Curcumol Alleviates Ferroptosis in Metabolic‐Associated Fatty Liver Disease by Inhibiting EGFR –Endoplasmic Reticulum Stress Axis

Hepatic ferroptosis has emerged as a crucial pathogenic mechanism and severe adverse outcome in metabolic-associated fatty liver disease (MAFLD). Curcumol (CCM), a sesquiterpenoid phytochemical with potential hepatoprotective properties, remains unexplored for its therapeutic properties in MAFLD management. In this study, the effects and mechanisms of CCM on hepatic ferroptosis in MAFLD were investigated using in silico approaches and evaluated at the cellular and molecular levels using both in vivo and in vitro disease models of MAFLD. Our results showed that hepatic ferroptosis was accompanied by endoplasmic reticulum stress (ERS) in high-fat-induced MAFLD. Administration of the ERS inhibitor 4-PBA significantly alleviated ferroptosis, suggesting the pathogenic role of ERS-mediated ferroptosis in MAFLD. Notably, CCM exhibited comparable effects to 4-PBA, indicating that CCM mitigated hepatic ferroptosis through inhibiting ERS. Subsequent data showed that the therapeutic effects of CCM were achieved by targeting epidermal growth factor receptor (EGFR), as evidenced by the phenomenon that the efficacy of CCM was reversed following the administration of an EGFR agonist. In conclusion, this study highlighted the therapeutic effects of CCM on alleviating hepatic ferroptosis in high-fat-induced MAFLD by inhibiting the EGFR-ERS axis, and emphasized the promising application of CCM in MAFLD management.