Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Int J Biol Sci. 2022 Aug 29;18(14):5475-5488. doi: 10.7150/ijbs.73790. eCollection 2022.
Ferroptosis is a novel type of regulated cell death driven by the excessive accumulation of iron-dependent lipid peroxidation. Therapy-resistant tumor cells, particularly those in the mesenchymal-like state and prone to metastasis, are highly susceptible to ferroptosis, suggesting that induction of ferroptosis in tumor cells is a promising strategy for cancer therapy. Although ferroptosis is regulated at various levels, ubiquitination is key to post-translational regulation of ferroptotic cell death. E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) are the most remarkable ubiquitin system enzymes, whose dysregulation accounts for the progression of multiple cancers. E3s are involved in the attachment of ubiquitin to substrates for their degradation, and this process is reversed by DUBs. Accumulating evidence has highlighted the important role of ubiquitin system enzymes in regulating the sensitivity of ferroptosis. Herein, we will portray the regulatory networks of ferroptosis mediated by E3s or DUBs and discuss opportunities and challenges for incorporating this regulation into cancer therapy.
铁死亡是一种新型的受铁依赖性脂质过氧化过度积累驱动的调节性细胞死亡。耐药肿瘤细胞，特别是那些具有间充质样状态且易于转移的肿瘤细胞，对铁死亡高度敏感，这表明诱导肿瘤细胞发生铁死亡是癌症治疗的一种有前途的策略。尽管铁死亡在多个水平上受到调节，但泛素化是铁死亡细胞死亡的翻译后调节的关键。E3 泛素连接酶（E3s）和去泛素化酶（DUBs）是最显著的泛素系统酶，其失调导致多种癌症的进展。E3s 参与将泛素连接到底物上以进行降解，这个过程被 DUBs 逆转。越来越多的证据强调了泛素系统酶在调节铁死亡敏感性方面的重要作用。本文将描绘由 E3s 或 DUBs 介导的铁死亡调控网络，并讨论将这种调控纳入癌症治疗的机会和挑战。
