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

Background: Diabetic cardiomyopathy (DbCM) is one of the common complications in diabetic patients, but there is no effective treatment for it up to now. Ketone bodies such as β-OHB have been widely reported to be beneficial for metabolic diseases including various diabetic complications. However, the role of ketone metabolism, especially the relevant enzymes, in the pathogenesis of DbCM is poorly understood.
Methods and Results: In this study, we firstly observed BDH1, the rate-limiting enzyme of ketone metabolism, was markedly diminished in cardiac tissues from db/db mice and diabetic patients, as well as in H9C2 cells treated with palmitic acid. Genetic deletion of BDH1 aggravated, whereas AAV-mediated BDH1 overexpression attenuated, the diastolic dysfunction and pathogenic progression including apoptosis, fibrosis and inflammation of hearts from db/db mice. Likewise, BDH1 knockdown promoted, whereas BDH1 overexpression reversed, the palmitic acid-induced lipotoxicity in H9C2 cells. Transcriptome analysis revealed that BDH1 negatively regulated LCN2 expression and LCN2 overexpression largely abrogated BDH1 overexpression-mediated myocardial protection in vitro and in vivo. Mechanistically, BDH1 overexpression reprogrammed ketone metabolism with increased AcAc and decreased β-OHB, thereby resulting in decreased β-hydroxybutyrylation of H3K9 on promoter region of LCN2, which repressed transcription of LCN2 and ultimately inhibited NF-κB activity through weakening interaction between NF-κB and RPS3. Furthermore, oral administration of β-hydroxybutyrylation inhibitor A485 to diabetic mice mitigated the cardiac injury concurrently with decreased expression of LCN2.
Conclusion: Our results uncovered a novel mechanism whereby myocardial BDH1 ameliorates DbCM via epigenetic regulation of LCN2, which highlights the potential of BDH1/LCN2-based therapeutics in DbCM.
Competing Interests: Declarations. Ethics approval and consent to participate: All procedures that involved human samples were approved by the Affiliated Hospital of Southwest Medical University Ethics Committee (KY2023221). Animal experiments were approved by the Institutional Animals Ethics Committees of Southwest Medical University (20220225-014). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2025. The Author(s).)