Porcine epidemic diarrhea virus (PEDV), a highly lethal alpha coronavirus, primarily infects piglet intestines, yet the role of the intestinal homeostasis regulator NEDD4-a HECT-family E3 ubiquitin ligase-in PEDV infection was previously unknown. This study reveals that NEDD4 inhibits PEDV infection by mediating K63-linked ubiquitination of the viral primase NSP8, targeting a conserved lysine (K170) within an NEDD4-recognized SPP motif. The C2 domain of NEDD4 is critical for this antiviral activ