{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:31:01Z","timestamp":1780461061019,"version":"3.54.1"},"reference-count":34,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"vor","delay-in-days":57,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2022JJ30825"],"award-info":[{"award-number":["2022JJ30825"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Digest Diseases"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>We aimed to disclose the molecular mechanism of snail1 in liver fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) was used to induce a liver fibrosis model in mice whereby serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated, and liver pathological alternations were assessed. Rat hepatic stellate cells (HSC\u2010T6) were irritated with transforming growth factor (TGF)\u2010\u03b21, followed by assessment of cell viability and migration. The levels of snail1, ALKBH5, and lysine specific demethylase 4C (KDM4C) were quantified by immunohistochemistry, western blot, or reverse transcription\u2010quantitative polymerase chain reaction, in addition to \u03b1\u2010smooth muscle actin (SMA), anti\u2010collagen type I \u03b11 (COL1A1), vimentin, and E\u2010cadherin. Photoactivatable ribonucleoside\u2010enhanced crosslinking and immunoprecipitation and RNA stability were evaluated to determine the relationship between ALKBH5 and snail1. Changes in KDM4C\u2010bound ALKBH5 promoter and enrichment of histone H3 lysine 9 trimethylation (H3K9me3) at the ALKBH5 promoter were determined using chromatin immunoprecipitation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In fibrosis mice, snail1 was upregulated while ALKBH5 and KDM4C were downregulated. KDM4C overexpression reduced serum ALT and AST levels, liver injury, and \u03b1\u2010SMA, COL1A1 and VIMENTIN expressions but increased E\u2010cadherin expression. However, the aforementioned trends were reversed by concurrent overexpression of snail1. In HSC\u2010T6 cells exposed to TGF\u2010\u03b21, ALKBH5 overexpression weakened cell viability and migration, downregulated \u03b1\u2010SMA, COL1A1 and VIMENTIN, upregulated E\u2010CADHERIN, and decreased m6A modification of snail1 and its mRNA stability. KDM4C increased ALKBH5 expression by lowering H3K9me3 level, but inhibited HSC\u2010T6 cell activation by regulating the ALKBH5\/snail1 axis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>KDM4C decreases H3K9me3 methylation to upregulate ALKBH5 and subsequently inhibits snail1, ultimately impeding liver fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1751-2980.13291","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T05:55:55Z","timestamp":1719554155000},"page":"298-309","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>KDM4C<\/scp> represses liver fibrosis by regulating <scp>H3K9me3<\/scp> methylation of <scp>ALKBH5<\/scp> and <scp>m6A<\/scp> methylation of snail1 <scp>mRNA<\/scp>"],"prefix":"10.1111","volume":"25","author":[{"given":"Hua Ying","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, The Second Xiangya Hospital Central South University  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing Qing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Second Xiangya Hospital Central South University  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng Xuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Second Xiangya Hospital Central South University  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Fan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Second Xiangya Hospital Central South University  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Fang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Second Xiangya Hospital Central South University  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8925-7686","authenticated-orcid":false,"given":"Jing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Second Xiangya Hospital Central South University  Changsha Hunan Province 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