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

{"title":"Multimodal psychological intervention improves psychological well-being and inflammatory profiles in patients with diabetic nephropathy","authors":"Hangyan Tang ,&nbsp;Shengquan Liu","doi":"10.1016/j.bbadis.2026.168171","DOIUrl":"10.1016/j.bbadis.2026.168171","url":null,"abstract":"<div><div>Patients with diabetic nephropathy (DN) often experience negative emotions and a decline in quality of life, conditions in which the neuro–endocrine–immune axis plays a crucial role. In this study, we explored the effects of an eight-week multimodal psychological intervention, incorporating cognitive behavioral therapy, mindfulness meditation, and relaxation training, on DN patients. Ninety participants were randomly assigned to an intervention group, a sham intervention group, or a control group. The sham intervention group received nonspecific contact of equivalent duration, while the control group received routine care only. Psychological outcomes were evaluated using HADS and SF-36 scales, and serum levels of cortisol, CRH, ACTH, IL-6, IL-1β, and TNF-α were measured by enzyme-linked immunosorbent assay. Bioinformatic analyses, including Gene Ontology/Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and protein-protein interaction network mapping, were employed to identify key molecular mechanisms. Results demonstrated that the intervention group exhibited significant improvements in emotional well-being and quality of life, accompanied by reductions in neuroendocrine hormones and inflammatory cytokines. Bioinformatic data further revealed the central role of IL-6 within the inflammatory regulatory network in DN. These findings suggest that multimodal psychological intervention can effectively improve psychological outcomes and inflammatory profiles in DN patients by targeting the neuro–endocrine–immune axis, with IL-6 acting as a pivotal mediator. This work provides novel evidence supporting the integration of psychological interventions into the management of DN and highlights IL-6 as a potential therapeutic target.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168171"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044326","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":"SIRT5 promotes vascular regeneration in peripheral muscle ischemia by regulating malonylation and glycolysis","authors":"Kanghui Chen ,&nbsp;Hang Chen ,&nbsp;Peng Wang ,&nbsp;Yueyi Pan ,&nbsp;Heng Yang ,&nbsp;Aijun Sun ,&nbsp;Junbo Ge ,&nbsp;Xueying Chen ,&nbsp;Lei Xu ,&nbsp;Xiaolei Sun","doi":"10.1016/j.bbadis.2026.168163","DOIUrl":"10.1016/j.bbadis.2026.168163","url":null,"abstract":"<div><div>Peripheral artery disease (PAD) is a prominent contributor to the global prevalence and mortality of cardiovascular diseases, yet the therapeutic strategies remain limited and urgently to explore the new methods of promoting vascular regeneration. Metabolism involves numerous aspects of angiogenesis, including the energetics, proliferation, signal transduction and gene expression of endothelial cells (ECs). Sirtuin (SIRT) family play an important role in regulating numerous metabolic processes due to its protein modification activity. Herein, the effect of SIRTs on regulating muscle vascular regeneration of PAD patients was demonstrated. We reanalyzed the SIRTs family by using the reported data of single-nuclei atlas of human PAD limb muscle and found that SIRT5 expression in ECs was significantly downregulated. Then the dynamic changes of SIRTs in ischemic hindlimb of mice and hypoxia-induced HUVECs were observed, among which, SIRT5 showed the most sensitive and significant change in responding to ischemia. Deletion of SIRT5 inhibited the blood flow perfusion recovery and consequently aggravated ischemic hindlimb injury in mice. SIRT5 knock down in vitro inhibited the proliferation, migration and angiogenesis of HUVECs both under normoxia and