ZDHHC3 is a palmitoyltransferase that catalyzes S-palmitoylation of diverse substrates, a post-translational lipid modification that stabilizes proteins and regulates their cellular localization. The enzyme transfers palmitate to cysteine residues on target proteins, preventing ubiquitin-mediated degradation and controlling their membrane trafficking. ZDHHC3 has emerged as a central regulator of immune checkpoint signaling, where it palmitoylates PD-L1 and B7-H4 to block their lysosomal degradation and sustain tumor immune evasion 1 2. In hepatocellular carcinoma, ZDHHC3 S-acylates SCAP to promote cholesterol biosynthesis and TME-mediated immune escape 3. ZDHHC3 also drives nonalcoholic steatohepatitis progression by palmitoylating IRHOM2, and elevated ZDHHC3 levels correlate with NASH severity in patients 4. In the central nervous system, ZDHHC3-catalyzed Cadm4 palmitoylation is essential for myelination; ZDHHC3 deletion causes demyelination and cognitive impairment 5. The enzyme inhibits antiviral immunity by degrading MAVS and blocking interferon responses 6. Clinically, ZDHHC3 inhibition with 2-bromopalmitate combined with anti-PD-1 therapy shows synergistic efficacy in pancreatic cancer 7. ZDHHC3 also facilitates SARS-CoV-2 virion assembly 8, underscoring its broad pathogenic roles across cancer, metabolic disease, neuroinflammation, and viral infection.