Exploring Protein S -Palmitoylation: Mechanisms, Detection, and Strategies for Inhibitor Discovery.

S -palmitoylation is a reversible and dynamic process that involves the addition of long-chain fatty acids to proteins. This protein modification regulates various aspects of protein function, including subcellular localization, stability, conformation, and biomolecular interactions. The zinc finger DHHC (ZDHHC) domain-containing protein family is the main group of enzymes responsible for catalyzing protein S -palmitoylation, and 23 members have been identified in mammalian cells. Many proteins that undergo S -palmitoylation have been linked to disease pathogenesis and progression, suggesting that the development of effective inhibitors is a promising therapeutic strategy. Reducing the protein S -palmitoylation level can target either the PATs directly or their substrates. However, there are rare clinically effective S -palmitoylation inhibitors. This review aims to provide an overview of the S -palmitoylation field, including the catalytic mechanism of ZDHHC, S -palmitoylation detection methods, and the functional impact of protein S -palmitoylation. Additionally, this review focuses on current strategies for expanding the chemical toolbox to develop novel and effective inhibitors that can reduce the level of S -palmitoylation of the target protein.