BDH1 overexpression alleviates diabetic cardiomyopathy through inhibiting H3K9bhb-mediated transcriptional activation of LCN2.

Summary

BDH1, diminished in diabetic hearts, protects against diabetic cardiomyopathy by reprogramming ketone metabolism to reduce H3K9 β-hydroxybutyrylation at the LCN2 promoter, thereby suppressing LCN2 and NF-κB activity. Genetic gain-of-function preserved diastolic function and reduced apoptosis, fibrosis, and inflammation; pharmacologic inhibition of β-hydroxybutyrylation recapitulated protection.

Key Findings

• BDH1 is reduced in diabetic human and db/db mouse hearts and in lipotoxic H9C2 cells.
• BDH1 deletion worsened, whereas AAV-mediated overexpression attenuated, diastolic dysfunction, apoptosis, fibrosis, and inflammation.
• BDH1 overexpression increased AcAc and decreased β‑OHB, reducing H3K9 β-hydroxybutyrylation at the LCN2 promoter, suppressing LCN2 and NF‑κB; LCN2 overexpression abrogated protection.
• The β-hydroxybutyrylation inhibitor A485 mitigated cardiac injury and reduced LCN2 in diabetic mice.

Clinical Implications

Suggests BDH1 activation or LCN2 suppression as therapeutic strategies for diabetic cardiomyopathy; supports testing epigenetic modulators (e.g., H3K9bhb inhibitors) in cardiometabolic disease.

Limitations

• Preclinical models may not fully recapitulate human diabetic cardiomyopathy
• Long-term safety and translational efficacy of epigenetic modulation remain untested in humans

Future Directions

Validate BDH1/LCN2 axis in larger human cohorts; develop selective BDH1 activators or LCN2 inhibitors; test translational efficacy in large animals and assess sex-specific effects.