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bioRxiv · 10.1101/2025.02.05.636725

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

Ma, Y.·Hui, K. L.·Ambaw, Y. A.·Walther, T. C.·Farese, R. V.·Lengyel, M.·Gelashvili, Z.·Lu, D.·Niethammer, P.
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Abstract

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.

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Ma, Y., Hui, K. L., Ambaw, Y. A., Walther, T. C., Farese, R. V., Lengyel, M., Gelashvili, Z., Lu, D., Niethammer, P.. 2025-02-08. DHRS7 Integrates NADP+/NADPH Redox Sensing with Inflammatory Lipid Signalling via the Oxoeicosanoid Pathway. https://doi.org/10.1101/2025.02.05.636725

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