Deubiquitinases in cancer: biology, mechanism, and therapeutic targeting

The ubiquitin-proteasome system (UPS) plays a central role in cellular protein homeostasis by regulating the degradation, trafficking, and activity of target proteins. Deubiquitinases (DUBs) are a crucial component of this regulatory network, catalyzing the removal of ubiquitin moieties from modified substrates to modulate signaling pathways that govern cell cycle control, apoptosis, DNA repair, immune responses, and stress adaptation. Aberrant DUB expression or activity is increasingly recognized as a driver of oncogenesis, tumor progression, drug resistance, and metastasis. As a result, DUBs have emerged as novel therapeutic targets in cancer, complementing existing proteasome inhibitors. This review provides an overview of DUB classification, their mechanistic roles in cancer biology, current progress in small-molecule DUB inhibitors and DUB-directed PROTACs, and discusses translational challenges and future opportunities for therapeutic development.