Cardiac Protein Palmitoylation: Mechanisms, Functions, and Therapeutic Potential.

Protein S-palmitoylation is a reversible lipid modification which regulates the localisation, stability, and activity of a substantial fraction of the proteome. In the heart S-palmitoylation controls the function of membrane proteins which regulate cardiac excitability and contractility. Recent work has moved the S-palmitoylation field beyond descriptive cataloguing towards mechanistic understanding, revealing how site-specific S-palmitoylation can modulate protein structure and function in a precise and quantifiable manner. These advances position S-palmitoylation as a tuneable regulator of cardiac proteins and consequently cardiac function, and a potential target for therapeutic modulation. In this review, we focus on the role of S-palmitoylation in cardiac function, highlighting its effects on key ion channels and transporters, including CaV1.2, NaV1.5 and NCX1, and the resulting consequences for cardiac electrophysiology and calcium handling. We also discuss emerging experimental tools and strategies to selectively manipulate S-palmitoylation and their limitations. Finally, we consider the translational potential of targeting S-palmitoylation, emphasising the need for selective intervention strategies informed by detailed molecular and structural insight.