USP8 (ubiquitin specific peptidase 8) is a deubiquitinating enzyme that removes ubiquitin chains from target proteins to regulate their stability and function 1. The enzyme processes both K48-linked and K63-linked ubiquitin chains, with enhanced catalytic activity during M phase 2. USP8 plays crucial roles in multiple cellular processes including protein stability regulation, endosomal trafficking, and immune signaling. Mechanistically, USP8 stabilizes key proteins through deubiquitination, including O-GlcNAc transferase (OGT) by preventing K48-linked ubiquitination at the K117 site 1, and PD-L1 by antagonizing K48-linked degradation while promoting K63-linked ubiquitination 23. The enzyme also deubiquitinates DDX3X to enhance cGAS phase separation and activation in innate immune responses 4. Disease relevance includes pituitary neuroendocrine tumors, where USP8 mutations are associated with corticotroph adenomas and Cushing syndrome 5. USP8 shows therapeutic potential as an oncology target, as its inhibition promotes ferroptosis in hepatocellular carcinoma 1 and enhances anti-PD-1/PD-L1 immunotherapy efficacy 23. Additionally, USP8 variants are associated with Parkinson's disease risk 67, suggesting broader neurological involvement.