NRF2-targeted therapeutics: New targets and modes of NRF2 regulation.
NRF2-targeted therapeutics: New targets and modes of NRF2 regulation.
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DOI：
10.1016/j.cotox.2016.10.005
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发表时间：
2016-12
影响因子：
4.6
通讯作者：
Zhang DD
中科院分区：
文献类型：
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作者：
Rojo de la Vega M;Dodson M;Chapman E;Zhang DD
转录因子核因子-红细胞衍生的2-样2（NRF 2）（细胞抗氧化反应的关键调节因子）的药理学激活已被认为是减少氧化/亲电应激和预防致癌或其他慢性疾病（如糖尿病和慢性肾病）的可行策略。相反，由于发现了NRF 2的“黑暗面”，其中NRF 2的长期激活导致组织损伤、癌症进展或化学抗性，因此一直致力于鉴定抑制剂。目前，只有一种NRF 2激活剂被批准用于临床，而尚未发现特异性NRF 2抑制剂。NRF 2靶向治疗的未来发展应该基于我们目前对这种蛋白质调控机制的理解。除了KEAP 1依赖性机制外，最近发现的参与NRF 2降解的其他途径为开发安全和特异性治疗开辟了新的可能性。在这里，我们回顾了现有的和假定的NRF 2靶向治疗方法，并讨论了它们的作用方式以及它们在疾病预防和治疗中的潜力。
Pharmacological activation of the transcription factor nuclear factor-erythroid derived 2-like 2 (NRF2), the key regulator of the cellular antioxidant response, has been recognized as a feasible strategy to reduce oxidative/electrophilic stress and prevent carcinogenesis or other chronic illnesses, such as diabetes and chronic kidney disease. In contrast, due to the discovery of the “dark side” of NRF2, where prolonged activation of NRF2 causes tissue damage, cancer progression, or chemoresistance, efforts have been devoted to identify inhibitors. Currently, only one NRF2 activator has been approved for use in the clinic, while no specific NRF2 inhibitors have been discovered. Future development of NRF2-targeted therapeutics should be based on our current understanding of the regulatory mechanisms of this protein. In addition to the KEAP1-dependent mechanisms, the recent discovery of other pathways involved in the degradation of NRF2 have opened up new possibilities for the development of safe and specific therapeutics. Here, we review available and putative NRF2-targeted therapeutics and discuss their modes of action as well as their potential for disease prevention and treatment.
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