SARS‐CoV‐2 Membrane Protein Induces MARCHF1/GPX4‐Mediated Ferroptosis by Promoting Lipid Accumulation

ABSTRACT The membrane protein (M), a key structural protein of SARS‐CoV‐2 that regulates virus assembly and morphogenesis, is involved in the pathological processes of multiple organ damage and metabolic disorders. This study aims to elucidate the mechanisms of M‐mediated host ferroptosis and lipid accumulation during SARS‐CoV‐2 infection. Here, we detected that M protein enhances cellular sensitivity to ferroptosis. Additionally, we uncovered the pivotal role of perilipin‐2 and sterol regulatory element‐binding protein 1 in M‐induced lipid accumulation. Xanthohumol, a cost‐effective and orally available diacylglycerol acyltransferase inhibitor, alleviated triglyceride and total cholesterol accumulation, thereby counteracting the M‐induced ferroptosis. Furthermore, we identified that the mitochondrial import inner membrane translocase subunit TIM23 and the mitochondrial import receptor subunit TOM20 homolog contribute to M‐induced mitochondrial dysfunction. Notably, inhibiting lipid synthesis effectively reduced mitochondrial reactive oxygen species and transmembrane potential, indicating a cross‐talk between lipid and ferro metabolic pathways. Mechanistically, glutathione peroxidase 4 (GPX4) interacts with SARS‐CoV‐2 M, leading to its subsequent degradation by the Membrane Associated Ring‐CH‐Type Finger 1 (MARCHF1) ubiquitin ligase. M‐GPX4 interaction occurs at the R72 residue, which may represent a potential therapeutic target against SARS‐CoV‐2 infection. M modulates lipid accumulation and further impairs mitochondrial functions, ultimately resulting in ferroptosis through MARCHF1‐GPX4 axis. Disrupting host‐virus interactions along this pathway may provide a therapeutic strategy for SARS‐CoV‐2 infection.