BDH1 (3-hydroxybutyrate dehydrogenase 1) is a mitochondrial matrix enzyme that catalyzes the final step of ketogenesis, converting β-hydroxybutyrate to acetoacetate. This rate-limiting enzyme for ketone body metabolism is embedded in the mitochondrial inner membrane and plays dual roles in energy metabolism and tissue protection across multiple organs. In hepatic metabolism, BDH1 contributes to ketone body catabolism, which appears to mediate protective effects beyond simple fat oxidation. In the heart, BDH1 expression is reduced in diabetic cardiomyopathy, and its overexpression attenuates diastolic dysfunction, apoptosis, and fibrosis in db/db mice through epigenetic reprogramming of ketone metabolism 1. Similarly, in the kidney, BDH1 downregulation occurs in diabetic kidney disease, and BDH1-mediated β-hydroxybutyrate metabolism activates NRF2-dependent antioxidative pathways; adeno-associated virus 9-mediated BDH1 renal expression reverses fibrosis and inflammation 2. In immune contexts, BDH1 expression in CD8+ T cells is elevated by the SGLT2 inhibitor empagliflozin, promoting ketone body production that suppresses T cell activation and improves metabolic dysfunction-associated steatohepatitis; Bdh1 ablation in T cells ablated this therapeutic benefit 3. Clinically, BDH1 duplications have been identified in rare cases of autism spectrum disorder, cardiac defects, and obesity 4. SGLT2 inhibitors such as empagliflozin enhance BDH1-dependent ketone utilization as a mechanism to improve both diabetic cardiomyopathy and metabolic liver disease 5.