hypoxia. The mechanism was involved in significantly decreased expression of glycolytic enzymes and increased malonylation of proteins, especially GAPDH, in HUVECs with SIRT5 knock down. In conclusion, SIRT5 controlled the vascular regeneration capacity of lower limb muscles by regulating glycolysis and malonylation modification. Regulating SIRT5 activity might be novel therapeutic target for PAD patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168163"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986073","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":"HMGA2 inhibits Pink1-mediated mitophagy and promotes vascular calcification","authors":"Shengjue Xiao ,&nbsp;Zhengdong Chen ,&nbsp;Yiqing Yang ,&nbsp;Liqun Ren ,&nbsp;Yuyu Yao ,&nbsp;Naifeng Liu","doi":"10.1016/j.bbadis.2025.168149","DOIUrl":"10.1016/j.bbadis.2025.168149","url":null,"abstract":"<div><div>Mitochondrial dysfunction is implicated in the development of vascular calcification, whereas protective mitophagy helps to hinder its progression. HMGA2 plays a pivotal role in regulating mitochondrial integrity and mitophagy. However, the precise impact of HMGA2-controlled mitophagy on vascular calcification remains unclear. In our study, we observed elevated HMGA2 expression during both Vitamin D3-induced aortic calcification in mice and β-GP-induced calcification of mouse aortic vascular smooth muscle (MOVAS). Additionally, we identified dynamic changes in mitophagy in MOVAS and demonstrated that HMGA2 knockdown promoted mitophagy, exerting a protective effect against vascular calcification in both in vivo and in vitro settings. Preconditioning with the autophagy inhibitor chloroquine diminished the protective effect of HMGA2 knockdown on aortic calcification in mice by inhibiting mitophagy. Furthermore, we observed an increase in cytoplasmic HMGA2 levels in MOVAS following vascular calcification, along with its binding to PTEN induced kinase 1 (Pink1) in the cytoplasm. This affects the distribution of Pink1, which cannot be transferred to the mitochondrial outer membrane to initiate mitophagy. Subsequently, silencing Pink1 exacerbated mitochondrial damage and apoptosis by inhibiting mitophagy, thereby promoting vascular calcification in β-GP-treated MOVAS. Our results indicated that cytosolic HMGA2 bound to Pink1, inhibiting mitophagy by impeding Pink1's relocation from the cytosol to the mitochondria, thereby reducing mitophagy activation, inducing apoptosis, ultimately accelerating the transition of MOVAS to an osteoblastic phenotype and calcium deposition. In conclusion, inducing mitophagy pharmacologically by targeting HMGA2 may represent a promising therapeutic approach for managing vascular calcification.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168149"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936739","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":"Urinary microbiome and metabolomic profiling reveal propionic acid as an enhancer of BCG immunotherapy in bladder cancer","authors":"Jing Liu ,&nbsp;Yizhao Luo ,&nbsp;Lu Chen ,&nbsp;Wei Xiong ,&nbsp;Yu An ,&nbsp;Zhiwei Ma ,&nbsp;Dan Zhang","doi":"10.1016/j.bbadis.2026.168192","DOIUrl":"10.1016/j.bbadis.2026.168192","url":null,"abstract":"<div><div>Bladder cancer (BC) is the tenth most common malignancy worldwide, with non-muscle invasive bladder cancer (NMIBC) accounting for approximately 75% of cases, and Bacillus Calmette-Guérin (BCG) remaining the standard intravesical therapy. In light of global BCG shortages, this study aimed to identify potential strategies to enhance BCG efficacy by integrating urinary microbiome profiling with targeted short-chain fatty acid (SCFA) metabolomics. Urine samples collected from BC patients before and after BCG instillation were analyzed to determine BCG-associated microbial and metabolic changes, and the functional role of the key metabolite propionic acid (PA) was evaluated through in