• A novel OTUD5 variant (p.Val233Met) disrupts neural progenitor cell proliferation and differentiation, linking OTUD5 dysfunction to neurodevelopmental disorders.
• Mechanistically, the variant impairs deubiquitinase activity, leading to accelerated degradation of GSK3β via K48-linked ubiquitination, a previously unrecognized pathway.
• Patient-derived iPSC and CRISPR-corrected isogenic models provide a robust platform for studying OTUD5-related NDDs and testing GSK3β-targeted therapies.
• The study underscores the critical role of ubiquitination regulation in neurodevelopment and offers potential therapeutic targets for OTUD5-associated conditions.