Electrostatic lipidopathy drives human diabetic heart failure.

BACKGROUND: Human diabetic heart failure (diHF) is a major contributor to cardiovascular morbidity and mortality and is characterized by myocardial lipid overload and oxidative injury; however, the specific lipid species and molecular mechanisms driving myocardial dysfunction remain unclear. OBJECTIVE: To identify lipid species and integrated molecular networks underlying human diHF using an untargeted multi-omics approach. METHODS: We performed integrated lipidomic, metabolomic, and proteomic profiling of human diabetic failing hearts and matched non-diabetic controls. Lipidomic and metabolomic analyses were conducted using high-resolution UPLC-MS/MS, and quantitative proteomics was performed using tandem mass tag-based LC-MS/MS. Multivariate modeling, differential abundance testing, pathway enrichment, and cross-platform network integration were used to define coordinated lipid-metabolite-protein signatures associated with diHF. RESULTS: Multi-omics integration identified “electrostatic lipidopathy”, a charge-dependent remodeling of membrane and metabolic lipid species, as a defining feature of diHF. Diabetic hearts exhibited enrichment of negatively charged polyunsaturated phospholipids and sphingolipids together with increased diradylglycerols, ceramides, and lactosylceramides, generating a highly anionic lipid environment consistent with increased susceptibility to lipid peroxidation and ferroptosis-related injury. Metabolomic profiling revealed disruption of the myocardial lipid-energy axis characterized by a pattern consistent with increased fatty-acid influx, acylcarnitine accumulation, incomplete β-oxidation, and metabolic inflexibility. Proteomic remodeling demonstrated coordinated suppression of oxidative phosphorylation, mitochondrial dysfunction, inflammatory activation, and extracellular matrix remodeling. Network analysis linked lipid charge remodeling with mitochondrial energetic failure, oxidative stress, and fibrotic remodeling in diHF myocardium. CONCLUSIONS: Electrostatic lipidopathy represents a previously unrecognized mechanism of diabetic cardiac remodeling. By linking membrane lipid charge architecture with mitochondrial dysfunction, redox imbalance, and inflammatory-fibrotic signaling, these findings highlight lipid charge imbalance and ferroptosis-related vulnerability as potential therapeutic targets in diabetic heart failure.