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Ductular reaction and liver fibrosis are typical liver changes seen in human PSC and cholestasis patients. The current study aimed to clarify the role of liver\u2010specific microRNA\u201034a in the cholestasis\u2010associated ductular reaction and liver fibrosis. We demonstrated that miR\u201034a expression was significantly increased in human PSC livers along with the enhanced ductular reaction, cellular senescence, and liver fibrosis. A liver\u2010specific miR\u201034a knockout mouse was established by crossing floxed miR\u201034a mice with albumin\u2010promoter\u2010driven Cre mice. Bile duct ligation (BDL) induced liver injury characterized by necrosis, fibrosis, and immune cell infiltration. In contrast, liver\u2010specific miR\u201034a knockout in BDL mice resulted in decreased biliary ductular pathology associated with the reduced cholangiocyte senescence and fibrotic responses. The miR\u201034a\u2010mediated ductular reactions may be functioning through Sirt\u20101\u2010mediated senescence and fibrosis. The hepatocyte\u2010derived conditioned medium promoted LPS\u2010induced fibrotic responses and senescence in cholangiocytes, and miR\u201034a inhibitor suppressed these effects, further supporting the involvement of paracrine regulation. In conclusion, we demonstrated that liver\u2010specific miR\u201034a plays an important role in ductular reaction and fibrotic responses in a BDL mouse model of cholestatic liver disease.<\/jats:p>","DOI":"10.1096\/fj.202201453r","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T10:38:05Z","timestamp":1672396685000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Liver\u2010specific deletion of\n                    <scp>microRNA<\/scp>\n                    \u201034a alleviates ductular reaction and liver fibrosis during experimental cholestasis"],"prefix":"10.1096","volume":"37","author":[{"given":"Ying","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Science Southwest Medical University  Luzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Medicine, Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Slevin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Medicine, Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6886-1961","authenticated-orcid":false,"given":"Sachiko","family":"Koyama","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Medicine, Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuedong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Basic Medical Science Southwest Medical University  Luzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Transplant Surgery Baylor Scott &amp; 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