Mitochondrial UPR is required for resveratrol mediated anti-bacterial immunity.

The mitochondrial unfolded protein response (UPR^mt), 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 to Pseudomonas aeruginosa PA14 infection in a dose-dependent manner. This protective effect was mediated not through direct antimicrobial activity, but rather via upregulation of the antimicrobial peptide irg-1 and reduction of intestinal bacterial load. Mechanistically, resveratrol activated the ATFS-1-dependent UPR^mt pathway, leading to increased expression of ATFS-1 and its downstream immune- and mitochondrial-protective genes. In human A549 cells, resveratrol attenuated P. aeruginosa PA14 cytotoxicity by activating the UPR^mt through 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-UPR^mt axis 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.