Student or educator? Sign up with your school email and get 6 months of Pro free.
Cited by 1,438

The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Open access
Cuadrado, Antonio, Rojo, Ana I., Wells, Geoffrey, Hayes, John D., Cousin, Sharon P., Rumsey, William L., Attucks, Otis C., Franklin, Stephen, Levonen, Anna-Liisa, Kensler, Thomas W., Dinkova-Kostova, Albena T.·2019·Nature Reviews Drug Discovery

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41573-018-0008-x

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 51 references

Research works printed but not linked: 276

  1. Chan, K., Lu, R., Chang, J. C. & Kan, Y. W. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc. Natl Acad. Sci. USA 93, 13943–13948 (1996). · DOI · Paper page
  2. Hayes, J. D. & Dinkova-Kostova, A. T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199–218 (2014). · DOI · Paper page
  3. Zhang, D. D., Lo, S. C., Cross, J. V., Templeton, D. J. & Hannink, M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol. Cell. Biol. 24, 10941–10953 (2004). · DOI · Paper page
  4. Cullinan, S. B., Gordan, J. D., Jin, J., Harper, J. W. & Diehl, J. A. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol. Cell. Biol. 24, 8477–8486 (2004). · DOI · Paper page
  5. Liby, K. T. & Sporn, M. B. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev. 64, 972–1003 (2012). This paper is a comprehensive review of the cyanoenone triterpenoids and their broad applicability for prevention and treatment of chronic disease. · DOI · Paper page
  6. Ogura, T. et al. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc. Natl Acad. Sci. USA 107, 2842–2847 (2010). · DOI · Paper page
  7. McMahon, M., Lamont, D. J., Beattie, K. A. & Hayes, J. D. Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc. Natl Acad. Sci. USA 107, 18838–18843 (2010). This article describes that KEAP1 has distinct cysteine sensors. · DOI · Paper page
  8. Takaya, K. et al. Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic. Biol. Med. 53, 817–827 (2012). · DOI · Paper page
  9. Sihvola, V. & Levonen, A. L. Keap1 as the redox sensor of the antioxidant response. Arch. Biochem. Biophys. 617, 94–100 (2017). · DOI
  10. Dinkova-Kostova, A. T., Kostov, R. V. & Canning, P. Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants. Arch. Biochem. Biophys. 617, 84–93 (2017). · DOI · Paper page
  11. Kumar, H., Kim, I. S., More, S. V., Kim, B. W. & Choi, D. K. Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat. Prod. Rep. 31, 109–139 (2014). · DOI · Paper page
  12. Crunkhorn, S. Deal watch: Abbott boosts investment in NRF2 activators for reducing oxidative stress. Nat. Rev. Drug Discov. 11, 96 (2012). · DOI
  13. Sies, H., Berndt, C. & Jones, D. P. Oxidative stress. Annu. Rev. Biochem. 86, 715–748 (2017). · DOI · Paper page
  14. Thimmulappa, R. K. et al. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 62, 5196–5203 (2002). This article presents one of the earliest microarray analyses of the NRF2-dependent effects of SFN in mice, identifying the importance of NRF2 in regulating the levels of NADPH.
  15. Lee, J. M., Calkins, M. J., Chan, K., Kan, Y. W. & Johnson, J. A. Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J. Biol. Chem. 278, 12029–12038 (2003). · DOI · Paper page
  16. Wu, K. C., Cui, J. Y. & Klaassen, C. D. Beneficial role of nrf2 in regulating NADPH generation and consumption. Toxicol. Sci. 123, 590–600 (2011). · DOI · Paper page
  17. Tanito, M., Agbaga, M. P. & Anderson, R. E. Upregulation of thioredoxin system via Nrf2-antioxidant responsive element pathway in adaptive-retinal neuroprotection in vivo and in vitro. Free Radic. Biol. Med. 42, 1838–1850 (2007). · DOI · Paper page
  18. MacLeod, A. K. et al. Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds. Carcinogenesis 30, 1571–1580 (2009). · DOI · Paper page
  19. Agyeman, A. S. et al. Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles. Breast Cancer Res. Treat. 132, 175–187 (2011). · DOI · Paper page
  20. Sedlak, T. W. et al. Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc. Natl Acad. Sci. USA 106, 5171–5176 (2009). · DOI · Paper page
  21. Holmstrom, K. M. et al. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol. Open 2, 761–770 (2013). This paper presents one of the first studies that describes the role of NRF2 in regulating mitochondrial function. · DOI · Paper page
  22. Hu, Q. et al. The mitochondrially targeted antioxidant MitoQ protects the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2/ARE signaling pathway. Cell Death Dis. 9, 403 (2018).
