ZDHHC16 is a palmitoyl acyltransferase that catalyzes S-palmitoylation of multiple protein substrates, including PLN, ZDHHC6, PCSK9, and SETD2 123. The enzyme mediates reversible lipid modification of target proteins, dynamically regulating their activity and cellular localization through interaction with depalmitoylases like APT2 1. ZDHHC16 plays critical roles in cardiac development and function, eye development, and neural stem cell proliferation via the FGF/ERK pathway, though detailed mechanisms remain incompletely characterized [UniProt annotations]. Disease relevance has emerged across multiple pathologies. In hepatocellular carcinoma, ZDHHC16-mediated PCSK9 palmitoylation promotes sorafenib resistance by activating PI3K/AKT signaling through PTEN degradation 2. In glioblastoma, ZDHHC16 controls DNA damage responses via SETD2 palmitoylation and H3K36 methylation 3. Conversely, ZDHHC16 upregulation promotes ferroptosis and poor outcomes in cerebral apoplexy and non-small cell lung cancer through CREB suppression 45. ZDHHC16 was recently identified as a novel autosomal recessive developmental disorder gene 6, while inhibiting ZDHHC16 enhances osteogenic differentiation of dental pulp stem cells by reducing ferroptosis 7. These findings position ZDHHC16 as a therapeutic target with context-dependent roles in tumorigenesis and tissue regeneration.