PORCN (porcupine O-acyltransferase) is a membrane-bound O-acyltransferase localized to the endoplasmic reticulum that serves as a critical regulator of Wnt signaling 1. The enzyme catalyzes palmitoleoylation of Wnt proteins by transferring palmitoleoyl groups to serine residues on the hairpin 2 motif of Wnt ligands 12. This post-translational lipid modification is essential for Wnt protein secretion and receptor binding, enabling Wnts to interact with Frizzled receptors to initiate downstream signaling 13. Mechanistically, PORCN accommodates two substrates in separate tunnels: palmitoleoyl-CoA enters from the cytosolic side while Wnt hairpin 2 inserts from the luminal side, with catalytic histidine facilitating the acyl transfer 12. During Wnt biogenesis, calreticulin functions as a chaperone to facilitate transfer of PORCN-modified Wnts to Wntless for intracellular transport 3. Clinically, PORCN mutations cause focal dermal hypoplasia (FDH), an X-linked dominant developmental disorder with skin, skeletal, and ocular manifestations 45. Additionally, aberrant Wnt signaling through PORCN dysregulation is implicated in multiple cancers including colorectal, pancreatic, and liver malignancies 67. PORCN inhibitors (LGK974, ETC-159, IWP-L6) are under development as cancer therapeutics, with some entering clinical trials 12.