From lipid modification to cell death: the diverse roles of S-palmitoylation in cell fate decisions

S-palmitoylation is a dynamic, reversible lipid modification that plays a crucial role in the regulation of various types of cell death. However, systematic insights into how S-palmitoylation modifications integrate and mediate crosstalk among diverse cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, to ultimately determine cell fate remain elusive. We propose the concept of the “palmitoylation code,” which posits that S-palmitoylation affects substrate function and signaling pathways through site specificity, kinetic dynamics, and spatial distribution, ultimately regulating the cell’s decision between survival and death. This review describes the regulatory principles of this code in major cell death pathways and provides a comprehensive overview of palmitoylation-targeting strategies and pharmacological inhibitors through an examination of how targeting the “palmitoylation code” can modulate cell fate transitions.