INTRODUCTIONrnWnt signaling plays key roles in many aspects of development and adult tissue homeostasis.1–2 WNTs are secreted palmitoleated glycoprotein ligands that bind to cell surface receptors to initiate signaling in diverse tissues and cell types. Downstream signaling commonly leads to stabilization ofβ?catenin and activation of cell?type specific transcriptional activation.3 Mutations that aberrantly activate the Wnt pathway are among the most common events associated with human cancers.4–5 Pathological activation of Wnt signaling is also critical in the progression of various fibrotic disorders.6–7 Targeted therapies to inhibit the Wnt pathway are being developed and have shown efficacy in various pre?clinical models of Wnt addicted cancers and in fibrosis (reviewed in ref. 8). For example, the secretion of all Wnts can be blocked by inhibition of PORCN. PORCN is an endoplasmic reticulum resident O?acyl transferase that catalyzes the palmitoleation of all Wnts.2,9 Pre?clinical studies of PORCN inhibitors have demonstrated robust activity against several tumor types. Orally available drugs that inhibit PORCN have been developed and have progressed to human clinical trials.6,10–13 However, concs regarding mechanism?based toxicity of Wnt pathway inhibitors could impact the clinical utility of these agents.