vitro experiments using MB49 and MBT2 murine BC cell lines and in vivo mouse BC models treated with BCG plus PA. Flow cytometry was used to quantify tumor-infiltrating CD4⁺ and CD8⁺ T cells to elucidate immune-related mechanisms. BCG treatment significantly reshaped urinary microbial composition, dominant flora, and fatty acid metabolic patterns, and notably increased urinary PA levels. Functional assays demonstrated that PA markedly augmented the antitumor activity of BCG, potentially by promoting CD4⁺/CD8⁺ T-cell infiltration into tumor tissues. Collectively, these findings indicate that BCG modulates the urinary microbiome and SCFA metabolic landscape in BC patients, and that PA enhances BCG efficacy by boosting T-cell-mediated immune responses, highlighting PA-BCG combination therapy as a promising therapeutic strategy for BC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168192"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146170146","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":"ATP6V0d2 alleviates acute liver injury via promoting hepatocyte autophagy","authors":"Mengxia Zhang ,&nbsp;Zhemin Shi ,&nbsp;Yi Yang ,&nbsp;Yue Huang ,&nbsp;Kefei Guo ,&nbsp;Yuying Sun ,&nbsp;Jianan Gao ,&nbsp;Jiajun Wang ,&nbsp;Yanjun Li ,&nbsp;Wei Hong ,&nbsp;Tao Han ,&nbsp;Kun Zhang","doi":"10.1016/j.bbadis.2026.168170","DOIUrl":"10.1016/j.bbadis.2026.168170","url":null,"abstract":"<div><div>Liver injury is the pathological basis of various liver diseases, and severe acute liver injury can progress to acute liver failure with a high mortality. Although continuous progress has been made over the past few decades, the molecular mechanism underlying the progress of acute liver injury is still unclear. ATP6V0d2, a subunit of the vacuolar ATPase (V-ATPase) complex, is implicated in organelle acidification and intracellular degradation processes. In this study, three liver injury datasets were analyzed to screen the differentially expressed genes (DEGs) and identify <em>Atp6v0d2,</em> which was initially downregulated, and then upregulated to slightly higher than normal levels in both hepatocytes (HCs) and liver tissues in carbon tetrachloride (CCl₄)-induced acute liver injury, with the most significant downregulation observed 24 h after CCl₄ injection. Moreover, hepatocyte-specific overexpression of ATP6V0d2 alleviated CCl₄, concanavalin A (ConA) and acetaminophen (APAP)-induced acute liver injury by promoting hepatocyte autophagy, while silencing ATP6V0d2 inhibited hepatocyte autophagy and aggravated liver injury <em>in vivo</em>. In addition, consistent with the results of gene enrichment analysis, <em>in vitro</em> data demonstrated that ATP6V0d2 promoted hepatocyte autophagy mainly <em>via</em> facilitating the formation of autophagosomes. In conclusion, our results demonstrated that ATP6V0d2 played a protective role in acute liver injury by facilitating hepatocyte autophagy, which may provide a theoretical basis for the treatment and prognosis of acute liver injury.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168170"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074776","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":"Vesicular nucleotide transporter (VNUT)-dependent ATP secretion by hepatic stellate cells promotes liver fibrosis","authors":"Masaharu Kabashima ,&nbsp;Nao Hasuzawa ,&nbsp;Lixiang Wang ,&nbsp;Junjiro Rikitake ,&nbsp;Seiji Nomura ,&nbsp;Tomohiro Niimoto ,&nbsp;Rie Tokubuchi ,&nbsp;Sawako Moriyama ,&nbsp;Mizuki Gobaru ,&nbsp;Yukihiro Inoguchi ,&nbsp;Ayako Nagayama ,&nbsp;Kenji Ashida ,&nbsp;Keisuke Ohta ,&nbsp;Yoshinori Moriyama ,&nbsp;Masatoshi Nomura","doi":"10.1016/j.bbadis.2026.168180","DOIUrl":"10.1016/j.bbadis.2026.168180","url":null,"abstract":"<div><div>Although liver fibrosis presents a substantial global health challenge, therapeutic options that directly target liver fibrosis remain limited. Hepatic stellate cells (HSCs) are key