NKD2 (naked cuticle homolog 2) functions as a cell autonomous antagonist of the canonical Wnt signaling pathway, serving as a negative regulator of Wnt/β-catenin/TCF signaling 1. The protein contains an EF-hand motif within its NH2 domain and shares structural homology with NKD1 1. NKD2 plays critical roles in cellular processes including growth factor processing, particularly in targeting TGFA to the basolateral membrane of polarized epithelial cells, and cell cycle regulation through G1-phase arrest 2. Functionally, NKD2 acts as a tumor suppressor in multiple cancer types, with low expression correlating with enhanced cell proliferation, poor prognosis, and resistance to chemotherapy in hepatocellular carcinoma 2. Conversely, high NKD2 expression is associated with better survival outcomes in ovarian cancer 3 but paradoxically with poor prognosis in thyroid carcinoma 4. In fibrotic diseases, NKD2 emerges as a potential therapeutic target, being specifically expressed in myofibroblasts during human kidney fibrosis 5 and playing roles in aortic valve stenosis through inflammatory processes 6. The protein also mediates epithelial-mesenchymal transition through Wnt signaling modulation 7.