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

Pei Sun1, Qian Liu1, Shuofeng Yuan2

  • 1Department of Biomedical Engineering, Hunan Provincial Key Laboratory of Medical Virology, College of Biology, Hunan University, Changsha, Hunan, China.

Journal of Medical Virology
|April 5, 2025
PubMed

Insights

The SARS-CoV-2 membrane protein (M) drives ferroptosis and lipid buildup by degrading glutathione peroxidase 4 (GPX4) via MARCH1. Targeting this interaction may treat COVID-19.

Area of Science:

  • Virology
  • Cellular Metabolism
  • Pathology

Background:

  • The SARS-CoV-2 membrane protein (M) is crucial for virus assembly and linked to organ damage and metabolic issues.
  • Understanding M protein's role in host cell processes like ferroptosis and lipid accumulation is vital for COVID-19 treatment strategies.

Purpose of the Study:

  • To investigate the mechanisms by which the SARS-CoV-2 M protein induces host ferroptosis and lipid accumulation.
  • To identify key host factors and pathways involved in M-mediated cellular damage.
  • To explore potential therapeutic targets within these pathways.

Main Methods:

  • Assessing cellular sensitivity to ferroptosis upon M protein expression.
  • Analyzing the role of perilipin-2 and SREBP1 in M-induced lipid accumulation.
  • Evaluating the effects of xanthohumol, a DGAT inhibitor, on lipid levels and ferroptosis.
  • Investigating the involvement of TIM23 and TOMM20 in M-induced mitochondrial dysfunction.
  • Examining the interaction between M protein and GPX4, and its ubiquitylation by MARCH1.

Main Results:

  • M protein expression increases cellular susceptibility to ferroptosis.
  • Perilipin-2 and SREBP1 are key mediators of M-induced lipid accumulation.
  • Xanthohumol reduces lipid accumulation and counteracts M-induced ferroptosis.
  • M protein contributes to mitochondrial dysfunction via TIM23 and TOMM20.
  • M protein interacts with GPX4, leading to its degradation by MARCH1, a process involving M's R72 residue.
  • Inhibiting lipid synthesis mitigates mitochondrial dysfunction, suggesting a lipid-ferroptosis pathway crosstalk.

Conclusions:

  • The SARS-CoV-2 M protein promotes ferroptosis and lipid accumulation through specific host factors and pathways.
  • M protein induces mitochondrial dysfunction, exacerbating cellular damage.
  • The interaction between M protein and GPX4, mediated by MARCH1, is a critical axis in SARS-CoV-2 pathogenesis.
  • Targeting the M-GPX4-MARCH1 axis or lipid metabolism presents a potential therapeutic strategy for COVID-19.
Keywords:
SARS‐CoV‐2 membrane proteinferroptosisglutathione peroxidase 4lipid accumulationmitochondrial damage

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