Myocardial Lipid Metabolism Imbalance: The Pathological Core and Novel Diagnostic‐Therapeutic Directions of Cardiovascular Diseases

FIGURE 1. Regulatory architecture of cardiac lipid metabolism in the healthy heart. This schematic integrates the key processes and regulators of free fatty acid (FFA) handling in cardiomyocytes under physiological conditions. Circulating FFAs, modulated by apolipoproteins (e.g., APOC3), are primarily taken up via the transporter CD36. Intracellular FFAs are either esterified and stored in LDs coated with Plin5 or directed to mitochondria for β‐oxidation and ATP production. The physical Mitochondria‐LDs contact site (MLC), facilitated by Plin5 and Mfn2, enables efficient channeling of FFAs. Systemic hormones (e.g., FGF21) and the core energy‐sensing AMPK/PGC‐1α/PPARα axis centrally coordinate this network to match energy supply with demand.

FIGURE 2. The lipotoxic cycle: a unifying pathological driver in cardiovascular diseases. This model illustrates the self‐reinforcing vicious cycle that propagates myocardial injury across various CVDs. The cycle is initiated by an imbalance between lipid uptake (e.g., via CD36) and oxidation capacity, leading to the accumulation of toxic lipid species (e.g., DAG, ceramides). These lipids trigger mitochondrial dysfunction (ROS overproduction, reduced ATP), insulin resistance, and inflammatory activation. Subsequent oxidative stress and lipid peroxidation generate reactive aldehydes (MDA, 4‐HNE), which inflict direct macromolecular damage and promote cell death, ultimately driving myocardial dysfunction and remodeling. This remodeling further exacerbates the initial metabolic imbalance, perpetuating the cycle. Key molecular nodes (e.g., CD36, Plin5, ROS) represent potential therapeutic targets for intervention.