DHRS7 Integrates NADP+/NADPH Redox Sensing with Inflammatory Lipid Signalling via the Oxoeicosanoid Pathway

During the innate immune response at epithelial wound sites, oxidative stress acts microbicidal and--mechanistically less well understood--as an immune and resilience signal. The reversible sulfhydryl (SH) oxidation of kinases, phosphatases, and transcription factors constitute the perhaps best-known redox signalling paradigm, whereas mechanisms that transduce metabolic redox cues, such as redox cofactor balance, remain little explored. Here, using mammalian cells, microsomes, and live zebrafish, we identify DHRS7, a short-chain fatty acid dehydrogenase/reductase (SDR), as conserved, 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Under oxidative stress, DHRS7 consumes NADP+ to convert arachidonic acid (AA)-derived 5(S)-HETE into the inflammatory lipid 5-KETE, which activates leukocyte chemotaxis via the OXER1 receptor. While Dhrs7 acts as a NADPH-dependent 5-KETE sink in unstressed, healthy tissue, it promotes rapid, 5-KETE dependent leukocytic inflammation in wounded zebrafish skin. Thus, DHRS7 epitomizes an underappreciated mode of redox signalling--beyond classic SH oxidation--that leverages NADPH metabolism to generate or quench a paracrine lipid signal. Metabolic redox sensors like DHRS7 might be promising therapeutic targets in diseases characterized by disturbed redox balance.