contributors to fibrosis through extracellular matrix production. This study uncovers a previously unrecognized function of HSCs: ATP secretion. We found that HSCs express the vesicular nucleotide transporter (VNUT) on secretory vesicles and actively release ATP. In mouse HSCs, VNUT is localized to the cytosol and around lipid droplets. In a thioacetamide-induced liver fibrosis model, VNUT inhibition with clodronate suppressed HSC proliferation and fibrosis progression, while restoring AMPK phosphorylation. In human hepatic stellate LX-2 cells, VNUT colocalized with v-SNARE proteins VAMP3 and VAMP7 and the vesicular proton pump V-ATPase. ATP secretion from LX-2 cells was observed upon stimulation with the Ca²⁺ ionophore ionomycin and was inhibited by Ca²⁺ chelation or low temperature, supporting an exocytotic mechanism. Clodronate and VNUT-targeting siRNA significantly reduced ATP release. Thapsigargin, an inducer of endoplasmic reticulum Ca²⁺ release, upregulated VNUT expression, suggesting a transcriptional regulation of VNUT-dependent ATP release by Ca²⁺ signaling. TGF-β1 stimulation also upregulated VNUT expression, suggesting its involvement in TGF-β1–induced fibrogenesis pathway. Additionally, serotonin was identified as an ATP secretion stimulator in LX-2 cells, and this effect was blocked by clodronate. Platelets—a major peripheral serotonin source—were increased in TAA-treated liver and found adjacent to serotonin receptor 5-HT2B-positive HSCs. Clodronate treatment reduced CD41-positive platelets in liver tissue. These findings highlight VNUT-mediated ATP secretion as a key regulator of HSC function and a potential therapeutic target for liver fibrosis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168180"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146127493","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":"Placental aberrant inflammation and spatial-specific lipid metabolism contribute to hypertensive disorder of pregnancy susceptibility in preeclampsia offspring","authors":"Pei-ran Hu ,&nbsp;Jing-hui Xu ,&nbsp;Yan Shi ,&nbsp;Ying Zhu ,&nbsp;Gao-chen Zhang ,&nbsp;Jie-ru Yang ,&nbsp;Yue Xu ,&nbsp;Ming-hao Li ,&nbsp;Xian-hua Lin ,&nbsp;Yu Zhang ,&nbsp;He-feng Huang","doi":"10.1016/j.bbadis.2026.168168","DOIUrl":"10.1016/j.bbadis.2026.168168","url":null,"abstract":"<div><div>Epidemiological studies have demonstrated that daughters of preeclamptic mothers have an increased risk of hypertensive disorders of pregnancy (HDP), but the underlying mechanisms remain unclear. To investigate the molecular changes underlying this HDP intergenerational transmission, we established an L-NAME-induced PE model in pregnant mice (F0) and examined female offspring (F1) during their pregnancies. F1 females developed gestational hypertension in late pregnancy, accompanied by enlarged placental labyrinthine areas and elevated VGFR1 expression, despite normal circulating sFlt1 levels. Across gestation, F2 placentas exhibited sustained impairment of apolipoprotein-mediated lipid transport beginning at mid-gestation, while inflammatory and HIF1α pathways were mainly activated at late gestation. Spatial transcriptomic data further showed that apolipoproteins were predominantly localized to yolk sac regions, whereas inflammatory factors exhibited widespread distribution. Importantly, F1 maternal lipid profiles remained normal before conception but manifested elevated serum triglyceride levels during pregnancy, concurrent with placental lipid accumulation. This pregnancy-specific dyslipidemia suggests that placental lipid metabolism dysfunction may contribute to maternal lipid dysregulation. Clinical validation in 28,117 women further confirmed that elevated mid-gestation triglyceride levels were strongly associated with HDP risk, consistent with the dyslipidemia observed in our mouse model. Together, these findings demonstrate that pregnancy-specific lipid dysregulation represents a conserved mechanism linking placental dysfunction to HDP susceptibility. Our study provides mechanistic insights into the intergenerational transmission of PE and identifies mid-gestation maternal lipid profiles as potential predictive biomarkers, offering a basis for early risk assessment and future therapeutic targeting.