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Endogenously generated nitric oxide (NO) is highly cardioprotective, but protection is not replicated by nitroso-vasodilators (e.g., nitrates, nitroprusside) used in clinical practice, highlighting specificity in NO-based signaling and untapped therapeutic potential. Signaling by NO is mediated largely by\n                    <jats:italic>S<\/jats:italic>\n                    -nitrosylation, entailing specific enzymes that form and degrade\n                    <jats:italic>S<\/jats:italic>\n                    -nitrosothiols in proteins (SNO-proteins), termed nitrosylases and denitrosylases, respectively. SNO-CoA Reductase 2 (SCoR2; product of the\n                    <jats:italic>Akr1a1<\/jats:italic>\n                    gene) is a recently discovered protein denitrosylase. Genetic variants in SCoR2 have been associated with cardiovascular disease, but its function is unknown. Here, we show that mice lacking SCoR2\/AKR1A1 exhibit robust protection in an animal model of MI. SCoR2 regulates ketolytic energy availability, antioxidant levels, and polyol homeostasis via\n                    <jats:italic>S<\/jats:italic>\n                    -nitrosylation of key metabolic effectors. Human cardiomyopathy shows reduced SCoR2 expression and an\n                    <jats:italic>S<\/jats:italic>\n                    -nitrosylation signature of metabolic reprogramming, mirroring SCoR2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Deletion of SCoR2 thus coordinately reprograms multiple metabolic pathways\u2014ketone body utilization, glycolysis, pentose phosphate shunt, and polyol metabolism\u2014to limit infarct size, establishing SCoR2 as a novel regulator in the injured myocardium and a potential drug target.\n                  <\/jats:p>","DOI":"10.7554\/elife.106601","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T10:30:31Z","timestamp":1749119431000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.106601","source":"Crossref","is-referenced-by-count":4,"title":["The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3820-2049","authenticated-orcid":true,"given":"Zachary W","family":"Grimmett","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/051fd9666","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical Scientist Training Program, Case 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