Celastrol Inhibits Porcine Epidemic Diarrhea Virus Replication by Promoting ROS‐Mediated Apoptosis

Porcine epidemic diarrhea virus (PEDV) causes acute, highly contagious enteric disease in pigs, leading to severe economic losses, particularly due to high mortality in suckling piglets. Currently, no specific antiviral drugs are available. In this study, we evaluated the anti-PEDV potential of celastrol, a natural triterpenoid derived from <i>Tripterygium wilfordii</i>, in Vero E6 cells. We found that celastrol significantly inhibited PEDV replication in a dose-dependent manner, primarily targeting the postentry stage of the viral life cycle. Network pharmacology analysis highlighted apoptosis as a key signaling pathway, and mechanistic studies revealed that celastrol enhanced PEDV-induced reactive oxygen species (ROS) accumulation, which triggered apoptosis and suppressed viral RNA synthesis, protein expression, and progeny production. Importantly, inhibition of ROS abolished celastrol's antiviral activity, confirming a ROS-dependent mechanism. Furthermore, celastrol demonstrated inhibitory effects against porcine deltacoronavirus (PDCoV) and porcine reproductive and respiratory syndrome virus (PRRSV) in vitro. These findings suggest celastrol as a promising candidate for the prevention and control of PED and other swine viral infections.