Activation of the transcription factor Nrf2 via the Keap1–Nrf2–ARE signaling system regulates the transcription and subsequent expression of cellular cytoprotective proteins and plays a crucial role in preventing pathological conditions exacerbated by the overproduction of oxidative stress. In addition to electrophilic modulators, direct noncovalent inhibitors that interrupt the Keap1–Nrf2 protein–protein interaction (PPI) leading to Nrf2 activation have attracted a great deal of attention as potential preventive and therapeutic agents for oxidative stress-related diseases. Structural studies of Keap1-binding ligands, development of biochemical and cellular assays, and new structure-based design approaches have facilitated the discovery of small molecule PPI inhibitors. This perspective reviews the Keap1–Nrf2–ARE system, its physiological functions, and the recent progress in the discovery and the potential applications of direct inhibitors of Keap1–Nrf2 PPI.

中文翻译：

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通过抑制Keap1-Nrf2蛋白质-蛋白质相互作用来激活Nrf2。

通过Keap1–Nrf2–ARE信号系统激活转录因子Nrf2调节细胞保护细胞蛋白的转录和后续表达，并在防止因过度氧化应激而加剧的病理状况中发挥关键作用。除亲电调节剂外，直接非共价抑制剂可中断Keap1-Nrf2蛋白质-蛋白质相互作用（PPI），从而导致Nrf2活化，作为潜在的预防和治疗氧化应激相关疾病的药物引起了广泛的关注。Keap1结合配体的结构研究，生化和细胞分析的发展以及新的基于结构的设计方法促进了小分子PPI抑制剂的发现。这个观点回顾了Keap1–Nrf2–ARE系统，