Ursolic Acid Activates Mitochondrial Unfolded Protein Response to Enhance Innate Immunity via Transcription Factor ATFS-1/ATF5

Ursolic acid (UA), a pentacyclic triterpenoid found in various plants, exhibits diverse biological activities. The mitochondrial unfolded protein response (UPR^mt) acts as a pivotal regulator in orchestrating innate immune responses. However, it remains unclear whether UA modulates innate immunity, and the molecular mechanisms involved have yet to be elucidated. In this study, we established that UA enhances the survival of <i>Caenorhabditis elegans</i> against <i>Pseudomonas aeruginosa</i> PA14 infection by promoting intestinal bacterial clearance, independent of inhibitory effects on bacterial growth or evasion behavior. Mechanistically, UA activates the UPR^mt via transcription factor ATFS-1 and its downstream immune-related genes to bolster innate immunity. Furthermore, UA also protects A549 human lung epithelial cells and mice from PA14 infection by activating the UPR^mt through ATF5. These findings provide a novel perspective and theoretical foundation for developing UA-based natural immune enhancers against infections, highlighting significant translational potential.