The resveratrol prodrug triacetylresveratrol targets the intestinal tract to alleviate PEDV infection via the AMPK-ULK1 autophagy axis.

Enteric coronaviruses, such as Porcine Epidemic Diarrhea Virus (PEDV), cause devastating mucosal infections in the swine industry. While host-directed natural compounds like resveratrol exhibit broad-spectrum antiviral potential in vitro, their in vivo translation is severely hindered by poor bioavailability. Here, we demonstrate that a lipophilic resveratrol prodrug, triacetylresveratrol (TCRV), overcomes these pharmacokinetic limitations to confer in vivo protection against PEDV infection. Utilizing a physiologically relevant suckling piglet model, we found that TCRV achieves targeted tissue retention in the small intestine, the primary site of infection. Orally administered TCRV alleviated clinical symptoms, restored intestinal mucosal barrier integrity, and suppressed virus-induced systemic and local inflammation by suppressing the NF-κB signaling pathway. Transcriptomic and molecular analyses revealed that TCRV executes direct antiviral clearance by inducing host protective autophagy. Mechanistically, TCRV activates the cellular energy sensor AMPK and its downstream target ULK1. By utilizing porcine intestinal epithelial cells (IPEC-J2), we demonstrated that pharmacological blockade of ULK1 kinase activity completely abrogates the autophagic and antiviral efficacy of the prodrug. Taken together, these data indicate a novel host-directed antiviral strategy. Although TCRV demonstrates therapeutic potential against enteric viral infections via AMPK-ULK1-mediated autophagic clearance, its efficacy in clinical settings requires further evaluation.