A screen-identified immunomodulator protects against Staphylococcus aureus infection via the VCP-PERK-Nrf2 signaling axis

Antibiotic resistance threatens the effectiveness of conventional antimicrobials, underscoring the need for host-directed therapies that enhance immune defense. Here, we present a cross-species discovery pipeline that couples a Caenorhabditis elegans–Staphylococcus aureus infection screen with mammalian mechanistic validation to identify small-molecule immunomodulators. Using six C. elegans innate immunity reporter strains, we identified SKI-II as a previously unrecognized host-protective compound that activates the SKN-1/Nrf2 oxidative-stress pathway to protect worms from S. aureus infection without directly killing the pathogen. In mammalian RAW264.7 macrophages, we found that SKI-II binds to the ATPase pocket of VCP (Valosin-Containing Protein), establishing a VCP–PERK (PRKR-like Endoplasmic Reticulum Kinase)–Nrf2 signaling axis that reduces the levels of pathogenic ROS (reactive oxygen species). PERK activation also promotes macrophage M1 polarization and a metabolic shift from oxidative phosphorylation to glycolysis, reducing mitochondrial ROS production. This work identifies VCP as a druggable node for host-directed immunomodulation and identifies SKI-II as a prototype small molecule that boosts host tolerance to infection, validating a C. elegans-based screening approach as a platform for discovering immunomodulators active in mammalian systems.