ZDHHC18 is a palmitoyltransferase that catalyzes the addition of palmitate to cysteine residues on various protein substrates, including cGAS, HRAS, MDH2, and LCK 123. Its primary characterized function is negative regulation of the cGAS-STING innate immune pathway. Palmitoylation of cGAS at C474 by ZDHHC18 reduces its enzymatic activity and DNA-binding capacity by inhibiting cGAS dimerization, thereby suppressing innate immune responses to double-stranded DNA 1. Zdhhc18-deficient mice demonstrate enhanced resistance to DNA virus infection, confirming this immunosuppressive role in vivo 1. Beyond immunity, ZDHHC18-mediated palmitoylation regulates metabolic and pathogenic processes. It catalyzes HRAS palmitoylation, promoting membrane translocation and activating downstream MEK/ERK and SMAD signaling to drive renal fibrosis development 2. Similarly, ZDHHC18-mediated MDH2 palmitoylation enhances mitochondrial respiration and promotes ovarian cancer growth through increased TCA cycle activity 3. Clinically, ZDHHC18 is significantly upregulated in multiple malignancies including renal fibrosis, ovarian cancer, B-cell lymphomas, and clear cell renal cell carcinoma, where its knockdown reduces cancer cell viability, proliferation, migration, and invasion 2345. These findings position ZDHHC18 as a potential therapeutic target across diverse cancers and fibrotic diseases.