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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月23日

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  • Jialin Zhang,
  • Lu Lu,
  • Wenchang Xu,
  • Na Zhou,
  • Yongfeng Song

摘要

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.