SFTSV exploits PPM1K to inhibit apoptosis through the Bcl-2/BAX/Caspase-3 axis for efficient replication.

SFTSV (Severe fever with thrombocytopenia syndrome virus) causes severe febrile illness with high case fatality rates and poses a growing public health threat, while the molecular basis by which it subverts host survival pathways remains poorly understood. In this study, transcriptomic profiling identified PPM1K as a prominently induced host factor in SFTSV-infected THP-1-derived macrophages. We further demonstrate that SFTSV infection promotes endoplasmic reticulum-mitochondria coupling, enabling the viral glycoprotein Gc to interact with mitochondrial PPM1K and enhance its expression at both transcriptional and protein levels. Mechanistically, the S248 residue of PPM1K is required for its dephosphorylation of Bcl-2, thereby decreasing Bcl-2 ubiquitination and stabilizing its anti-apoptotic activity, which ultimately suppresses the BAX-Caspase-3 signaling cascade. This anti-apoptotic remodeling markedly limits apoptosis in infected cells and facilitates efficient SFTSV replication. These findings uncover a previously unrecognized viral strategy in which SFTSV hijacks host PPM1K-dependent mitochondrial signaling to evade apoptosis and promote replication.