ZNRF3 is an E3 ubiquitin ligase that functions as a negative regulator of Wnt/β-catenin signaling by mediating ubiquitination and degradation of Wnt receptor components, including Frizzled and LRP6 1. ZNRF3 acts on both canonical and non-canonical Wnt pathways and serves as a tumor suppressor in intestinal stem cells by restricting Wnt-dependent proliferation 2. Mechanistically, ZNRF3 maintains minimal essential levels of Wnt receptors at the cell membrane 1. Notably, R-spondin ligands antagonize ZNRF3 activity by binding directly to the protein, enabling Wnt pathway amplification independent of LGR4/5/6 receptors; RSPO2 and RNF43 together with ZNRF3 constitute a master developmental switch governing limb specification 3. Beyond Wnt signaling, ZNRF3 regulates other tumor-related proteins including EGFR and BMP pathway components 1. In cancer, loss of RNF43/ZNRF3 drives abnormal β-catenin activation in gastrointestinal tumors and predisposes to hepatocellular carcinoma by impairing liver regeneration and altering lipid metabolism 4. Clinically, higher ZNRF3 expression correlates with improved colorectal carcinoma prognosis and reduced cancer cell proliferation 5, supporting its role as a therapeutic target for Wnt-driven malignancies.