HMGCS2 encodes the mitochondrial enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2, which catalyzes the rate-limiting step in ketogenesis by condensing acetyl-CoA and acetoacetyl-CoA to form HMG-CoA 1. This enzyme plays crucial roles in metabolic homeostasis across multiple organ systems. In the liver, HMGCS2-mediated ketogenesis protects against hepatic steatosis, with knockout mice developing spontaneous fatty liver during postnatal development and showing increased susceptibility to diet-induced NAFLD 2. The enzyme is essential for renal protection, as SGLT2 inhibitor-mediated renoprotection in diabetic kidney disease depends on HMGCS2-driven ketone body production, with renoprotective effects abolished by Hmgcs2 gene deletion 3. In cardiac tissue, HMGCS2 expression promotes cardiomyocyte proliferation and protects against diabetic cardiomyopathy by improving mitochondrial function and reducing oxidative stress 45. Additionally, HMGCS2 distinguishes intestinal stem cells from differentiated cells, with its product β-hydroxybutyrate acting as a signaling molecule that inhibits histone deacetylases to reinforce Notch signaling and regulate stem cell self-renewal 1. Deficiency in HMGCS2 is associated with metabolic disorders and represents a potential therapeutic target for treating fatty liver disease, diabetic complications, and chr1 kidney disease 6.