The deubiquitinase USP35: from an oncogenic hub to a therapeutic target in human cancers

Ubiquitination is a critical post-translational modification in eukaryotic cells, mediated by a sequential enzymatic cascade involving E1 (activating), E2 (conjugating), and E3 (ligase) enzymes that catalyze the covalent conjugation of ubiquitin to substrate proteins. This modification precisely controls substrate stability, localization, and function, thereby governing fundamental cellular processes such as the cell cycle, DNA repair, and apoptosis. Deubiquitinating enzymes (DUBs) counteract ubiquitination by hydrolyzing ubiquitin chains, thereby maintaining cellular protein homeostasis. Ubiquitin-Specific Protease 35 (USP35), a core member of the USP family, relies on a conserved Cys-His-Asp catalytic triad and C-terminal domain (CTD)-dependent dimerization for its enzymatic activity to specifically remove ubiquitin modifications from diverse substrates. USP35 is frequently overexpressed in diverse malignancies, including clear cell renal cell carcinoma and breast cancer. By stabilizing key oncogenic factors-such as Aurora B (a proliferation regulator), NRF2 and BRD4 (inhibitors of ferroptosis), and Snail1 (a promoter of EMT)-USP35 acts as a central driver of core malignant phenotypes, including tumor cell proliferation, apoptotic evasion, metabolic reprogramming, epithelial-mesenchymal transition (EMT), and resistance to chemotherapy and immunotherapy. This review systematically summarizes the multi-dimensional regulatory mechanisms of USP35 in tumorigenesis and progression across various cancers, highlights its clinical significance as a pan-cancer prognostic biomarker and potential therapeutic target, and provides a forward-looking perspective on the development of USP35-targeted small-molecule inhibitors and combination therapies. We aim to establish a theoretical foundation and highlight translational directions for developing USP35-based precision oncology approaches.