S-nitroso-coenzyme A reductase 2 (SCoR2)

S-nitroso-coenzyme A reductase 2 (SCoR2), also known as AKR1A1, is a protein denitrosylase that serves as a master regulator of metabolic homeostasis by modulating the S-nitrosylation status of key proteins [4, 6, 13]. This enzyme acts as a biological switch for fat and cholesterol production; while it normally removes nitric oxide (NO) from target proteins to facilitate lipogenesis and cholesterol secretion, its inhibition keeps these proteins in an S-nitrosylated, inactive state [1, 2, 5]. Specifically, SCoR2 regulates a signaling cascade involving PCSK9, where its inhibition leads to increased S-nitrosylation and reduced secretion of PCSK9, thereby lowering LDL cholesterol levels [6, 11]. Preclinical evidence indicates that targeting SCoR2 can prevent weight gain, protect against fatty liver disease, and improve cardiovascular health simultaneously [3, 5]. Beyond metabolic disorders, SCoR2 inhibition has shown protective effects in models of acute kidney injury and myocardial infarction by reprogramming energy utilization pathways such as glycolysis and ketolysis [4, 9]. Selective small-molecule inhibitors, most notably JSD26, are currently being developed to exploit these multi-action therapeutic benefits for treating metabolic and cardiovascular diseases [9, 12].

Other names

Aldo-keto reductase family 1 member A1AKR1A1Aldehyde reductaseS-nitroso-CoA reductase 2Protein denitrosylase SCoR2

Selective inhibition of S-nitroso-coenzyme A reductase 2 increases the S-nitrosylation of metabolic proteins, which subsequently inhibits lipogenesis and suppresses the secretion of PCSK9, leading to reduced cholesterol and fat accumulation.