OTUD7A is a deubiquitinase that cleaves Lys-11-linked polyubiquitin chains and regulates protein stability through the ubiquitin-proteasome system 1. In the brain, OTUD7A localizes to dendritic spines and regulates Ankyrin proteins, which are critical for axon initial segment structure and neuronal function 2. Loss of OTUD7A expression impairs dendritic spine development, synapse formation, and glutamatergic synaptic transmission 3, 4. OTUD7A haploinsufficiency is the primary driver of 15q13.3 microdeletion syndrome, a neurodevelopmental disorder characterized by developmental delay, seizures, intellectual disability, and hypotonia 5, 3. Epilepsy-associated OTUD7A mutations (L233F) disrupt interaction with Ankyrin-G, causing protein instability and reduced dendritic spine nanodomains 2. Beyond neurodevelopment, OTUD7A stabilizes the EWS-FLI1 oncofusion protein in Ewing sarcoma 6 and regulates KDM5B in KRAS-mutant lung cancer, affecting ferroptosis sensitivity 7. In cardiac tissue, OTUD7A promotes pathological hypertrophy by stabilizing TAK1, suggesting context-dependent roles across tissues 8. Restoration of OTUD7A expression reverses neuronal dysfunction in disease models, indicating therapeutic potential.