Electrostatic lipidopathy drives human diabetic heart failure

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. To identify lipid species and integrated molecular networks underlying human diHF using an untargeted multi-omics approach. 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. 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. 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. What is currently known about this topic? Diabetic heart failure (diHF) is associated with excess cardiovascular mortality and is characterized by myocardial lipid overload, mitochondrial dysfunction, oxidative stress, and metabolic inflexibility. However, the specific lipid species and integrated molecular networks that drive diabetic cardiac remodeling in humans remain unclear. What is the key research question? What lipid species and coordinated lipid-metabolite-protein networks define human diHF, and could charge-dependent lipid remodeling represent a systems-level organizing feature of diabetic cardiac dysfunction? What is new? This study identifies electrostatic lipidopathy - a charge-dependent remodeling of membrane and metabolic lipid species - as a previously unrecognized molecular phenotype of human diHF. Integrated multi-omics analysis reveals enrichment of negatively charged lipid species, disruption of the myocardial lipid-energy axis, mitochondrial dysfunction, ferroptosis-associated signatures, and inflammatory activation, defining a coordinated lipid-metabolic-proteomic remodeling network. How might this study influence clinical practice? By reframing diabetic cardiac remodeling through the lens of membrane electrostatics and metabolic inflexibility, these findings highlight charge-defined lipid species and ferroptosis-associated pathways as potential biomarkers and therapeutic targets, supporting future studies aimed at precision risk stratification and treatment of diabetic heart failure.