Bovine viral diarrhea virus E2 targets SLC3A2 to modulate lipid peroxidation for replication advantage

Pestiviruses, part of the Flaviviridae family, are responsible for major livestock diseases such as bovine viral diarrhea, classical swine fever, and border disease. These infections lead to substantial economic losses worldwide. However, their pathogenesis remains incompletely understood, limiting the development of effective control strategies. In this study, we explored how bovine vial diarrhea virus (BVDV) regulate host lipid peroxidation (LPO) to support viral replication. We initially found that early infection with BVDV enhanced intracellular redox balance by upregulating the cystine/glutamate antiporter system xc^- in Madin-Darby bovine kidney (MDBK) cells, thereby increasing glutathione (GSH) synthesis and glutathione peroxidase (GPX) activity. Consistently, Erastin2, a selective inhibitor of system xc^-, induced LPO and suppressed BVDV replication. Further analysis identified SLC3A2, a subunit of system xc^-, as a key regulator of redox homeostasis during infection. Both siRNA knockdown and CRISPR/Cas9 knockout of SLC3A2 significantly impaired viral replication. Co-immunoprecipitation and confocal microscopy revealed that BVDV E2 domain 3 subdomain III directly binds to the N-terminal region (amino acids 1-146) of SLC3A2. These findings uncover a novel viral strategy to suppress LPO via the E2-SLC3A2-GSH-GPX4 axis, offering new targets for antiviral intervention.