The dual role of OTUD3 in cancer: mechanisms and therapeutic implications

OTUD3 (Ovarian Tumor Domain-Containing Protein 3), a deubiquitinating enzyme, has emerged as a pivotal and context-dependent regulator in cancer pathogenesis, exhibiting a striking functional duality as either a tumor suppressor or oncoprotein across different cancer types. Acting as a dual regulator, it influences key cellular processes-including proliferation, apoptosis, immune evasion, and metabolic reprogramming-by stabilizing specific substrates such as PTEN, p53, GRP78, YY1, and PD-L1. Its role extends to modulating inflammatory signaling, antiviral immunity, and metabolic homeostasis, highlighting its broad functional versatility. The development of OTUD3-targeted inhibitors like Rolapitant, Rupatadine, and OTUDin3 shows promise in preclinical models, particularly in combination with immunotherapy. However, its tissue-specific duality poses both challenges and opportunities for therapeutic intervention. Further research is needed to elucidate OTUD3's mechanistic networks and advance its clinical translation as a prognostic biomarker and therapeutic target in precision oncology.