β-Hydroxybutyrylation in Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) is characterized by metabolic remodeling and energetic stress independent of coronary artery disease. Increased reliance on fatty acid and ketone body metabolism has been observed in DCM, but the regulatory mechanisms linking altered substrate utilization to myocardial dysfunction remain poorly understood. In particular, lysine β-hydroxybutyrate (Kbhb), a ketone body-derived post-translational modification, has emerged as a potentially critical regulator, but has not been fully investigated. We conducted a comprehensive multi-omics study integrating metabolomics, transcriptomics, proteomics, and Kbhb-specific proteomics on myocardial tissues in a well-established mouse model of DCM. Kbhb-modified proteins were systematically mapped and quantified, followed by motif, subcellular localization, and protein–protein interaction analyses. DCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Kbhb profiling revealed extensive mitochondrial protein modification, with Atp5f1a-K239 identified as a key modification site strongly correlated with β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb as a potential metabolic-epigenetic modifier linking ketone body availability to the regulation of mitochondrial proteins in DCM. Our findings provide novel insights into metabolic-epigenetic crosstalk and identify potential therapeutic targets for interventions to restore mitochondrial function in alleviating diabetic heart disease.