The transcription factor NRF2 (nuclear factor E2-related factor 2) (also known as nuclear factor, erythroid 2 like 2 [NFE2L2]) is the master regulator of cellular antioxidant responses. NRF2 is repressed by interaction with a redox-sensitive protein KEAP1 (Kelch-like ECH-associated protein 1). Dysregulation of KEAP1/NRF2 transcriptional activity has been associated with the pathogenesis of multiple diseases, and the KEAP1/NRF2 axis has emerged to be the most important modulator of cellular homeostasis. Oxidative stress plays an important role in the initiation and progression of many chronic diseases, including diabetes, cancer, and neurodegenerative diseases. Although its role in immunotherapy is still somewhat controversial, it is well documented from clinical studies that KEAP1/NRF2 mutations in NSCLCs are associated with resistance to various cancer treatments including chemotherapy, X-irradiation, TKI treatment, and a shorter OS and currently available results from clinical trials suggest that KEAP1/NRF2 mutations can be used as a prognostic biomarker (poorer prognosis) for determining prognosis following immunotherapy and a predictive marker for chemo-, radio-, immunotherapy- and TKI-resistance. Despite overwhelming enthusiasm about the various KEAP1/NRF2 inhibitors that have been described during the last decades, none of these inhibitors are currently explored in clinical trials or in clinical applications which clearly add weight to the proposal that the development of these inhibitors remains challenging, but will be beneficial for novel treatment approaches in NSCLC in the near future. In this review we highlight the molecular features, the key components, and possible inhibitors of the KEAP1/NRF2 pathway, its role as prognostic and predictive biomarker, and the resulting clinical implications in NSCLC patients.

转录因子 NRF2（核因子 E2 相关因子 2）（也称为核因子，类红细胞 2 样 2 [NFE2L2]）是细胞抗氧化反应的主要调节因子。NRF2 通过与氧化还原敏感蛋白 KEAP1（Kelch 样 ECH 相关蛋白 1）相互作用而受到抑制。KEAP1/NRF2 转录活性的失调与多种疾病的发病机制有关，并且 KEAP1/NRF2 轴已成为细胞稳态的最重要调节剂。氧化应激在许多慢性疾病的发生和发展中起着重要作用，包括糖尿病、癌症和神经退行性疾病。虽然它在免疫治疗中的作用仍然有些争议，临床研究充分证明，NSCLC 中的 KEAP1/NRF2 突变与对包括化疗、X 射线、TKI 治疗和较短 OS 在内的各种癌症治疗的耐药性相关，目前临床试验的结果表明 KEAP1/NRF2 突变可以可用作预后生物标志物（预后较差），用于确定免疫治疗后的预后以及化疗、放疗、免疫治疗和 TKI 耐药性的预测标志物。尽管对过去几十年中描述的各种 KEAP1/NRF2 抑制剂充满热情，但目前这些抑制剂都没有在临床试验或临床应用中进行探索，这显然增加了这些抑制剂的开发仍然具有挑战性的提议的重要性，但在不久的将来有利于 NSCLC 的新治疗方法。在这篇综述中，我们重点介绍了 KEAP1/NRF2 通路的分子特征、关键成分和可能的抑制剂，其作为预后和预测生物标志物的作用，以及由此产生的对 NSCLC 患者的临床意义。