IRF2BPL is a nuclear transcriptional regulator that functions as an E3 ubiquitin ligase mediating proteasome-dependent protein degradation 1. It negatively regulates Wnt signaling through CTNNB1 degradation downstream of FOXF2 1 and may regulate genes controlling female reproductive function. The protein contains two zinc-finger domains and a C3HC4 RING domain characteristic of ubiquitin ligases 2. Pathogenic variants in IRF2BPL cause neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS) 3. Disease mechanisms involve heterozygous truncations that sequester wild-type protein to the cytoplasm and trigger aggregation, leading to mitochondrial dysfunction and neuronal death in astrocytes 4. IRF2BPL mutations present highly heterogeneous phenotypes ranging from developmental delay to severe neurodegenerative disease with progressive myoclonus epilepsies, infantile spasms, and drug-resistant epilepsy 56. Missense and in-frame indel variants particularly associate with seizures and developmental delay 2. Recent exome studies identified IRF2BPL as a novel genetic risk locus for depressive symptoms, suggesting broader neuropsychiatric relevance 7. Outside the nervous system, IRF2BPL suppresses osteosarcoma progression by degrading FOSL2 and inhibiting PI3K/AKT signaling 8. Treatment with copper chelator CuATSM shows promise in rescuing neuronal survival and restoring mitochondrial function in patient-derived cells and animal models 49.