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168168"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020518","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":"Berbamine attenuates acetaminophen-induced liver injury by engaging GCLC and enhancing ferroptosis-regulatory antioxidant pathways","authors":"Mengli Tao ,&nbsp;Jiayi Shi ,&nbsp;Yingying Zhang ,&nbsp;Yigang Zheng ,&nbsp;Yufen Zhao ,&nbsp;Huabin Ma ,&nbsp;Long Li","doi":"10.1016/j.bbadis.2026.168154","DOIUrl":"10.1016/j.bbadis.2026.168154","url":null,"abstract":"<div><h3>Objective</h3><div>Acetaminophen (APAP)-induced liver injury (ALI), the major cause of acute drug-induced hepatotoxicity, lacks effective therapies. Berbamine (BBM), a bisbenzylisoquinoline alkaloid derived from the genus <em>Berberis</em>, exhibits diverse pharmacological properties but its efficacy against ALI and involvement in ferroptosis remains unexplored. This study aims to investigate the hepatoprotective effects and mechanisms of BBM against ALI and ferroptosis.</div></div><div><h3>Methods</h3><div>The in vivo model of ALI and the in vitro ferroptosis models were established using APAP and RSL3, respectively. Models received BBM or Ferrostatin-1 (Fer-1) treatment. The direct target of BBM was identified through molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays.</div></div><div><h3>Results</h3><div>In vivo, BBM pretreatment dose-dependently alleviated APAP-induced hepatic damage, inflammation, and ferroptosis markers, including lipid peroxidation, GSH depletion, and PTGS2 upregulation, while upregulating GPX4. Meanwhile, the hepatoprotective effects of BBM against ALI matched Fer-1, confirming ferroptosis as an ALI driver. In vitro, BBM inhibited RSL3-induced ferroptosis, reducing ROS, lipid peroxidation, and mitochondrial dysfunction. These effects were mediated by NRF2/GCLC/GPX4 axis activation and FSP1 upregulation. Crucially, BBM directly bound GCLC confirmed by Molecular docking, CETSA, and DARTS.</div></div><div><h3>Conclusion</h3><div>BBM protects against ALI by mitigating ferroptosis, oxidative stress, and inflammation, in part through direct modulation of GCLC and coordinated activation of the NRF2/GCLC/GPX4 axis together with FSP1. These findings provide pharmacological evidence supporting the potential of BBM as a promising therapeutic candidate for ALI.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168154"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975514","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":"Oncogenic epigenetic factor EP300 is a potential therapeutic target for bladder carcinoma","authors":"Qing Zhang ,&nbsp;Yingzhou Hong ,&nbsp;Chongjie He ,&nbsp;Rui Guo ,&nbsp;Xianbin Duan ,&nbsp;Chenxi Mo ,&nbsp;Tao Huang ,&nbsp;Junwei He ,&nbsp;Shi Fu ,&nbsp;Shuangsheng Deng ,&nbsp;Cheng Peng ,&nbsp;Haifeng Wang ,&nbsp;Chunming Guo","doi":"10.1016/j.bbadis.2026.168182","DOIUrl":"10.1016/j.bbadis.2026.168182","url":null,"abstract":"<div><div>Bladder cancer remains a major cause of global mortality with limited therapies. Here, we reported that epigenetic regulator EP300 acts as oncogenic role in bladder cancer. Public data show <em>EP300</em> mutations correlated with better prognosis, while high <em>EP300</em> expression predicted poor outcomes. Our clinical cohort demonstrated that EP300 expressed higher in tumors rather than adjacent tissues. Functionally, impairing of <em>EP300</em> decreased both cell viability and organoids growth in bladder cancer cells. The selective EP300 inhibitor A485 similarly reduced bladder cancer cell growth <em>in vitro</em> and <em>in