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Superoxide dismutase 3 (SOD3) is an extracellular antioxidant defense against oxidative damage. Here, we found downregulation of SOD3 in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl\n                    <jats:sub>4<\/jats:sub>\n                    ). SOD3 deficiency induced spontaneous liver injury and fibrosis with increased collagen deposition, and further aggravated CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010induced liver injury in mice. Depletion of SOD3 enhanced HSC activation marked by increased \u03b1\u2010smooth muscle actin and subsequent collagen synthesis primarily collagen type I in vivo, and promoted transforming growth factor\u2010\u03b21 (TGF\u2010\u03b21)\u2010induced HSC activation in vitro. SOD3 deficiency accelerated EMT process in the liver and TGF\u2010\u03b21\u2010induced EMT of AML12 hepatocytes, as evidenced by loss of E\u2010cadherin and gain of N\u2010cadherin and vimentin. Notably, SOD3 expression and its pro\u2010fibrogenic effect were positively associated with sirtuin 1 (SIRT1) expression. SOD3 deficiency inhibited adenosine monophosphate\u2010activated protein kinase (AMPK) signaling to downregulate SIRT1 expression and thus involving in liver fibrosis. Enforced expression of SIRT1 inhibited SOD3 deficiency\u2010induced HSC activation and EMT, whereas depletion of SIRT1 counteracted the inhibitory effect of SOD3 in vitro. These findings demonstrate that SOD3 deficiency contributes to liver fibrogenesis by promoting HSC activation and EMT process, and suggest a possibility that SOD3 may function through modulating SIRT1 via the AMPK pathway in liver fibrosis.\n                  <\/jats:p>","DOI":"10.1002\/jcp.30174","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T00:47:58Z","timestamp":1606178878000},"page":"4313-4329","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["SOD3 deficiency induces liver fibrosis by promoting hepatic stellate cell activation and epithelial\u2013mesenchymal transition"],"prefix":"10.1002","volume":"236","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5289-4673","authenticated-orcid":false,"given":"Yu\u2010Ling","family":"Sun","sequence":"first","affiliation":[{"name":"Department\u2004of\u2004Hepatobiliary\u2004and\u2004Pancreatic\u2004Surgery The 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