Lipotoxicity in Diabetic Cardiomyopathy: Molecular Basis and Emerging Therapeutic Targets

Diabetic cardiomyopathy (DbCM) is an important contributor to heart failure (HF) in diabetes, occurring independently of other cardiovascular risk factors. Accumulating evidence demonstrates that cardiac lipotoxicity is a key driver of the onset and progression of DbCM and HF. Myocardial lipid homeostasis is coordinated by multiple transcriptional regulations, signaling pathway activation, and endoplasmic reticulum-mediated management involved in lipid metabolism. In DbCM, unbalanced fatty acid (FA) influx, handling, storage, and utilization initiates lipid overload, accumulation of toxic lipid intermediates (e.g., diacylglycerols and ceramides), and activation of maladaptive response. Notably, these lipid intermediates amplify reactive oxygen species (ROS) generation, which serves as a critical link between lipotoxic signaling and mitochondrial dysfunction by promoting electron leak, mitochondrial damage, and activation of inflammatory and cell-death pathways. These processes converge on adverse remodeling and contractile impairment, accelerating DbCM progression. This review integrates mechanistic and translational evidence linking dysregulated lipid handling to DbCM and discusses the potential therapeutic strategies that target lipid abnormalities.