vivo</em>. Long-term treatment of A485 alleviated tumor invasion in a BBN-induced spontaneous bladder cancer mouse model. Bioinformatic analysis evaluated both basal/squamous-like markers and papillary-like markers were decreased in A485 treatment. Furthermore, downregulated genes by A485 are mainly related to cell cycle regulation. Mechanistically, A485 decreased the levels of EP300 and H3K27ac upon <em>MYC</em> enhancer, consequently inhibited MYC expression. Additionally, the MYC inhibitor demonstrated similar effects as A485 to decrease cell viability and organoid growth. Critically, in patient-derived organoids (PDOs), A485 selectively attenuated tumor organoid growth and reduced MKI67⁺ and CD44⁺ cell populations, sparing adjacent normal tissue organoids. Collectively, EP300 promotes bladder cancer progression by sustaining proliferation through MYC regulation, and its inhibitor A485 represents a promising targeted therapeutic candidate.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168182"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146144983","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":"Goosecoid promotes hepatic stellate cell epithelial-mesenchymal transition via transcriptional activation of serum- and glucocorticoid-induced protein kinase 1 in liver fibrosis","authors":"Yongjuan Wang ,&nbsp;Xiaoli Xie ,&nbsp;Jiajun Tian ,&nbsp;Xiaoyu Jiang ,&nbsp;Huiqing Jiang","doi":"10.1016/j.bbadis.2026.168169","DOIUrl":"10.1016/j.bbadis.2026.168169","url":null,"abstract":"<div><h3>Background</h3><div>Goosecoid (GSC) is a transcription factor implicated in epithelial-mesenchymal transition (EMT) during embryogenesis and cancer, but its function in organ fibrosis remains poorly understood. This study investigates the role and mechanistic targets of GSC in hepatic stellate cell (HSC) EMT during liver fibrogenesis.</div></div><div><h3>Methods</h3><div>We analyzed GSC and EMT marker expression in primary HSCs isolated from murine liver fibrosis models induced by carbon tetrachloride (CCl₄) or bile duct ligation (BDL), and in TGF-β-stimulated LX-2 cells. The functional role of GSC was validated via in vitro and in vivo GSC knockdown, while chromatin immunoprecipitation sequencing (ChIP-seq) combined with experimental verification was used to identify its target genes and regulatory mechanisms.</div></div><div><h3>Results</h3><div>GSC expression was significantly upregulated in activated HSCs from fibrotic mouse models and TGF-β-induced LX-2 cells, which was closely associated with enhanced EMT (downregulation of epithelial markers, upregulation of mesenchymal markers). Functional assays confirmed that GSC knockdown suppressed HSC EMT in vitro and ameliorated liver fibrosis in vivo via AAV-mediated HSC-specific GSC silencing. Mechanistically, we found that GSC undergoes increased nuclear translocation during HSC activation. ChIP-seq analysis identified Serum- and glucocorticoid-induced protein kinase 1 (SGK1) as a direct transcriptional target of GSC. Further validation revealed that SGK1, in turn, promotes HSC EMT by activating the NF-κB signaling pathway.</div></div><div><h3>Conclusion</h3><div>This study uncovers a novel mechanism by which GSC promotes HSC EMT and liver fibrosis through direct transcriptional activation of SGK1, followed by downstream NF-κB pathway activation.</div></div><div><h3>Summary</h3><div>GSC is markedly upregulated in activated HSCs from murine fibrosis models (CCl₄/BDL) and during TGF-β-induced EMT. HSC-specific GSC knockdown attenuated liver fibrosis progression. Mechanistically, GSC translocates to the nucleus where it binds the SGK1 promoter to enhance transcription, subsequently driving HSC EMT and promoting fibrogenesis through the NF-κB signaling pathway.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168169"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024615","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}