ZNRF1 (zinc and ring finger 1) is an E3 ubiquitin ligase that regulates multiple cellular processes through targeted protein degradation. The protein plays critical roles in neuronal function and differentiation by mediating ubiquitination of key substrates. In peripheral nervous system development, ZNRF1 controls Schwann cell differentiation by targeting glutamine synthetase (GS) for proteasomal degradation, which increases glutamate levels and promotes undifferentiated Schwann cell phenotypes 12. In mature neurons, ZNRF1 promotes neurodegeneration by mediating Lys-48-linked polyubiquitination of AKT1, leading to GSK3B activation and subsequent axonal microtubule destabilization 3. ZNRF1 also regulates membrane protein trafficking by ubiquitinating the Na+/K+ ATPase α1 subunit, influencing its endocytosis and degradation 4. Additionally, ZNRF1 modulates inflammatory responses through caveolin-1 (CAV1) ubiquitination, though this function can be disrupted in disease contexts - in glioblastoma, TRAF4 prevents ZNRF1-mediated CAV1 degradation, contributing to cancer stemness and drug resistance 5. The protein's dysfunction is implicated in neurodevelopmental disorders, highlighting its importance in maintaining proper neuronal homeostasis 6. Recent studies also suggest ZNRF1's involvement in renal protection through interactions with mitochondrial factors 7.