Myocardial Lipotoxicity in Cardiovascular Diseases: Mechanisms, Therapeutic Strategies, and Drug Target Discovery

Myocardial lipotoxicity is a fundamental pathological mechanism responsible for myocardial injury associated with various metabolic disorders such as obesity and type 2 diabetes. This condition arises from an imbalance in lipid metabolic homeostasis, leading to the excessive accumulation of toxic lipid intermediates in cardiomyocytes, which ultimately results in structural and functional impairments of the myocardium. This review provides a comprehensive overview of the mechanisms by which myocardial lipotoxicity occurs and its significant involvement in cardiovascular diseases, including heart failure, arrhythmias, and atherosclerosis. The myocardium primarily acquires exogenous fatty acids through albumin-bound free fatty acids and lipoprotein lipase-mediated lipolysis, facilitated by transporter proteins like CD36 and FATP. When the uptake of fatty acids surpasses oxidative capacity, toxic lipids such as ceramides and DAG accumulate, disrupting essential signaling pathways—including AMPK, PPAR, PKC, and NF-κB. This disruption triggers mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, inflammatory responses, and various forms of cell death. Together, these mechanisms lead to myocardial remodeling, abnormalities in electrical activity, and the onset and progression of vascular pathologies. The article also reviews current therapeutic strategies aimed at mitigating myocardial lipotoxicity, including lifestyle modifications and pharmacological interventions such as SGLT2 inhibitors and trimetazidine. Furthermore, it explores future research directions, focusing on ceramide synthesis, inflammatory pathways, and personalized medicine, with the goal of providing a theoretical foundation and innovative insights for the clinical prevention and treatment of lipotoxicity-related cardiovascular diseases.