摘要
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.
摘要译文
转录因子核因子 - 红细胞衍生的2样2（NRF2）的药理活化，细胞抗氧化反应的关键调节因子，已被公认为减少氧化/亲电应激和预防致癌作用或其他慢性疾病（如糖尿病和慢性肾病）的可行策略。相反，由于发现NRF2的“暗侧”，其中NRF2的长期活化导致组织损伤，癌症进展或化学抗性，已经致力于鉴定抑制剂。目前，只有一种NRF2激活剂已被批准用于临床，而未发现特定的NRF2抑制剂。NRF2靶向疗法的未来发展应基于我们目前对该蛋白质调节机制的理解。除了依赖KEAP1的机制外，最近发现了与NRF2降解有关的其他途径，为开发安全和特异性疗法开辟了新的可能性。这里，我们回顾了现有和推定的NRF2靶向治疗方法，并讨论了它们的作用方式以及它们对疾病预防和治疗的潜力。
MontserratRojo de la Vega[1];MatthewDodson[1];EliChapman[1];Donna D.Zhang[1][2];. NRF2-targeted therapeutics: New targets and modes of NRF2 regulation[J]. Current Opinion in Toxicology, 2016,1: 62-70