UCHL3 (ubiquitin C-terminal hydrolase L3) is a deubiquitinating enzyme (DUB) that processes ubiquitin precursors and removes ubiquitin modifications from target proteins 1. As a cysteine protease, UCHL3 exhibits catalytic preferences for Lys-48-linked ubiquitin chains and possesses both deubiquitination and deneddylation activities 1. UCHL3 plays critical roles in fundamental cellular processes including cell cycle regulation, DNA repair, and protein homeostasis 1. Mechanistically, UCHL3 stabilizes diverse oncoproteins through deubiquitination-dependent interactions. In non-small cell lung cancer, UCHL3 deubiquitylates and stabilizes the aryl hydrocarbon receptor (AhR), promoting stemness genes including ABCG2, KLF4, and c-Myc 2. Similarly, in ovarian cancer, UCHL3 removes K48-linked ubiquitin chains from RIPK4 at the K469 site, enhancing its stabilization and promoting metastasis 3. In anaplastic thyroid cancer, UCHL3 stabilizes YAP through deubiquitylation, activating Hippo pathway signaling 4. In hepatocellular carcinoma, UCHL3 stabilizes both EEF1A1 and PKM2 through deubiquitination 56. UCHL3 demonstrates paradoxical roles in disease: while functioning as an oncogene in multiple cancer types 7, it is required for normal stress response maintenance in retinal, skeletal muscle, and germ cells 1. Dysregulation associates with neurodegenerative diseases, learning deficits, and cellular stress responses 1. UCHL3 inhibitors show therapeutic promise for cancer treatment by reducing oncoprotein stability 23.