the BTB domain of Keap1. BTB domain promotes Keap1's homodimerization resulting in Cul3 recruitment providing scaffold formation to E2 ubiquitin ligase to form ubiquitin complex. Under normal conditions, this complex regularly degrades Nrf2. However, once the cell is exposed to oxidative stress by ROS interaction with Keap1 resulting in conformational changes that stabilize the Nrf2. Nrf2 further concentrates on the nucleus where it binds with the transcriptional factor to perform the desired genes transcription for synthesizing SOD, GSH, CAT, and various other proteins which reduce the ROS levels preventing certain diseases. To prevent cells from oxidative stress, molecular hydrogen activates the Nrf2 pathway. To activate the Nrf2 pathway, molecular hydrogen oxidizes the iron porphyrin which acts as an electrophile and interacts with Keap1's cysteine residue.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167764"},"PeriodicalIF":4.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619633","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":"N6-methyladenosine RNA modification in stomach carcinoma: Novel insights into mechanisms and implications for diagnosis and treatment","authors":"Zhengmao Lu ,&nbsp;Zhaojie Lyu ,&nbsp;Peixin Dong ,&nbsp;Yunmei Liu ,&nbsp;Lei Huang","doi":"10.1016/j.bbadis.2025.167793","DOIUrl":"10.1016/j.bbadis.2025.167793","url":null,"abstract":"<div><div>N6-methyladenosine (m⁶A) RNA methylation is crucially involved in the genesis and advancement of gastric cancer (GC) by controlling various pathobiological aspects including gene expression, signal transduction, metabolism, cell death, epithelial-mesenchymal transition, angiogenesis, and exosome function. Despite its importance, the exact mechanisms by which m⁶A modification influences GC biology remain inadequately explored. This review consolidates the latest advances in uncovering the mechanisms and diverse roles of m⁶A in GC and proposes new research and translational directions. Key regulators (writers, readers, and erasers) of m⁶A, such as METTL3/14/16 and WTAP, significantly affect cancer progression, anticancer immune response, and treatment outcomes. m⁶A modification also impacts immune cell infiltration and the tumor microenvironment, highlighting its potential as a diagnostic and prognostic marker. Interactions between m⁶A methylation and non-coding RNAs offer further novel insights into GC development and therapeutic targets. Targeting m⁶A regulators could enhance immunotherapy response, overcome treatment resistance, and improve oncological and clinical outcomes. Models based on m⁶A can precisely predict treatment response and prognosis in GC. Additional investigation is needed to fully understand the mechanisms of m⁶A methylation and its potential clinical applications and relevance (e.g., as precise markers for early detection, prediction of outcome, and response to therapy and as therapeutic targets) in GC. Future research should focus on in vivo studies, potential clinical trials, and the examination of m⁶A modification in other types of cancers.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167793"},"PeriodicalIF":4.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619632","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":"Ferroptosis, necroptosis, and pyroptosis in calcium oxalate crystal-induced kidney injury","authors":"Kun Tang ,&nbsp;Tao Ye ,&nbsp;Yu He ,&nbsp;Xiaozhuo Ba ,&nbsp;Ding Xia ,&nbsp;Ejun Peng ,&nbsp;Zhiqiang Chen ,&nbsp;Zhangqun Ye ,&nbsp;Xiaoqi Yang","doi":"10.1016/j.bbadis.2025.167791","DOIUrl":"10.1016/j.bbadis.2025.167791","url":null,"abstract":"<div><div>Kidney stones represent a highly prevalent urological disorder worldwide, with high incidence and recurrence rates. Calcium oxalate (CaOx) crystal-induced kidney injury serves as the foundational mechanism for the formation and progression of CaOx stones. Regulated cell death (RCD) such as ferroptosis, necroptosis, and pyroptosis are essential in the pathophysiological process of kidney injury. Ferroptosis, a newly discovered RCD, is characterized by its reliance on iron-mediated lipid peroxidation. Necroptosis, a widely studied programmed necrosis, initiates with a necrotic phenotype that resembles apoptosis in appearance. Pyroptosis, a type of RCD that involves the gasdermin protein, is accompanied by inflammation and immune response. In recent years, increasing amounts of evidence has demonstrated that ferroptosis, necroptosis, and pyroptosis are significant pathophysiological processes involved in CaOx crystal-induced kidney injury. Herein, we summed up the roles of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury. Furthermore, we delved into the curative potential of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167791"},"PeriodicalIF":4.