HMOX1 Inhibits Ferroptosis in Non-Alcoholic Fatty Liver Disease

Background & Aims: This research seeks to elucidate the significance of ferroptosis-related genes in the diagnosis, prognosis, and treatment of non-alcoholic fatty liver disease (NAFLD). Methods: Key genes pertinent to NAFLD were identified using the GEO database. The role of Heme oxygenase-1 (HMOX1) in NAFLD was validated via immunohistochemical analysis of hepatic tissues. Mice on a methionine-choline-deficient (MCD) diet were administered Hemin, followed by the collection of serum and liver samples for biochemical and histopathological examinations. HL7702 cells were transfected with a plasmid to elevate HMOX1 expression, then treated with oleic acid (OA) to induce lipid accumulation, and subsequently with erastin and AZD1480. A series of assays measured iron levels, reactive oxygen species, lipid peroxidation, and mitochondrial damage. Western blotting analysis was employed to elucidate the underlying molecular mechanisms. Results: HMOX1 is crucial in the pathogenesis of NAFLD, evidenced by its decreased expression in patient liver tissues. Mice on an MCD diet exhibited significant hepatic steatosis, along with elevated levels of ALT, AST, TG, LDL, Fe ²⁺ , MDA, and ROS, and reduced levels of HMOX1 and GSH. Notably, Hemin effectively ameliorated NAFLD and prevented ferroptosis. Cellular analysis revealed activation of the JAK/STAT pathway in NAFLD. Upregulation of HMOX1 reduced OA-induced lipid peroxidation, inhibited ferroptosis, and suppressed the JAK/STAT pathway. Erastin negated the protective effects of HMOX1 overexpression. Moreover, the JAK/STAT pathway inhibitor AZD1480, which had the opposite effect with erastin, suppressed ferroptosis and ameliorated NAFLD. Conclusions: This study elucidates that HMOX1 suppresses ferroptosis by inhibiting the JAK/STAT pathway in NAFLD.