Porcine epidemic diarrhea virus promotes viral replication via ROS/HIF-1α-mediated glycolysis.

Abstract

Porcine epidemic diarrhea virus (PEDV), a highly pathogenic coronavirus, causes recurrent outbreaks of severe enteric disease, posing a significant threat to the global swine industry. The persistent challenge highlights the urgent need for a deeper understanding of host-virus interactions to improve prevention and control strategies. Here, we demonstrated that PEDV infection reprogrammed host metabolism toward aerobic glycolysis, a metabolic shift that not only facilitated viral replication but also established an immunosuppressive microenvironment. PEDV infection activated the hypoxia-inducible factor-1α (HIF-1α) pathway and induced mitochondrial dysfunction, leading to the accumulation of mitochondrial reactive oxygen species (mROS), which in turn stabilized HIF-1α, creating a positive feedback loop that amplified glycolytic gene expression and lactate production. We confirmed that glycolysis was essential for PEDV replication, and that elevated glucose levels enhanced replication efficiency. Furthermore, PEDV-induced glycolysis and lactate accumulation inhibited the generation of interferons (IFNs), thereby facilitating immune evasion. Collectively, our findings revealed a metabolic-immune axis exploited by PEDV to optimize viral replication and subvert host defenses. This study not only provides novel insights into the metabolic adaptations underlying PEDV pathogenesis but also highlights host metabolic pathways as potential therapeutic targets to combat PEDV and other related coronaviruses.