The protein denitrosylase SCoR2 regulates lipogenesis and fat storage

Lipid homeostasis is subject to control by posttranslational modification machinery, such as sirtuin deacetylases that reverse coenzyme A (CoA)-dependent acetylation. Here, we showed that a mammalian denitrosylase (SCoR2), which counteracts CoA-dependent S-nitrosylation, promoted both fat storage and lipogenesis to impair metabolic health. In mice, SCoR2 protein abundance correlated with body mass, and deleting or pharmacologically inhibiting SCoR2 prevented both diet-induced obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Loss of <i>SCoR2</i> in adipocytes promoted the S-nitrosylation of the actin cytoskeletal regulator myosin 9, which inhibited the activity of the lipogenesis-promoting transcription factors PPARγ, SREBP1, and CEBPα to prevent fat storage. In hepatocytes, inhibition of SCoR2-mediated denitrosylation of lipogenic enzymes reduced fat synthesis and induced fat oxidation. In humans, an obesity-linked polymorphism was associated with increased <i>SCoR2</i> mRNA expression, and in patient adipose and liver tissues, SCoR2 protein or mRNA abundance directly correlated with adipocyte size or MASLD. These results indicate that SCoR2 regulates nutrient metabolism, similar to sirtuins, and is a potential drug target for obesity and MASLD.