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAT2 activity increases cytotoxicity of anthracycline antibiotics and HDAC inhibitors","authors":"Natallia Rameika ,&nbsp;Ioanna Tsiara ,&nbsp;Xiaonan Zhang ,&nbsp;Wawrzyniec Haberek ,&nbsp;Verónica Rendo ,&nbsp;Snehangshu Kundu ,&nbsp;Mario S.P. Correia ,&nbsp;Ivaylo Stoimenov ,&nbsp;Daniel Globisch ,&nbsp;Tobias Sjöblom","doi":"10.1016/j.bbadis.2025.167755","DOIUrl":"10.1016/j.bbadis.2025.167755","url":null,"abstract":"<div><div>The Arylamine-<em>N</em>-acetyltransferase-2 (NAT2) enzyme is involved in metabolism of commonly used drugs driving differences in efficacy and tolerability of treatments. To bridge the current knowledge gap on metabolism of cytotoxic drugs by NAT2, and identify anticancer agents whose effects depend on NAT2 activity, we assessed 147 clinically used drugs. Hit compounds were evaluated for metabolic conversion by acetylation in presence of recombinant NAT2. Among those 147 drugs we found doxorubicin, daunorubicin, epirubicin, valrubicin, teniposide, afatinib, carmustine, vincristine, panobinostat, and vorinostat to have increased toxicity to cancer cells expressing the rapid <em>NAT2</em> allele. Additionally, we report NAT2-mediated acetylation of idarubicin, daunorubicin, doxorubicin, vorinostat, and CUDC-101. These findings have implications for pharmacogenomics and cancer precision medicine using conventional chemotherapeutic drugs, as improving their efficacy and safety may affect &gt;4 million cancer patients worldwide that receive these drugs as standard of care.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167755"},"PeriodicalIF":4.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The IGF2BP2-circ-DAPK1 axis promotes high-glucose-induced ferroptosis of HUVECs by decreasing NQO1 expression","authors":"Chenyang Qiu ,&nbsp;Xiangtao Zheng ,&nbsp;Xiaoxiang Zhou ,&nbsp;Bing Wang ,&nbsp;Tianchi Chen ,&nbsp;Yiting Xu ,&nbsp;Xinyu Yu ,&nbsp;Wei Lu ,&nbsp;Ziheng Wu","doi":"10.1016/j.bbadis.2025.167797","DOIUrl":"10.1016/j.bbadis.2025.167797","url":null,"abstract":"<div><div>Circular RNAs (circRNAs) are non-coding RNAs with covalently closed loop structures that participate in various biological processes. However, the functions of many circRNAs remain unclear. Endothelial cell dysfunction, which involves abnormal ferroptosis, a unique form of regulated cell death, is a characteristic of various diseases. However, the mechanisms governing ferroptosis in endothelial cells are not fully understood. Here, we investigated the impact of a novel circRNA, circ-DAPK1, on ferroptosis in human umbilical vein endothelial cells (HUVECs) under high-glucose conditions. Our data showed that high-glucose conditions upregulate circ-DAPK1 expression in HUVECs. Overexpression of circ-DAPK1 induced ferroptosis in HUVECs, whereas depletion of circ-DAPK1 mitigated the ferroptosis triggered by high-glucose treatment. Inhibition of ferroptosis reversed the decrease in cell viability induced by high glucose or circ-DAPK1 overexpression. Using RNA immunoprecipitation analyses, we identified several ferroptosis-regulating proteins, including NAD(<em>P</em>)H dehydrogenase [quinone] 1 (NQO1) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Mechanistically, circ-DAPK1 interacts with NQO1, enhancing its ubiquitination and accelerating its degradation. NQO1 overexpression partially rescues HUVECs from high-glucose-induced ferroptosis. We also found that IGF2BP2 binds to the m⁶A site on circ-DAPK1. Depletion of IGF2BP2 in HUVECs reduced circ-DAPK1 expression and inhibited high-glucose-induced ferroptosis. These findings reveal the effects of the IGF2BP2-circ-DAPK1 axis in regulating ferroptosis in HUVECs under high-glucose conditions and extend our understanding of the mechanisms controlling ferroptosis in endothelial cells.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167797"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631120","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":"MBD2 promotes epithelial-to-mesenchymal transition (EMT) and ARDS-related pulmonary fibrosis by modulating FZD2","authors":"Yang Zhou ,&nbsp;Guifang Yang ,&nbsp;Jiqiang Liu ,&nbsp;Shuo Yao ,&nbsp;Jingsi Jia ,&nbsp;Xianming Tang ,&nbsp;Xun Gong ,&nbsp;Fang Wan ,&nbsp;Ren Wu ,&nbsp;Zhenyu Zhao ,&nbsp;Hengxing Liang ,&nbsp;Linxia Liu ,&nbsp;Qimi Liu ,&nbsp;Shanshan Xie ,&nbsp;Xian Long ,&nbsp;Xudong Xiang ,&nbsp;Guyi Wang ,&nbsp;Bing Xiao","doi":"10.1016/j.bbadis.2025.167798","DOIUrl":"10.1016/j.bbadis.2025.167798","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the role and underlying mechanism of Methyl-CpG binding domain protein 2 (MBD2) in the pathogenesis of acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis.