The mitochondrial unfolded protein response (UPR), a crucial mechanism for maintaining mitochondrial homeostasis, has recently been shown to regulate innate immune responses. Resveratrol, a natural polyphenolic compound abundant in grapes and peanuts, exhibits diverse biological activities including anti-inflammatory, antioxidant, anti-aging, and anticancer effects. However, whether resveratrol modulates innate immunity and its underlying mechanisms remain unclear. In this study, we demonstrated that resveratrol significantly enhanced resistance toPA14 infection in a dose-dependent manner. This protective effect was mediated not through direct antimicrobial activity, but ratherupregulation of the antimicrobial peptideand reduction of intestinal bacterial load. Mechanistically, resveratrol activated the ATFS-1-dependent UPRpathway, leading to increased expression of ATFS-1 and its downstream immune- and mitochondrial-protective genes. In human A549 cells, resveratrol attenuatedPA14 cytotoxicity by activating the UPRthrough ATF5. The conservation of this mechanism was further validated in mice, where resveratrol treatment improved survival, reduced bacterial burden in lung tissue, and upregulated mitochondrial-protective genes. Our study identifies the ATFS-1/ATF5-UPRaxis as a novel mechanism through which resveratrol enhances innate immunity, providing a foundation for developing natural compound-based anti-infective therapies. These findings advance our understanding of plant polyphenols in immune regulation and offer potential strategies to address antibiotic resistance. mt mt mt mt Pseudomonas aeruginosa via irg-1P. aeruginosa
