Rojo de la Vega Montserrat, Dodson Matthew, Chapman Eli, Zhang Donna D
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA, 85721.
Arizona Cancer Center, University of Arizona, Tucson, AZ, USA, 85724.
Curr Opin Toxicol. 2016 Dec;1:62-70. doi: 10.1016/j.cotox.2016.10.005. Epub 2016 Oct 12.
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.
转录因子核因子红系衍生 2 样 2（NRF2）是细胞抗氧化反应的关键调节因子，其药理学激活已被认为是减轻氧化/亲电应激以及预防癌症或其他慢性疾病（如糖尿病和慢性肾病）的可行策略。相比之下，由于 NRF2“黑暗面”的发现，即 NRF2 的长期激活会导致组织损伤、癌症进展或化疗耐药性，人们致力于寻找抑制剂。目前，仅有一种 NRF2 激活剂已获批用于临床，而尚未发现特异性 NRF2 抑制剂。NRF2 靶向治疗的未来发展应基于我们目前对该蛋白调控机制的理解。除了 KEAP1 依赖机制外，最近发现的其他参与 NRF2 降解的途径为开发安全且特异性的治疗方法开辟了新的可能性。在此，我们综述了现有的和假定的 NRF2 靶向治疗方法，并讨论了它们的作用模式以及疾病预防和治疗潜力。
