ZDHHC13 encodes a palmitoyltransferase that catalyzes the addition of palmitate groups to various protein substrates, playing critical roles in cellular signaling and disease processes 1. The enzyme palmitoylates key proteins including pyruvate kinase M2 (PKM2), where palmitoylation at Cys31 impairs PKM2 tetramerization and glycolysis, contributing to endothelial injury and cardiovascular dysfunction 1. ZDHHC13 is essential for melanocortin-1 receptor (MC1R) palmitoylation, which activates MC1R signaling, enhances DNA repair after UV irradiation, and prevents melanomagenesis 2. AMPK phosphorylation of ZDHHC13 at S208 strengthens its interaction with MC1R variants, providing a potential therapeutic target for melanoma prevention in red-haired individuals 3. The enzyme also palmitoylates ULK1, facilitating its translocation to autophagosome formation sites and initiating autophagy 4. Loss-of-function mutations in ZDHHC13 cause severe phenotypes in mice including alopecia, osteoporosis, and systemic amyloidosis, establishing palmitoylation as crucial for diverse physiological functions 5. Clinical relevance extends to neurological diseases, with ZDHHC13 expression changes associated with Parkinson's disease progression through DNA methylation regulation 6 and protective effects against ischemic stroke through metabolite regulation 7.