Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer
Open accessAbstract
During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc- antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited.
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NRF2 activation causes glutamine dependence in KRAS-mutant lung and pancreatic cancer cells and preclinical mouse models.
“The activation of NRF2 causes glutamine dependence in KRAS mutant lung and pancreatic cancers cells and preclinical mouse models60,62,63, and BRAF mutants can similarly activate NRF2 to promote reactive oxygen species (ROS) detoxification59.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [63]
In cells with NRF2 activation, most glutamate is secreted, and cystine is imported by the SLC7A11 (xCT) antiporter mechanism.
“In cells with NRF2 activation, most glutamate is secreted, and cystine is imported by the SLC7A11 (xCT) antiporter mechanism47 (Fig. 3).”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [47]
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Sayin, V. I., & Papagiannakopoulos, T. Y. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.03.029 · Cited by 19 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Hayes, J. D., Dinkova-Kostova, A. T., & Tew, K. D. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.06.001 · Cited by 2,654 · see citing works
NRF2, a Transcription Factor for Stress Response and Beyond
He, F., Ru, X., & Wen, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134777 · Cited by 1,820 · see citing works
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Sullivan, M. R., Danai, L. V., Lewis, C. A., Chan, S. H., Gui, D. Y., Kunchok, T., Dennstedt, E. A., Vander Heiden, M. G., & Muir, A. (2019) · eLife · doi:10.7554/elife.44235 · Cited by 588 · see citing works
Self-citationBACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis
Wiel, C., Le Gal, K., Ibrahim, M. X., Jahangir, C. A., Kashif, M., Yao, H., Ziegler, D. V., Xu, X., Ghosh, T., Mondal, T., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.005 · Cited by 579 · see citing works
Self-citationNrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1
Lignitto, L., LeBoeuf, S. E., Homer, H., Jiang, S., Askenazi, M., Karakousi, T. R., Pass, H. I., Bhutkar, A. J., Tsirigos, A., Ueberheide, B., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.003 · Cited by 573 · see citing works
Self-citationThe metabolic landscape of RAS-driven cancers from biology to therapy
Mukhopadhyay, S., Vander Heiden, M. G., & McCormick, F. (2021) · Nature Cancer · doi:10.1038/s43018-021-00184-x · Cited by 315 · see citing works
Mukhopadhyay, S., Goswami, D., Adiseshaiah, P. P., Burgan, W., Yi, M., Guerin, T. M., Kozlov, S. V., Nissley, D. V., & McCormick, F. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-1363 · Cited by 279 · see citing works
Muir, A., Danai, L. V., Gui, D. Y., Waingarten, C. Y., Lewis, C. A., & Vander Heiden, M. G. (2017) · eLife · doi:10.7554/elife.27713 · Cited by 311 · see citing works
Self-citationGalan-Cobo, A., Sitthideatphaiboon, P., Qu, X., Poteete, A., Pisegna, M. A., Tong, P., Chen, P.-H., Boroughs, L. K., Rodriguez, M. L. M., Zhang, W., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3527 · Cited by 292 · see citing works
Thirty years of NRF2: advances and therapeutic challenges.
Zhang, D. D. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01145-0 · Cited by 282 · see citing works
LeBoeuf, S. E., Wu, W. L., Karakousi, T. R., Karadal, B., Jackson, S. R., Davidson, S. M., Wong, K.-K., Koralov, S. B., Sayin, V. I., & Papagiannakopoulos, T. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.012 · Cited by 150 · see citing works
Self-citationBest, S. A., Ding, S., Kersbergen, A., Dong, X., Song, J.-Y., Xie, Y., Reljic, B., Li, K., Vince, J. E., Rathi, V., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12164-y · Cited by 108 · see citing works
Metabolic features of cancer cells in NRF2 addiction status
Okazaki, K., Papagiannakopoulos, T., & Motohashi, H. (2020) · Biophysical Reviews · doi:10.1007/s12551-020-00659-8 · Cited by 57 · see citing works
Self-citationDistinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression
DeBlasi, J. M., Falzone, A., Caldwell, S., Prieto-Farigua, N., Prigge, J. R., Schmidt, E. E., Chio, I. I. C., Karreth, F. A., & DeNicola, G. M. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-3848 · Cited by 49 · see citing works
“NRF2 stabilization is 53 associated with poor prognosis (13-20), resistance to chemo- and radiotherapy (21, 22), cancer cell 54 survival (22), proliferation (23), metabolic reprogramming (20, 24-26), and metastasis (27).”
Shining a light on metabolic vulnerabilities in non-small cell lung cancer
Dowling, C. M., Zhang, H., Chonghaile, T. N., & Wong, K.-K. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188462 · Cited by 26 · see citing works
“The activation of NRF2 by KEAP1 mutation results in the system xc- dependent export of glutamate, leading to a depletion in intracellular glutamate [85, 88].”
BackgroundCuadrado, A., Cazalla, E., Bach, A., Bathish, B., Naidu, S. D., DeNicola, G. M., Dinkova-Kostova, A. T., Fernández-Ginés, R., Grochot-Przeczek, A., Hayes, J. D., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103569 · Cited by 28 · see citing works
- Authors
- Sayin, V. I., LeBoeuf, S. E., Singh, S. X., Davidson, S. M., Biancur, D., Guzelhan, B. S., Alvarez, S. W., Wu, W. L., Karakousi, T. R., Zavitsanou, A. M., Ubriaco, J., Muir, A., Karagiannis, D., Morris, P. J., Thomas, C. J., Possemato, R., Vander Heiden, M. G., & Papagiannakopoulos, T.
- Affiliations
- New York University (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- National Institutes of Health (US)
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
- Corresponding author
- Papagiannakopoulos, Thales
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-10-02
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5624783
- OpenAlex
- W2758805707
- Cited by
- 231
- References
- 82
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 23 · 2023: 38 · 2022: 22 · 2021: 26 · 2020: 35 · 2019: 31 · 2018: 14 · 2017: 3
- FWCI
- 9.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (K22CA201088-01, 5T32HL007151-38)
- European Molecular Biology Organization (GA-2013-609409)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Nrf2, cancer metabolism, glutamine dependency, glutamate, glutathione synthesis, TCA cycle, oxidative stress, reactive oxygen species, metabolic reprogramming, antioxidant pathways, metabolic bottlenecks, cancer therapy
- MeSH terms
- Animals, Antioxidants, Carbon, Cell Survival, Glutathione, Homeostasis, Humans, Neoplasms, Glutamic Acid, Cell Line, Tumor, Cell Proliferation, NF-E2-Related Factor 2, Mice
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