PORCN is a membrane-bound O-acyltransferase localized to the endoplasmic reticulum that catalyzes the attachment of palmitoleate to Wnt proteins, a modification essential for their secretion and signaling. This palmitoleoylation of a conserved serine on Wnt hairpin 2 is required for efficient binding to Frizzled receptors and activation of downstream β-catenin signaling 1. PORCN also works with the chaperone calreticulin and the transport protein Wntless to facilitate Wnt secretion 2. Inherited loss-of-function mutations in PORCN cause focal dermal hypoplasia, an X-linked dominant developmental disorder characterized by patchy hypoplastic skin, split hand/foot deformities, and ocular manifestations 34. Because Wnt signaling is frequently dysregulated in cancers including colorectal, pancreatic, liver, and head and neck malignancies, PORCN has emerged as a therapeutic target 5. The PORCN inhibitor LGK974 is currently in clinical trials for cancer treatment 1, and additional inhibitors such as ETC-159 and IWP-L6 are in development to block Wnt-dependent tumor growth 6.