ZDHHC5 is a palmitoyltransferase that catalyzes S-palmitoylation of diverse protein substrates, regulating multiple cellular processes 1. Primary substrates include inflammasome components (NLRP3, GSDMD), pattern recognition receptors (NOD1/2), adhesion proteins (CTNND2, DSG2), metabolic regulators (CD36, CLOCK), and signaling proteins (FAK, STAT3) 2345. Functionally, ZDHHC5-mediated palmitoylation promotes membrane localization and stabilization of target proteins, enabling their activation and signaling 6. In innate immunity, ZDHHC5 palmitoylates NOD1/2 for bacterial sensing and NLRP3 for inflammasome assembly, while also activating pyroptotic pathways through GSDMD palmitoylation, which promotes pore formation independent of caspase cleavage 234. Disease relevance includes inflammatory disorders, neurodegeneration, and cancer; ZDHHC5 dysregulation enhances tumorigenesis through FAK and CLOCK palmitoylation, while ZDHHC5-deficiency or palmitoylation inhibition mitigates inflammasome-driven diseases and septic shock 571. Clinical significance emerges as ZDHHC5 represents a potential therapeutic target for conditions ranging from autoinflammatory diseases to glioblastoma and sepsis through modulation of palmitoylation-dependent signaling.