Lipid overload meets S-palmitoylation: a metabolic signalling nexus driving cardiovascular and heart disease.

Abstract

S-palmitoylation has emerged as a critical integrator of lipid overload and cardiovascular dysfunction. Disordered lipid metabolism inundates endothelial cells, vascular smooth muscle cells and macrophages with triglyceriderich lipoproteins, oxidized LDL and saturated fatty acids, expanding the intracellular palmitoylCoA pool and perturbing redox balance. Protein Spalmitoylation, the reversible attachment of palmitate to cysteine residues, converts excess palmitoylCoA into broad alterations in signalling and membrane dynamics. The FASN-ACSL-ZDHHC axis channel excess fatty acids into palmitoylCoA, which is transferred to pivotal proteins including the lipid transporter CD36, endothelial nitric oxide synthase (eNOS), key ion channels and the pyroptosis effector gasdermin D (GSDMD). Cycles of palmitate addition and removal regulate membrane residency, foam cell formation, nitric oxide production, calcium handling and inflammatory cell death, thereby linking lipid burden to atherosclerotic plaque growth, arrhythmogenic risk, heart failure progression and pulmonary hypertension. Therapeutic targeting of fatty acid uptake, palmitoyltransferases or thioesterases alleviates metabolic overload, restores endothelial reactivity and preserves myocardial viability in experimental models. This review synthesizes mechanistic and preclinical studies to delineate how lipiddriven protein palmitoylation reprograms cardiovascular physiology and pathology.