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Kr\u00fcppel\u2010like factor 14 (KLF14) regulates various biological processes, however, roles, mechanisms and implications of KLF14 in liver fibrosis are unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>KLF14 expression was detected in human, rat and mouse fibrotic models, and its effects on HSCs were assessed. Chromatin immunoprecipitation assays were utilized to investigate the binding of KLF14 to peroxisome proliferator\u2010activated receptor \u03b3 (PPAR\u03b3) promoter, and the binding of enhancer of zeste homolog 2 (EZH2) to KLF14 promoter. In vivo, KLF14\u2010overexpressing adenovirus was injected via tail vein to thioacetamide (TAA)\u2010treated rats to investigate the role of KLF14 in liver fibrosis progression. EZH2 inhibitor EPZ\u20106438 was utilized to treat TAA\u2010induced rat liver fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>KLF14 expression was remarkably decreased in human, rat and mouse fibrotic liver tissues. Overexpression of KLF14 increased LD accumulation, inhibited HSCs activation, proliferation, migration and induced G2\/M arrest and apoptosis. Mechanistically, KLF14 transactivated PPAR\u03b3 promoter activity. Inhibition of PPAR\u03b3 blocked the suppressive role of KLF14 overexpression in HSCs. Downregulation of KLF14 in activated HSCs was mediated by EZH2\u2010regulated histone H3 lysine 27 trimethylation. Adenovirus\u2010mediated KLF14 overexpression ameliorated TAA\u2010induced rat liver fibrosis in PPAR\u03b3\u2010dependent manner. Furthermore, EPZ\u20106438 dramatically alleviated TAA\u2010induced rat liver fibrosis. Importantly, KLF14 expression was decreased in human with liver fibrosis, which was significantly correlated with EZH2 upregulation and PPAR\u03b3 downregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>KLF14 exerts a critical anti\u2010fibrotic role in liver fibrosis, and targeting the EZH2\/KLF14\/PPAR\u03b3 axis might be a novel therapeutic strategy for liver fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cpr.13072","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T04:27:18Z","timestamp":1621916838000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["EZH2\u2010mediated inhibition of KLF14 expression promotes HSCs activation and liver fibrosis by downregulating PPAR\u03b3"],"prefix":"10.1111","volume":"54","author":[{"given":"Zhipeng","family":"Du","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of 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