CISD2-mediated mitochondrial dysfunction and iron redistribution contributes to ferroptosis in arsenic-induced nonalcoholic steatohepatitis

Arsenic in the environment, such as sodium arsenic (NaAsO 2 ), is a frequently occurring hazard that has been linked to nonalcoholic steatohepatitis (NASH). Our prior research established the involvement of ferroptosis in arsenic-induced NASH, but the precise underlying mechanisms remain elusive. Here, we found that exposure to NaAsO 2 had a suppressive effect on the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2) at the protein and gene levels, and overexpression of CISD2 inhibited NaAsO 2 -induced ferroptosis and NASH. Additionally, administration of NaAsO 2 to hepatocytes triggered mitochondrial dysfunction, manifesting as the release of cytochrome c, impairment of the mitochondrial respiratory chain, and reduction in ATP synthesis. However, these adverse effects were alleviated through overexpression of CISD2. Intracellular iron redistribution was induced by overexpression of CISD2 and inhibited NaAsO 2 -induced ferroptosis. This inhibition was characterized by a reduction in cytoplasmic iron levels and an increase in mitochondrial iron levels. Our study demonstrated that NaAsO 2 induced intracellular iron reorganization and mitochondrial dysfunction through CISD2 inhibition, leading to ferroptosis and NASH. This may provide a novel means of treatment of nonalcoholic fatty liver disease triggered by environmental factors. Schematic diagrams of mechanisms underlying NaAsO 2 -induced ferroptosis and NASH. • NaAsO 2 induced ferroptosis and NASH via targeting CISD2. • CISD2 inhibition contributes to NaAsO 2 -induced mitochondrial dysfunction. • CISD2-mediated iron redistribution facilitates NaAsO 2 -induced ferroptosis.