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PINK1 (PTEN\u2010induced kinase 1) and NIPSNAP1 (nonneuronal SNAP25\u2010like protein 1), which cooperatively regulate mitophagy, have been predicted to include the sites of lysine acetylation related to SIRT3 (mitochondrial deacetylase sirtuin 3). Our study aimed to discuss whether SIRT3 deacetylates PINK1 and NIPSNAP1 to regulate mitophagy in liver fibrosis. Carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)\u2010induced liver fibrosis as an in vivo model and LX\u20102 cells as activated cells were used to simulate liver fibrosis. SIRT3 expression was significantly decreased in mice in response to CCl<jats:sub>4<\/jats:sub>, and SIRT3 knockout in vivo significantly deepened the severity of liver fibrosis, as indicated by increased \u03b1\u2010SMA and Col1a1 levels both in vivo and in vitro. SIRT3 overexpression decreased \u03b1\u2010SMA and Col1a1 levels. Furthermore, SIRT3 significantly regulated mitophagy in liver fibrosis, as demonstrated by LC3\u2010\u2161\/\u2160 and p62 expression and colocalization between TOM20 and LAMP1. Importantly, PINK1 and NIPSNAP1 expression was also decreased in liver fibrosis, and PINK1 and NIPSNAP1 overexpression significantly improved mitophagy and attenuated ECM production. Furthermore, after simultaneously interfering with PINK1 or NIPSNAP1 and overexpressing SIRT3, the effect of SIRT3 on improving mitophagy and alleviating liver fibrosis was disrupted. Mechanistically, we show that SIRT3, as a mitochondrial deacetylase, specifically regulates the acetylation of PINK1 and NIPSNAP1 to mediate the mitophagy pathway in liver fibrosis. SIRT3\u2010mediated PINK1 and NIPSNAP1 deacetylation is a novel molecular mechanism in liver fibrosis.<\/jats:p>","DOI":"10.1002\/jcp.31069","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T14:13:50Z","timestamp":1688739230000},"page":"2090-2102","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["SIRT3 regulates mitophagy in liver fibrosis through deacetylation of PINK1\/NIPSNAP1"],"prefix":"10.1002","volume":"238","author":[{"given":"Ruixi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology Dalian Medical University Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhecheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Dalian Medical University Dalian 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