VPS34-mediated autophagosome-lysosome fusion facilitates classical swine fever virus replication

CSFV remains a major pathogen of global concern, causing severe disease in swine and incurring substantial economic losses in the pig industry. The absence of effective antiviral agents underscores the pressing need for host-targeted therapeutic strategies. In this study, we identified Vps34-IN-1, a selective inhibitor of VPS34, as a potent suppressor of CSFV replication in a dose-dependent manner. Remarkably, Vps34-IN-1 also exhibits potent inhibitory activity against other economically important swine viruses, including BVDV, PRV, and PEDV, demonstrating its potential as a broad-spectrum antiviral agent. Knockdown experiments further validated VPS34 as an essential host factor required for CSFV propagation. Mechanistically, the viral p7 protein engages in a specific interaction with UVRAG, a pivotal constituent of the VPS34 complex II, thereby potentially augmenting VPS34-UVRAG complex assembly and facilitating autophagosome-lysosome fusion. These findings delineate VPS34 as a compelling host-oriented antiviral target and open new therapeutic avenues for the control of CSF and other economically significant swine viral diseases.