Ursolic Acid Activates Mitochondrial Unfolded Protein Response to Enhance Innate Immunity via Transcription Factor ATFS-1/ATF5
Jun Xiong, Xiaocong Li, Fangfang Mao, Nengyue Wang, Fang Liu, Yi Xiao
Abstract
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 Caenorhabditis elegans against Pseudomonas aeruginosa 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.