Perfluorooctanoic acid disrupts lysine metabolism and autophagy to promote white spot syndrome virus infection in shrimp.

Perfluorooctanoic acid (PFOA), a globally distributed per- and polyfluoroalkyl substance (PFAS), is increasingly recognized for its immunotoxic and metabolic effects in aquatic organisms; however, its role in viral disease susceptibility remains poorly understood. Using Pacific white shrimp (Penaeus vannamei) and white spot syndrome virus (WSSV) as a model system, we investigated the effects of chronic PFOA exposure on antiviral immunity and viral transmission. Chronic exposure to environmentally relevant concentrations of PFOA resulted in significant accumulation of PFOA in the hepatopancreas and markedly increased WSSV replication, host mortality, and horizontal transmission. Integrated metabolomic and transcriptomic analyses identified lysine degradation as a consistently affected metabolic pathway, along with significant enrichment of lysosome-related pathways. Biophysical assays, including molecular docking, biolayer interferometry, and cellular thermal shift analysis, demonstrated that PFOA directly binds to the lysine-catabolizing enzyme aminoadipate semialdehyde synthase (AASS), which may contribute to lysine accumulation. Importantly, enzymatic activity assays further revealed that PFOA significantly inhibited both lysine-ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH) activities, accompanied by marked lysine accumulation in shrimp hepatopancreas. PFOA exposure alone induced basal autophagic dysfunction, as evidenced by reduced LC3/LAMP1 co-localization, decreased LC3 abundance, increased p62 accumulation, and impaired autophagosome-lysosome fusion. Dietary lysine supplementation reproduced these autophagic defects and significantly promoted WSSV replication, supporting a role for lysine accumulation in mediating impaired antiviral defense. Together, this study uncovers a previously unrecognized lysine-autophagy-lysosome regulatory axis through which PFOA enhances viral susceptibility and transmission in shrimp, providing mechanistic insight into pollutant-driven disease risk in aquaculture ecosystems.