Multi-omics profiling of the diabetic human heart reveals coupled dysregulation in lipid metabolism, mitophagy, and extracellular matrix remodeling.

Diabetic cardiomyopathy (DbCM) is a major complication of type 2 diabetes whose molecular basis in human hearts remains poorly understood. This study aimed to define the multi-omics landscape of DbCM in the human myocardium. We performed integrated transcriptomic, 4D-DIA proteomic, and full-spectrum widely targeted metabolomic analysis on left ventricular tissues from matched Chinese cohorts: DbCM (n = 11), non-diabetic cardiomyopathy (n = 11), and healthy donors (n = 4). Key findings were validated by histological assessment and western blotting of candidate proteins. External validation was conducted using public datasets, and phenotypic support was derived from mouse models. Multi-omics profiling revealed distinct, coordinated dysregulation in DbCM. Proteomics and transcriptomics profiling revealed a rewired fatty acid oxidation-mitophagy axis characterized by elevated acyl-CoA synthetase long-chain family member 1 (ACSL1) and suppressed fatty acid synthase (FASN), impaired mitochondrial quality control marked by a significant reduction in the mitophagy regulator BNIP3L, which showed a strong inverse correlation with ACSL1, and disrupted extracellular matrix homeostasis, with specific downregulation of key structural components (COL5A1, COL5A2, and fibrillin-1). Metabolomics confirmed enhanced but incomplete fatty acid oxidation, evidenced by triglyceride depletion and accumulation of acylcarnitines and lipotoxic lipids. Integrated multi-omics identified impaired BNIP3L-associated mitophagy as a potential molecular node associated with lipid metabolic dysregulation with mitochondrial dysfunction. This human multi-omics study defines DbCM by the concurrent dysregulation of cardiac fuel metabolism, mitochondrial quality control, and matrix remodeling, offering novel mechanistic insights and highlighting ACSL1 and BNIP3L as potential therapeutic targets for diabetes-associated cardiac dysfunction.