Pexophagy-driven redox imbalance promotes virus-induced ferroptosis

Abstract

Peroxisomes are critical organelles that maintain cellular redox homeostasis. Many viruses induce oxidative stress and degrade peroxisomes, but the mechanisms and consequences remain unclear. In this study, we systematically investigate how virus-induced pexophagy regulates peroxisome homeostasis. Using Newcastle disease virus (NDV) as a model, we demonstrate that NDV infection triggers excessive reactive oxygen species (ROS) production, activating the phosphorylation and peroxisomal localization of ataxia-telangiectasia mutated (ATM). Activated ATM promotes the interaction between the peroxisomal receptor PEX5 and the autophagy receptor p62, driving pexophagy. Pexophagy-mediated peroxisome degradation leads to excess active iron and ROS accumulation, contributing to NDV-induced ferroptosis. Notably, this mechanism is shared by other viruses, such as vesicular stomatitis virus and H9N2 avian influenza virus. Our study provides insights into how virus-induced pexophagy disrupts redox homeostasis to promote ferroptosis, highlighting a link between viral infection, peroxisome degradation, and programmed cell death.

Keywords: CP: Immunology; CP: Microbiology; PEX5; ROS; ferroptosis; peroxisome; pexophagy; virus.