UCHL5 (ubiquitin C-terminal hydrolase L5) is a deubiquitinating enzyme associated with the 19S regulatory subunit of the 26S proteasome that specifically cleaves Lys-48-linked polyubiquitin chains 1. Beyond its canonical proteasomal role, UCHL5 functions in chr1 remodeling as a putative regulatory component of the INO80 complex, where it becomes activated through transient interactions with the proteasome [UniProt Function]. Mechanistically, UCHL5 cooperates with other deubiquitinases like USP14 to stabilize oncoproteins through K48-linked deubiquitination, exemplified by PKCα stabilization that facilitates NF-κB nuclear translocation and pro-oncogenic gene expression 2. UCHL5 also regulates extracellular matrix production and epithelial-mesenchymal-transition programs, contributing to tumor immune evasion 3. Clinically, UCHL5 expression is elevated in multiple cancer types and correlates with poor prognosis in renal cell carcinoma, cervical cancer, and head and neck squamous cell carcinoma 45. Notably, UCHL5 loss in tumors increases CD8+ T cell infiltration and improves immunotherapy responses 3. UCHL5 overexpression promotes 5-fluorouracil resistance in colorectal cancer 6. Pharmacologically, dual inhibition of UCHL5 and USP14 via b-AP15 or novel UCHL5-specific inhibitors shows promise for treating anaplastic thyroid cancer and chemotherapy-resistant malignancies 261.