Zhang Jialin, Lu Lu, Xu Wenchang, Zhou Na, Song Yongfeng
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Department of Endocrinology, Ministry of Education, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong Province, China.
Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong Province, China.
Cancer Cell Int. 2025 Dec 23;26(1):43. doi: 10.1186/s12935-025-04129-7.
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.
