RNF43 is an E3 ubiquitin ligase that functions as a critical negative regulator of Wnt signaling by mediating ubiquitination and degradation of Frizzled receptors, affecting both canonical and non-canonical Wnt pathways 1. Beyond Wnt regulation, RNF43 also modulates other tumor-related proteins including EGFR, BRAF, and BMP signaling 1. RNF43 mutations are frequently detected across gastrointestinal malignancies. In colorectal cancer, RNF43 mutations increase oncogenic Wnt pathway alterations and are enriched in right-sided microsatellite-stable tumors with worse prognosis 2. In pancreatic ductal adenocarcinoma, RNF43 is among the most recurrent somatic mutations identified 3. Gastric adenocarcinoma subtypes with RNF43 expression show activated Wnt/β-catenin signaling 4. A colorectal organoid with RNF43 mutation demonstrated exquisite sensitivity to Wnt secretion inhibitors, supporting therapeutic targeting 5. Clinically, RNF43 germline mutations predispose to colorectal cancer and sessile serrated polyposis cancer syndrome 6. In inflammatory bowel disease-associated colorectal cancer, RNF43 downregulation contributes to distinct mesenchymal tumor subtype development and altered prognosis compared to sporadic colorectal cancer 7.