Deubiquitinases at the crossroads of ferroptosis and cancer therapy: mechanisms and therapeutic potential.

Ferroptosis is an iron-dependent form of regulated cell death driven by lethal lipid peroxidation and has emerged as a promising therapeutic vulnerability in cancer. Increasing evidence highlights its critical role in controlling tumor progression, overcoming therapeutic resistance, and enhancing antitumor immunity. Recent studies have identified the ubiquitin-proteasome system (UPS), particularly deubiquitinases (DUBs), as key regulatory nodes that determine ferroptotic susceptibility and represent attractive therapeutic targets. DUBs promote cancer cell survival and drug resistance by modulating the ubiquitination, stability, and functional activity of central ferroptosis regulators, thereby enabling tumor cells to evade oxidative stress and treatment-induced cytotoxicity. Several DUBs, such as OTUD5, OTUB1, USP7, USP14, USP22, and USP35, have been recognized as potent suppressors of ferroptosis that contribute to resistance against chemotherapy, radiotherapy, and targeted therapies. Importantly, pharmacological inhibitors or genetic silencing of these DUBs can reactivate ferroptotic cell death, resensitize resistant tumors to conventional and targeted therapies, and improve overall therapeutic outcomes. These findings position DUBs as highly actionable drug targets and support the development of DUB-directed inhibitors as ferroptosis-sensitizing agents in cancer treatment. Beyond regulating intrinsic tumor cell survival, DUB-mediated ferroptosis control also influences tumor-immune interactions and the tumor microenvironment, thereby affecting immune evasion and responsiveness to immunotherapy. This review comprehensively summarizes current progress in targeting DUB-mediated ferroptosis regulation, highlights emerging pharmacological strategies against UPS components, and discusses their translational potential for overcoming therapeutic resistance and improving cancer treatment efficacy.