ZDHHC5: a pivotal palmitoyltransferase orchestrating signaling networks – unraveling mechanisms and therapeutic horizons

ZDHHC5, a key member of the DHHC family of palmitoyltransferases, catalyzes S-acylation—a reversible post-translational modification involving the covalent attachment of fatty acids, typically palmitate, to specific cysteine residues on target proteins. This lipid modification plays a critical regulatory role in protein trafficking, membrane association, stability, and the assembly of signaling complexes, thereby modulating diverse cellular processes such as cell proliferation, inflammatory signaling, and metabolic homeostasis. Accumulating evidence underscores the significant involvement of ZDHHC5 in various pathological states, particularly in oncogenesis and cancer progression. Nevertheless, the comprehensive landscape of ZDHHC5-regulated molecular networks across disease contexts remains incompletely understood. In this review, we summarize the structural architecture and catalytic mechanism of ZDHHC5, and elaborate on its biological functions with an emphasis on its role in major signaling pathways and disease pathogenesis. Furthermore, we assess the therapeutic potential of targeting ZDHHC5 through selective inhibitors, discuss current challenges and emerging opportunities in drug development, and highlight how artificial intelligence may accelerate the discovery of novel therapeutic strategies by enabling deeper mechanistic insights into ZDHHC5 function and regulation.