{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T23:26:29Z","timestamp":1782429989540,"version":"3.54.5"},"reference-count":75,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007225","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["2018YFA0108802"],"award-info":[{"award-number":["2018YFA0108802"]}],"id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dysregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of many cancers. However, the role of EZH2 in peritoneal fibrosis remains unknown. We investigated EZH2 expression in peritoneal dialysis (PD) patients and assessed its role in peritoneal fibrosis in cultured human peritoneal mesothelial cells (HPMCs) and murine models of peritoneal fibrosis induced by chlorhexidine gluconate (CG) or high glucose peritoneal dialysis fluid (PDF) by using 3\u2010deazaneplanocin A (3\u2010DZNeP), and EZH2 conditional knockout mice. An abundance of EZH2 was detected in the peritoneum of patients with PD associated peritonitis and the dialysis effluent of long\u2010term PD patients, which was positively correlated with expression of TGF\u2010\u03b21, vascular endothelial growth factor, and IL\u20106. EZH2 was found highly expressed in the peritoneum of mice following injury by CG or PDF. In both mouse models, treatment with 3\u2010DZNeP attenuated peritoneal fibrosis and inhibited activation of several profibrotic signaling pathways, including TGF\u2010\u03b21\/Smad3, Notch1, epidermal growth factor receptor and Src. EZH2 inhibition also inhibited STAT3 and nuclear factor\u2010\u03baB phosphorylation, and reduced lymphocyte and macrophage infiltration and angiogenesis in the injured peritoneum. 3\u2010DZNeP effectively improved high glucose PDF\u2010associated peritoneal dysfunction by decreasing the dialysate\u2010to\u2010plasma ratio of blood urea nitrogen and increasing the ratio of dialysate glucose at 2\u00a0h after PDF injection to initial dialysate glucose. Moreover, delayed administration of 3\u2010DZNeP inhibited peritoneal fibrosis progression, reversed established peritoneal fibrosis and reduced expression of tissue inhibitor of metalloproteinase 2, and matrix metalloproteinase\u20102 and \u20109. Finally, EZH2\u2010KO mice exhibited less peritoneal fibrosis than EZH2\u2010WT mice. In HPMCs, treatment with EZH2 siRNA or 3\u2010DZNeP suppressed TGF\u2010\u03b21\u2010induced upregulation of \u03b1\u2010SMA and Collagen I and preserved E\u2010cadherin. These results indicate that EZH2 is a key epigenetic regulator that promotes peritoneal fibrosis. Targeting EZH2 may have the potential to prevent and treat peritoneal fibrosis. \u00a9 2019 Pathological Society of Great Britain and Ireland. 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