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However, the role of GSDMD\u2010mediated pyroptosis in peritoneal fibrosis (PF) remains unclear. This study observed NLRP3 inflammasome activation and pyroptosis in the peritoneum of long\u2010term peritoneal dialysis (PD) patients with PF. Moreover, it is found that high glucose (HG) can induce the activation of NLRP3 inflammasome by regulating TLR4\/NF\u2010\u03baB and JNK\/p38 MAPK signaling in human peritoneal mesothelial cells (HPMCs), leading to subsequent Caspase\u20101 activation. The cleaved Caspase\u20101 promoted pyroptosis\u2010related transmembrane pore formation through activating GSDMD\u2010N, and stimulated the HPMCs to secrete inflammatory factors including IL\u20101\u03b2 and IL\u201018. GSDMD global deletion or pharmacologic pretreatment with Caspase\u20101 specific inhibitor VX\u2010765 effectively inhibited the pyroptosis and inflammation, thereby ameliorating PF. Additionally, treatment with VX\u2010765 and transfected with Caspase\u20101 siRNA or GSDMD siRNA also inhibited the transmembrane pore formation and inflammatory factors secretion in HG\u2010induced HPMCs. Consistent with these results, delayed treatment with VX\u2010765 also alleviated PF, indicating the therapeutic effect of VX\u2010765. Taken together, the results demonstrate that pyroptosis may be a novel therapeutic target for peritoneal fibrosis.<\/jats:p>","DOI":"10.1002\/smll.202409362","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T06:42:21Z","timestamp":1741588941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Inhibition of Caspase\u20101 Suppresses GSDMD\u2010mediated Peritoneal Mesothelial Cell Pyroptosis and Inflammation in Peritoneal Fibrosis"],"prefix":"10.1002","volume":"21","author":[{"given":"Yingfeng","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Nephrology Shanghai East Hospital Tongji University School of Medicine  Shanghai 200120 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Shanghai East Hospital Tongji University School of Medicine  Shanghai 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