</div></div><div><h3>Methods</h3><div>Murine models for ARDS-related pulmonary fibrosis were established in wildtype or MBD2 knockout mice, expressions of MBD2 were determined with immunohistochemistry (IHC), immunofluorescence, and western blot. Epithelial-to-mesenchymal transition (EMT) was detected with determined with decreased expression of E-cadherin and increased expressions of N-cadherin, Vimentin, and α-smooth muscle actin (α-SMA). Transforming growth factor β (TGF-β) treated mouse lung epithelial-12 (MLE-12) cells and primary human type II alveolar epithelial cells were applied to establish in vitro model for EMT. Transcriptional sequencing with RNA-Seq and Chromatin immunoprecipitation (ChIP) assay were used to explore the potential targets of MBD2. Single cell sequencing data and Human pulmonary fibrosis samples were analyzed.</div></div><div><h3>Results</h3><div>Bleomycin (BLM) and lipopolysaccharide (LPS) induced EMT, pulmonary fibrosis, and increased expression of MBD2 in alveolar epithelial cells of mice, and MBD2 knockout significantly alleviated BLM- and LPS-induced pulmonary fibrosis and EMT. TGF-β induced EMT and elevated MBD2 expressions in alveolar epithelial cells, which was mitigated by MBD2 knockdown and aggravated by MBD2 overexpression. Frizzled 2 (FZD2) was found to be the potential target of MBD2. Single-cell sequencing analysis of ARDS patients suggested elevated expression of MBD2 in alveolar epithelial cells, and MBD2 expression was elevated in the lungs of patients with pulmonary fibrosis.</div></div><div><h3>Conclusion</h3><div>Our results indicated that MBD2 could promote EMT and ARDS-related pulmonary fibrosis, potentially by modulating the expression of FZD2.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167798"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610815","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":"AAV8-mediated silencing of Atad3 prevents the progression from simple steatosis to MASH in mice by reduced IL6 secretion","authors":"Liting Chen ,&nbsp;Yuchang Li ,&nbsp;Rahil Nitinkumar Patel ,&nbsp;Chantal Sottas ,&nbsp;Mahima Chandrakant Raul ,&nbsp;Nrupa Dinesh Patel ,&nbsp;Alexander Zambidis ,&nbsp;Meng Li ,&nbsp;Shefali Chopra ,&nbsp;Vassilios Papadopoulos","doi":"10.1016/j.bbadis.2025.167792","DOIUrl":"10.1016/j.bbadis.2025.167792","url":null,"abstract":"<div><div>ATAD3A deficiency in hepatocytes has been shown to promote simple steatosis (SS). ATAD3 is upregulated in MCD diet-induced MASH. Since the MCD diet is commonly used to induce liver fibrosis, which is related to HSCs activation, we are prompted to investigate the functions of ATAD3 in these two cell types and their mediated transition from SS to MASH. To investigate the role of ATAD3A in HSCs, human LX-2 cells were treated with TGFβ. The results showed that ATAD3A expression was linked to the fibrotic markers ACTA2 and COL1A1. Knockdown of <em>ATAD3A</em> reversed TGFβ-induced HSC activation by downregulating both canonical (SMAD2/3) and non-canonical (ERK1/2 and p38 MAPK) TGFβ signaling pathways. To examine the effect of ATAD3 on the transition from SS to MASH, MASH was induced in mice using the GAN diet for 24 weeks. After 12 weeks, AAV8-conjugated <em>Atad3</em> shRNA was administered to knock down <em>Atad3</em> in the liver. This intervention suppressed steatosis and fibrosis while enhancing insulin sensitivity. Further analysis using conditioned medium (CM) from WT and <em>ATAD3A KO</em> Huh7 cells treated with LPS and PA revealed that IL-6 secretion from Huh7 hepatocytes activated HSCs. However, IL-6 secretion was diminished in <em>ATAD3A KO</em> CM. CM from <em>ATAD3A KO</em> cells also suppressed expression of fibrotic markers ACTA2, P<img>P38, and P-SMAD3 compared to WT cells under MASH conditions. These data suggest that AAV8-mediated <em>Atad3</em> silencing in hepatocytes prevents the transition from SS to MASH, at least in part, by downregulating IL-6 secretion to suppress HSC activation in MASH.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167792"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610960","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}