5-oxoETE links redox control of epithelial damage detection and resilience.

Organisms harness oxidative stress to rapidly attract white blood cells to wound sites and to kill pathogens1-3. To this end, host tissues increase their own oxidative stress resilience and repair capacity via adaptive redox signalling4-6. Here, using live zebrafish and human cells, we identify a metabolic redox signalling mechanism that integrates oxidative immune defence with tissue adaptation. We demonstrate that DHRS7, an orphan short-chain fatty acid dehydrogenase-reductase, generates or consumes the pro-inflammatory lipid 5-oxoETE as a function of cytoplasmic NADP+/NADPH ratio. At wounds, where oxidative stress and NADP+ are high, 5-oxo-eicosatetraenoic acid (5-oxoETE) production by DHRS7 rapidly alerts antimicrobial white blood cells through the G-protein-coupled receptor OXER1. In undamaged tissue, where NADP+ is low, DHRS7 quenches unnecessary inflammation. Notably, we find that 5-oxoETE also supports epithelial redox resilience; OXER1-deficient zebrafish exhibit intestinal apoptosis, barrier disruption and microbial inflammation. Mechanistically, 5-oxoETE induces the expression of NUDIX hydrolases, which protect the cytoplasmic nucleotide pool from oxidation and prevent apoptosis in zebrafish and human intestinal cells. Thus, our data reveal a conserved mode of redox sensing and signalling-beyond classic thiol oxidation-that leverages NADPH metabolism to orchestrate the antimicrobial and pro-resilience functions of oxidative stress.