ZDHHC4 is a palmitoyltransferase enzyme that catalyzes the S-acylation (palmitoylation) of multiple protein substrates to regulate their function, localization, and stability 1. The enzyme localizes to the endoplasmic reticulum and Golgi apparatus where it adds palmitate groups to cysteine residues of target proteins. Key substrates include MAVS, where ZDHHC4-mediated palmitoylation at Cys79 promotes protein stabilization and activation by inhibiting K48-linked ubiquitination while facilitating K63-linked ubiquitination, thereby enhancing antiviral immunity 1. In cardiac metabolism, ZDHHC4 palmitoylates CD36 at multiple cysteine residues (C3, C7, C464, C466), promoting its sarcolemmal localization and contributing to diabetic cardiomyopathy through enhanced fatty acid oxidation 23. ZDHHC4 also regulates cellular senescence by palmitoylating CCDC50, facilitating selective autophagy of MAP2K4/MKK4 and suppressing MAPK/JNK signaling in osteoarthritis 4. The enzyme modulates pain sensation through TRPV1 palmitoylation, promoting channel degradation and pain relief 5. In cancer, ZDHHC4 stabilizes ZEB-2 through palmitoylation, promoting epithelial-mesenchymal transition in melanoma 6. ZDHHC4 expression is upregulated in lung adenocarcinoma and correlates with poor prognosis 7.