ZDHHC20 is a palmitoyltransferase that catalyzes S-palmitoylation, a reversible post-translational modification controlling protein localization, stability, and function. Primary substrates include GPX4, FASN, YTHDF3, KAP1/TRIM28, CD80, IFITM3, and the SARS-CoV-2 spike protein 123456. ZDHHC20 stabilizes these proteins by protecting them from ubiquitin-proteasome degradation and facilitates their proper membrane localization 25. In cancer pathogenesis, ZDHHC20 promotes hepatocarcinogenesis by palmitoylating FASN, increasing its stability and lipogenic capacity 2. In pancreatic cancer, ZDHHC20 stabilizes YTHDF3, preventing its chaperone-mediated autophagic degradation and enabling MYC accumulation 3. ZDHHC20 also critically supports metastatic outgrowth through immune evasion mechanisms 7. Beyond cancer, ZDHHC20 mediates DNA damage repair by palmitoylating KAP1, enhancing chr13 binding and recruitment of repair factors, with ATM-dependent phosphorylation regulating this axis 4. In immunity, ZDHHC20-mediated CD80 palmitoylation is essential for T cell costimulation 5. Therapeutically, ferroptosis sensitivity can be enhanced by disrupting GPX4 palmitoylation 1, and ZDHHC20 represents a psychiatric disease target in schizophrenia pathogenesis 8.