Aldehyde dehydrogenase 2 activation ameliorates CC l 4 ‐induced chronic liver fibrosis in mice by up‐regulating Nrf2/ HO ‐1 antioxidant pathway

Mitochondrial aldehyde dehydrogenase 2 ( ALDH 2) is critical in the pathogenesis of alcoholic liver cirrhosis. However, the effect of ALHD 2 on liver fibrosis remains to be further elucidated. This study aimed to demonstrate whether ALDH 2 regulates carbon tetrachloride ( CC l 4 )‐induced liver fibrosis and to investigate the efficacy of Alda‐1, a specific activator of ALDH 2, on attenuating liver fibrosis. ALDH 2 expression was increased after chronic CC l 4 exposure. ALDH 2 deficiency accentuated CC l 4 ‐induced liver fibrosis in mice, accompanied by increased expression of collagen 1α1, α‐ SMA and TIMP ‐1. Moreover, ALDH 2 knockout triggered more ROS generation, hepatocyte apoptosis and impaired mitophagy after CC l 4 treatment. In cultured HSC ‐T6 cells, ALDH 2 knockdown by transfecting with lentivirus vector increased ROS generation and α‐ SMA expression in an in vitro hepatocyte fibrosis model using TGF ‐β1. ALDH 2 overexpression by lentivirus or activation by Alda‐1 administration partly reversed the effect of TGF ‐β1, whereas ALDH 2 knockdown totally blocked the protective effect of Alda‐1. Furthermore, Alda‐1 administration protected against liver fibrosis in vivo, which might be mediated through up‐regulation of Nrf2/ HO ‐1 cascade and activation of Parkin‐related mitophagy. These findings indicate that ALDH 2 deficiency aggravated CC l 4 ‐induced hepatic fibrosis through ROS overproduction, increased apoptosis and mitochondrial damage, whereas ALDH 2 activation through Alda‐1 administration alleviated hepatic fibrosis partly through activation of the Nrf2/ HO ‐1 antioxidant pathway and Parkin‐related mitophagy, which indicate ALDH 2 as a promising anti‐fibrotic target and Alda‐1 as a potential therapeutic agent in treating CC l 4 ‐induced liver fibrosis.