CXXC4 (CXXC finger protein 4) is a tumor suppressor that functions as a negative regulator of Wnt/β-catenin signaling 1. CXXC4 stabilizes the β-catenin destruction complex by binding to dishevelled (Dvl), with critical amino acid residues K161 and T162 essential for this interaction 2. Beyond Wnt inhibition, CXXC4 directly inactivates MAPK signaling by binding to ERK-1/2 and disrupting MEK1/2-ERK1/2 interaction, with leucine 183 critical for this function 3. CXXC4 expression is epigenetically silenced by EZH2 in gastric cancer, and downregulation associates with poor prognosis (hazard ratio: 5.053, P<0.05) 2. In colorectal cancer, miR-629-5p suppresses CXXC4 expression post-transcriptionally to promote proliferation and chemoresistance 4. CXXC4 methylation occurs in head and neck squamous cell carcinomas and correlates with overall survival 5. In myelodysplastic syndrome, reduced CXXC4 mRNA levels associate with survival outcomes 6. CXXC4 mutations in severe congenital neutropenia-derived AML increase CXXC4 protein while reducing TET2 levels, driving pro-inflammatory pathways and malignant transformation 7. CXXC4 also functions in DNA methylation regulation through TET2 modulation 6.