ZDHHC6 is an endoplasmic reticulum palmitoyl acyltransferase that catalyzes S-palmitoylation and stearoylation of diverse substrate proteins 1234. Mechanistically, ZDHHC6 mediates palmitoylation of ER-resident proteins including calnexin (required for ribosome-translocon association and glycoprotein folding), AMFR (promoting ER peripheral distribution), ITPR1 (regulating calcium signaling), and transferrin receptor (inhibiting JNK pathway activation) 1235. ZDHHC6 activity itself is regulated by upstream palmitoyltransferase ZDHHC16, forming the first known palmitoylation cascade 4. Clinically, ZDHHC6-mediated palmitoylation impacts multiple disease pathways. In acute myeloid leukemia, ZDHHC6 palmitoylates FLT3-ITD to retain it in the ER, restricting leukemogenic signaling; disrupting this palmitoylation accelerates disease progression 6. ZDHHC6 similarly palmitoylates MYD88 in sepsis and tumor immunity, where this modification drives inflammatory signaling and immune escape 78. In hepatocellular carcinoma and colorectal cancer, ZDHHC6 stabilizes oncogenic AEG-1 and PPARγ through palmitoylation, promoting lipid biosynthesis and tumor progression 910. Additionally, ZDHHC6 genetic variants associate with amyotrophic lateral sclerosis and weight loss 11. Artemisinin inhibits ZDHHC6 to reduce NRas palmitoylation, providing a therapeutic approach under clinical investigation 12.