APCDD1 is a transmembrane protein that functions as a negative regulator of the Wnt signaling pathway, operating upstream of β-catenin 1. Structurally, APCDD1 contains two β-barrel domains, with the second domain harboring a hydrophobic pocket that binds lipids and WNT ligands, enabling it to function as a negative feedback regulator by titrating WNT ligands at the cell surface 2. Beyond Wnt inhibition, APCDD1 is a dual BMP/Wnt inhibitor in developing nervous system and skin tissues, coordinating outputs of these critical developmental pathways 3. APCDD1 is a direct target of the β-catenin/TCF4 transcription complex; elevated expression contributes to colorectal tumorigenesis, with increased APCDD1 levels observed in primary colon cancers 1. Disease relevance extends beyond cancer: APCDD1 variants cosegregate with left ventricular noncompaction in cardiac disease families 4, while ectopic upregulation via altered 3D chr18 topology causes central iris hypoplasia 5. APCDD1+ cell populations serve as key mediators in inflammatory contexts—cancer-associated fibroblasts expressing APCDD1 promote prostate cancer castration resistance through lactate secretion 6, and dermal APCDD1+ fibroblasts amplify stress-induced skin inflammation via prolactin-NR4A1-midkine signaling 7. APCDD1 downregulation in humans contributes to neuronal maturation and cognitive development 8.