4-octyl itaconate inhibits porcine epidemic diarrhea virus replication by modulating the ferroptosis axis and the autophagy pathway.

Porcine epidemic diarrhea virus (PEDV) continues to pose a significant threat to the swine industry, leading to high mortality in neonatal piglets and substantial economic losses. The emergence of antigenic variants often compromises vaccine efficacy, highlighting the need for novel antiviral strategies. This study investigates the potential of 4-octyl itaconate (4-OI) as a novel therapeutic agent against PEDV. In vitro studies demonstrated that 4-OI exhibited dose-dependent antiviral activity across multiple cell lines, directly reduced viral infectivity, and displayed broad-spectrum inhibitory effects against enveloped viruses. In a piglet model, 4-OI administration (100 mg/kg) significantly reduced disease severity, as evidenced by decreased intestinal viral load and tissue damage, improved weight gain, reduced diarrhea, and enhanced survival. Mechanistically, 4-OI inhibits PEDV replication by modulating ferroptosis and autophagy pathways, thereby restricting viral exploitation of host autophagy-ferroptosis crosstalk. These findings suggest that 4-OI is a promising therapeutic candidate for PEDV infection, offering a novel host-targeted antiviral approach and opening up a promising new direction for antiviral therapy.