NRF2 is a transcription factor that promotes the expression of genes encoding anti-oxidant molecules under conditions of high oxidative stress. NRF2 is normally restrained through interactions with KEAP1 under low stress, which promotes NRF2 degradation. Increased levels of NRF2 were thought to enable cancer cells and tumors to tolerate high levels of reactive oxygen species to survive and proliferate, which led to the classification of NRF2 as an oncogene. Weiss-Sadan et al. analyzed a panel of more than 50 genetically diverse non–small-cell lung cancer cell lines with genetic or chemical activation of NRF2 and/or inhibition of KEAP1 and unexpectedly found that over 13% of these cell lines exhibited reduced proliferation (called KEAP1-dependent cells). Metabolic analysis of these KEAP1-dependent cell lines revealed decreased glycolytic rates, which when increased restored proliferation. Weiss-Sadan et al. hypothesized that the low glycolytic rate may make the cell unable to deal with reductive stress caused by an imbalance of NADH/NAD⁺ after activation of NRF2. The use of a genetically encoded NADH/NAD⁺ reporter confirmed a high NADH/NAD⁺ ratio in the KEAP1-dependent cells, with the expression of NADH-oxidizing enzymes restoring proliferation. ALDH3A1, encoded by an NRF2 target gene, was identified as a mediator of NRF2-activation-induced NADH/NAD⁺ imbalance, and mass spectrometry analysis of ALDH3A1 depletion revealed phenylacetaldehyde and 4-hydroxy-phenylacetaldehyde as potential substrates of ALDH3A1. Finally, treatment with mitochondrial complex I inhibitors that block NADH oxidation was effective in disrupting the growth of tumors expressing mutated KEAP. Although further work is needed to elucidate the mechanistic details, these findings from Weiss-Sadan et al. reveal unique interplay among NRF2, NADH and reductive stress in a metabolically sensitive subset of non–small-cell lung cancer cell lines.

NRF2是一种转录因子，可在高氧化应激条件下促进编码抗氧化分子的基因表达。NRF2 通常在低压力下通过与 KEAP1 的相互作用受到抑制，从而促进 NRF2 降解。人们认为 NRF2 水平升高可使癌细胞和肿瘤耐受高水平的活性氧以生存和增殖，这导致NRF2被归类为致癌基因。Weiss-Sadan 等人。分析了一组超过 50 种具有 NRF2 遗传或化学激活和/或 KEAP1 抑制的遗传多样性非小细胞肺癌细胞系，意外地发现超过 13% 的这些细胞系表现出增殖减少（称为KEAP1依赖性细胞）。这些的代谢分析KEAP1依赖性细胞系显示糖酵解速率降低，当糖酵解速率增加时恢复增殖。Weiss-Sadan 等人。假设低糖酵解率可能使细胞无法应对NRF2 激活后NADH/NAD ⁺失衡引起的还原应激。使用遗传编码的 NADH/NAD ^{+报告基因证实了}KEAP1依赖性细胞中的高 NADH/NAD ⁺比率，同时 NADH 氧化酶的表达恢复了增殖。^{由 NRF2 靶基因编码的 ALDH3A1 被确定为 NRF2 激活诱导的 NADH/NAD +}的介质ALDH3A1 耗尽的不平衡和质谱分析表明苯乙醛和 4-羟基苯乙醛是 ALDH3A1 的潜在底物。最后，用阻断 NADH 氧化的线粒体复合物 I 抑制剂治疗可有效破坏表达突变KEAP的肿瘤的生长。尽管需要进一步的工作来阐明机械细节，但 Weiss-Sadan 等人的这些发现。在非小细胞肺癌细胞系的代谢敏感亚群中，揭示了 NRF2、NADH 和还原应激之间独特的相互作用。