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.
Original reference: Cell Metab. 35, 487–503 (2023).
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