The Interplay Between Autophagy and Porcine Epidemic Diarrhea Virus: From Molecular Mechanisms to Therapeutic Perspectives

Autophagy is a highly conserved degradation and recycling process in eukaryotic cells that plays a critical role in maintaining cellular homeostasis and responding to external stress. During viral infection, autophagy exhibits a classic “double-edged sword” effect—it can act as a host defense mechanism by directly degrading viral components, but it can also be hijacked by viruses to promote their own replication. Porcine epidemic diarrhea virus (PEDV), an important enteric coronavirus that severely affects the global swine industry, engages in a complex and sophisticated interplay with the host autophagy system. This review systematically dissects the dual regulatory mechanisms of autophagy during PEDV infection and reveals two intertwined functional axes. On one hand, PEDV utilizes multiple viral proteins to cooperatively manipulate the autophagic pathway—inducing mitophagy to suppress innate immune responses, utilizing autophagic membranes to construct replication platforms, and blocking autophagic flux to evade degradation—thereby establishing a multi-level pro-viral network. On the other hand, host cells deploy a unified molecular axis of “ubiquitination–autophagy receptor–lysosome” by mobilizing a broad array of restriction factors to target and degrade viral proteins, forming a coordinated defense system. These two axes converge at the oxidative stress–endoplasmic reticulum stress–autophagy hub, where PEDV NSP1 and NSP2 synergistically inhibit the NRF2 antioxidant system to trigger this cascade, while host factors such as DDX6 and ACE2 finely regulate the process. Based on this mechanistic framework, we discuss the therapeutic implications of targeting autophagy for PEDV intervention, with particular emphasis on the development of selective autophagy modulators as potential antiviral agents. We also identify key knowledge gaps and propose future research directions to translate these mechanistic insights into clinical or field applications. This review synthesizes the peer-reviewed literature published between 2013 and 2026, identified through systematic searches of PubMed, Web of Science, and Scopus databases. Notably, the majority of mechanistic findings discussed are derived from in vitro cell culture models, and their translation to in vivo settings remains a significant challenge. Bridging this gap will require validation in physiologically relevant models, such as porcine intestinal organoids and controlled piglet challenge studies, to assess the efficacy and safety of autophagy-targeting interventions in the context of intestinal homeostasis and mucosal immunity.