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.