RNF216 is a RING-in-between-RING (RBR) E3 ubiquitin ligase that functions as a critical regulator of protein degradation and cellular stress responses. Mechanistically, RNF216 catalyzes mixed K11/K63 polyubiquitin chain formation and acts as an autophagy adaptor through liquid-liquid phase separation (LLPS) droplets, targeting substrates like tau for autophagic degradation 1. RNF216 also promotes ubiquitination-mediated degradation of key regulatory proteins including p53 2, NOX1 3, and PRKACB 4. Clinically, RNF216 mutations cause Gordon Holmes syndrome, a neuroendocrine disorder characterized by cerebellar ataxia, chorea, cognitive impairment, and hypogonadotropic hypogonadism, with disease-associated mutations affecting the RBR domain 5. RNF216 exhibits context-dependent pathological roles: disease-associated mutations increase phosphorylated tau accumulation and tau spreading in neurodegeneration 1, while elevated RNF216 expression promotes glioblastoma tumorigenesis and radioresistance through p53 degradation 2. Conversely, RNF216 protects neurons against subarachnoid hemorrhage-induced injury via the Arc-AMPAR pathway 6 and mediates neuroprotection in spinal cord injury by degrading NOX1 to inhibit ferroptosis 3. RNF216 represents both a disease target in cancer and neurodegeneration and a potential therapeutic candidate in acute neurological injury.