ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease with no available therapies. Currently, the pathogenesis of MASLD remains to be further elucidated. Ferroptosis and ferroptosis‐related genes may play a vital role in the development of MASLD. Thus, this study investigated the role of heme oxygenase‐1 (HMOX1/HO‐1) in ferroptosis associated with MASLD. Here, we applied bioinformatics to identify ferroptosis‐related genes. HMOX1 expression was validated by immunohistochemistry. Mice fed a methionine‐choline‐deficient diet for 8 weeks were treated with hemin, followed by biochemical and histological analyses. HL7702 cells were transfected to overexpress HMOX1, exposed to oleic acid, and treated with erastin or AZD1480. Iron, ROS, lipid peroxidation, and mitochondrial damage were assessed by ELISA, flow cytometry, and electron microscopy. Western blotting explored molecular mechanisms. HMOX1 was identified as a ferroptosis‐related hub gene in MASLD datasets and was decreased in patient liver tissues. MCD‐fed mice developed hepatic steatosis with elevated ALT, AST, TG, LDL, Fe²⁺, MDA, and ROS, along with reduced HMOX1 and GSH. Hemin ameliorated MASLD and inhibited ferroptosis. Cell experiments showed JAK/STAT pathway activation in MASLD. HMOX1 upregulation reduced lipid peroxidation, inhibited ferroptosis, and downregulated JAK/STAT, whereas erastin reversed these effects. AZD1480 reversed the effects of erastin and improved MASLD. Collectively, our results suggest that HMOX1 protects against MASLD by suppressing ferroptosis through JAK/STAT pathway inhibition.
Yao et al. (Thu,) studied this question.
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