OTUD5 is an X-linked deubiquitinase that functions as a multifaceted cellular regulator with distinct roles across immune, metabolic, and disease contexts. As a negative regulator of innate immunity, OTUD5 cleaves K48- and K63-linked polyubiquitin chains on substrates including TRAF3 and STING, suppressing type I interferon production 1. Beyond immunity, OTUD5 stabilizes GPX4, a critical ferroptosis suppressor, protecting against ischemia-reperfusion injury in cardiac and renal tissues by deubiquitinating K48-linked chains 23. In diabetic kidney disease, OTUD5 deubiquitinates TAK1 at K63-linked sites, reducing podocyte inflammation 4. OTUD5 also promotes DNA repair at deprotected telomeres by stabilizing UBR5, which activates ATM-dependent signaling 5. In neurodegeneration, OTUD5 uniquely promotes K63-linked polyubiquitination of α-synuclein independent of its catalytic activity, facilitating NEDD4-mediated degradation and protecting dopaminergic neurons in Parkinson's disease models 6. Disease-relevant interactions include THBS1 and GBP2 binding to OTUD5, blocking its interaction with GPX4 and promoting ferroptosis in stroke and sepsis contexts 78. OTUD5 mutations cause multiple congenital anomalies-neurodevelopmental syndrome, underscoring its developmental importance.