Multi-omics profiling reveals coordinated metabolic and immuno-inflammatory remodeling in a high-fat diet and single-dose streptozotocin-induced mouse model of diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is a major myocardial complication of type 2 diabetes and a contributor to heart failure. However, coordinated remodeling across the cardiac transcriptome, proteome and metabolome in DCM remains incompletely defined. Type 2 diabetes was induced in mice by a high-fat diet combined with single-dose streptozotocin. DCM was characterized by echocardiography, histology, transmission electron microscopy, and systemic metabolic and inflammatory assessments. Left ventricular myocardium underwent RNA sequencing, quantitative proteomics and untargeted metabolomics, followed by integrated pathway and network analyses. Selected pathways were further examined by biochemical assays, with additional evaluation of mitochondrial injury and cGAS–STING signaling. Diabetic mice developed systolic and diastolic dysfunction with ventricular remodeling, interstitial fibrosis, mitochondrial ultrastructural damage, insulin resistance, and heightened systemic and myocardial inflammation. Transcriptomic and proteomic profiling revealed concordant suppression of sarcomeric organization, calcium handling, and mitochondrial oxidative metabolism, indicating downregulation of a contraction–calcium–mitochondrial energetics axis. Metabolomics showed reduced pyruvate-linked intermediates and enrichment of pentose phosphate, nucleotide and glutathione-related metabolites, consistent with diversion of central carbon flux from mitochondrial oxidation toward redox and biosynthetic programs. Across all three omics layers, phospholipid–choline metabolism emerged as a remodeled hub connecting central carbon pathways with complement, cell adhesion and inflammatory signaling. Increased cGAS–STING activity in DCM myocardium further linked mitochondrial injury to innate immune activation. Integrated multi-omics analysis reveals coordinated remodeling across mitochondrial function, metabolism, inflammation, and fibrosis in experimental DCM. Alterations in phospholipid–choline metabolism, pentose phosphate and central carbon pathways, cGAS–STING signaling, and the contraction–calcium–mitochondrial module were concurrently observed and collectively characterize the molecular landscape of diabetic cardiomyopathy. These findings provide a framework for future mechanistic studies and may help identify candidate biomarkers and potential therapeutic pathways for further investigation. Integrated multi-omics remodeling in HFD/STZ-induced diabetic cardiomyopathy. HFD plus single-dose STZ induced DCM with metabolic dysfunction, inflammation, mitochondrial injury, cardiac dysfunction, and fibrosis. Integrated transcriptomic, proteomic, and metabolomic analyses revealed suppression of the contraction–calcium–mitochondrial energetics axis, central carbon reprogramming toward the pentose phosphate pathway, phospholipid–choline remodeling, and cGAS–STING-associated innate immune and fibrotic activation. Green arrows indicate activation, red dashed lines indicate suppression, and gray lines indicate associations.