Hsu Sheng-Kai, Kuo I-Ying, Lin Pin-Yuan, Chou Chon-Kit, Ko Ching-Chung, Chang Wen-Tsan, Chiu Chien-Chih
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.
Int J Biol Sci. 2025 Jun 9;21(9):3993-4009. doi: 10.7150/ijbs.111867. eCollection 2025.
Most chemotherapeutic drugs are introduced to eliminate tumors by targeting apoptotic cell death, but chemoresistance frequently develops owing to the aberrant apoptotic machinery. Although the emergence of immune checkpoint blockade (ICB) has revolutionized cancer therapeutics, poor responses to ICB and an immunosuppressive tumor microenvironment are commonly observed in solid tumors. Hence, restoring chemosensitivity and immunosurveillance is important for improving patient outcomes. Recently, the induction of nonapoptotic programmed cell death (PCD), such as ferroptosis and pyroptosis, has received much attention since these alternative forms of cell death potentially increase chemosensitivity and augment antitumor immunity. Ubiquitination and deubiquitination are well-recognized posttranslational modifications, and the balance between these processes is important for maintaining cellular homeostasis. Dysregulation of deubiquitinating enzymes (DUBs) is reportedly associated with tumor progression. Additionally, emerging studies have suggested the involvement of DUBs in modulating cellular susceptibility to nonapoptotic PCD. Nevertheless, the crosstalk between DUBs and nonapoptotic PCDs and their implications for cancer treatment have not been thoroughly reviewed. In this review, we elucidate the roles of DUBs in regulating ferroptosis and pyroptosis via their DUB activities or noncanonical functions. Moreover, we thoroughly discuss the challenges and urgent problems associated with targeting DUBs to induce nonapoptotic PCDs as cancer therapeutics.
大多数化疗药物通过靶向凋亡性细胞死亡来消除肿瘤，但由于凋亡机制异常，化疗耐药性经常出现。尽管免疫检查点阻断（ICB）的出现彻底改变了癌症治疗方法，但在实体瘤中普遍观察到对ICB的不良反应和免疫抑制性肿瘤微环境。因此，恢复化疗敏感性和免疫监视对于改善患者预后很重要。最近，非凋亡性程序性细胞死亡（PCD）的诱导，如铁死亡和焦亡，受到了广泛关注，因为这些细胞死亡的替代形式可能会增加化疗敏感性并增强抗肿瘤免疫力。泛素化和去泛素化是公认的翻译后修饰，这些过程之间的平衡对于维持细胞稳态很重要。据报道，去泛素化酶（DUBs）的失调与肿瘤进展有关。此外，新出现的研究表明DUBs参与调节细胞对非凋亡性PCD的敏感性。然而，DUBs与非凋亡性PCD之间的相互作用及其对癌症治疗的影响尚未得到全面综述。在本综述中，我们阐明了DUBs通过其DUB活性或非经典功能在调节铁死亡和焦亡中的作用。此外，我们深入讨论了将DUBs作为癌症治疗手段来诱导非凋亡性PCD所面临的挑战和紧迫问题。
