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However, the effect of ALHD<\/jats:styled-content>2 on liver fibrosis remains to be further elucidated. This study aimed to demonstrate whether ALDH<\/jats:styled-content>2 regulates carbon tetrachloride (CC<\/jats:styled-content>l4<\/jats:sub>)\u2010induced liver fibrosis and to investigate the efficacy of Alda\u20101, a specific activator of ALDH<\/jats:styled-content>2, on attenuating liver fibrosis. ALDH<\/jats:styled-content>2 expression was increased after chronic CC<\/jats:styled-content>l4<\/jats:sub> exposure. ALDH<\/jats:styled-content>2 deficiency accentuated CC<\/jats:styled-content>l4<\/jats:sub>\u2010induced liver fibrosis in mice, accompanied by increased expression of collagen 1\u03b11, \u03b1\u2010SMA<\/jats:styled-content> and TIMP<\/jats:styled-content>\u20101. Moreover, ALDH<\/jats:styled-content>2 knockout triggered more ROS<\/jats:styled-content> generation, hepatocyte apoptosis and impaired mitophagy after CC<\/jats:styled-content>l4<\/jats:sub> treatment. In cultured HSC<\/jats:styled-content>\u2010T6 cells, ALDH<\/jats:styled-content>2 knockdown by transfecting with lentivirus vector increased ROS<\/jats:styled-content> generation and \u03b1\u2010SMA<\/jats:styled-content> expression in an in\u00a0vitro hepatocyte fibrosis model using TGF<\/jats:styled-content>\u2010\u03b21. ALDH<\/jats:styled-content>2 overexpression by lentivirus or activation by Alda\u20101 administration partly reversed the effect of TGF<\/jats:styled-content>\u2010\u03b21, whereas ALDH<\/jats:styled-content>2 knockdown totally blocked the protective effect of Alda\u20101. Furthermore, Alda\u20101 administration protected against liver fibrosis in\u00a0vivo, which might be mediated through up\u2010regulation of Nrf2\/HO<\/jats:styled-content>\u20101 cascade and activation of Parkin\u2010related mitophagy. These findings indicate that ALDH<\/jats:styled-content>2 deficiency aggravated CC<\/jats:styled-content>l4<\/jats:sub>\u2010induced hepatic fibrosis through ROS<\/jats:styled-content> overproduction, increased apoptosis and mitochondrial damage, whereas ALDH<\/jats:styled-content>2 activation through Alda\u20101 administration alleviated hepatic fibrosis partly through activation of the Nrf2\/HO<\/jats:styled-content>\u20101 antioxidant pathway and Parkin\u2010related mitophagy, which indicate ALDH<\/jats:styled-content>2 as a promising anti\u2010fibrotic target and Alda\u20101 as a potential therapeutic agent in treating CC<\/jats:styled-content>l4<\/jats:sub>\u2010induced liver 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