BDH1 regulates cardiomyocyte apoptosis and diabetic cardiomyopathy by modulating mitochondrial dynamics and attenuating oxidative stress.

Diabetic cardiomyopathy (DCM) is a significant cardiovascular consequence of diabetes, marked by increasing myocardial dysfunction that culminates in heart failure. Current treatments prioritize glucose control but frequently neglect the fundamental metabolic dysfunction and excessive cardiomyocyte death that propel disease progression. Recent data indicates that β-hydroxybutyrate dehydrogenase 1 (BDH1), the rate-limiting enzyme in ketolysis may serve a protective function by supplying alternative energy substrates and regulating apoptosis. This study demonstrates that BDH1 overexpression in H9c2 and AC16 cardiomyocytes treated with high glucose and palmitate dramatically decreases apoptosis. In a streptozotocin-induced diabetic mouse model, cardiac-specific BDH1 overexpression via AAV9 delivery maintained cardiac structure and function by inhibiting apoptosis through two primary mechanisms: (1) interaction with KIF1Bβ to modulate mitochondrial dynamics, and (2) suppression of ROS-mediated apoptosome formation (Cytc/Apaf-1 complex). These findings designate BDH1 as an innovative therapeutic target for DCM by illustrating its dual function in metabolic regulation and apoptosis inhibition, while recognizing ROS and KIF1Bβ as pivotal mediators of DCM pathogenesis.