  23. Komatsu, M. et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213–223 (2010). This paper presents one of the first studies that describes the role of NRF2 in regulating the expression of p62. · DOI · Paper page
  24. Lau, A. et al. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol. Cell. Biol. 30, 3275–3285 (2010). Refs 34 and 35 present two of the first studies to describe the role of NRF2 in regulating the expression of p62. · DOI · Paper page
  25. Lee, Y. et al. Keap1/Cullin3 modulates p62/SQSTM1 activity via UBA domain ubiquitination. Cell Rep. 19, 188–202 (2017). · DOI
  26. Ichimura, Y. et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol. Cell 51, 618–631 (2013). · DOI · Paper page
  27. Taguchi, K. et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc. Natl Acad. Sci. USA 109, 13561–13566 (2012). · DOI · Paper page
  28. Pajares, M. et al. Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A. Autophagy 14, 1310–1322 (2018). · DOI · Paper page
  29. Pajares, M. et al. Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy 12, 1902–1916 (2016). This article presents one of the first studies that describes the role of NRF2 in regulating autophagy. · DOI · Paper page
  30. Dayalan Naidu, S. et al. Transcription factors NRF2 and HSF1 have opposing functions in autophagy. Sci. Rep. 7, 11023 (2017). · DOI
  31. Cullinan, S. B. et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 23, 7198–7209 (2003). This study links NRF2 with endoplasmic reticulum stress. · DOI · Paper page
  32. Pajares, M., Cuadrado, A. & Rojo, A. I. Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases. Redox Biol. 11, 543–553 (2017). · DOI · Paper page
  33. Kwak, M. K., Wakabayashi, N., Greenlaw, J. L., Yamamoto, M. & Kensler, T. W. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol. Cell. Biol. 23, 8786–8794 (2003). · DOI · Paper page
  34. Kwak, M. K. & Kensler, T. W. Induction of 26S proteasome subunit PSMB5 by the bifunctional inducer 3-methylcholanthrene through the Nrf2-ARE, but not the AhR/Arnt-XRE, pathway. Biochem. Biophys. Res. Commun. 345, 1350–1357 (2006). · DOI
  35. Bolanos, J. P. Bioenergetics and redox adaptations of astrocytes to neuronal activity. J. Neurochem. 139 (Suppl. 2), 115–125 (2016). · DOI · Paper page
  36. Shih, A. Y. et al. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci. 23, 3394–3406 (2003). · DOI · Paper page
  37. Long, M. et al. An essential role of NRF2 in diabetic wound healing. Diabetes 65, 780–793 (2016). · DOI · Paper page
  38. Knatko, E. V. et al. Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans. Cancer Prev. Res. (Phila) 8, 475–486 (2015). · DOI
  39. Quinti, L. et al. KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington’s disease patients. Proc. Natl Acad. Sci. USA 114, E4676–E4685 (2017). · DOI · Paper page
  40. Innamorato, N. G. et al. The transcription factor Nrf2 is a therapeutic target against brain inflammation. J. Immunol. 181, 680–689 (2008). · DOI · Paper page
  41. Jazwa, A. et al. Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid. Redox Signal 14, 2347–2360 (2011). · DOI · Paper page
  42. Cuadrado, A., Kugler, S. & Lastres-Becker, I. Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy. Redox Biol. 14, 522–534 (2018). · DOI · Paper page
  43. Saw, C. L. et al. Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. Mol. Carcinog. 50, 479–486 (2011). · DOI
  44. Lin, W. et al. Sulforaphane suppressed LPS-induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway. Biochem. Pharmacol. 76, 967–973 (2008). · DOI · Paper page
  45. Arisawa, T. et al. Nrf2 gene promoter polymorphism is associated with ulcerative colitis in a Japanese population. Hepatogastroenterology 55, 394–397 (2008).
  46. Arisawa, T. et al. The relationship between Helicobacter pylori infection and promoter polymorphism of the Nrf2 gene in chronic gastritis. Int. J. Mol. Med. 19, 143–148 (2007). This article presents one of the first studies to show associations between polymorphisms in the NFE2L2 gene and human disease.
  47. Wenzel, P., Kossmann, S., Munzel, T. & Daiber, A. Redox regulation of cardiovascular inflammation - Immunomodulatory function of mitochondrial and Nox-derived reactive oxygen and nitrogen species. Free Radic. Biol. Med. 109, 48–60 (2017). · DOI
  48. Liu, X. et al. Dimethyl fumarate ameliorates dextran sulfate sodium-induced murine experimental colitis by activating Nrf2 and suppressing NLRP3 inflammasome activation. Biochem. Pharmacol. 112, 37–49 (2016). · DOI
  49. Kovac, S. et al. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim. Biophys. Acta 1850, 794–801 (2014). · DOI · Paper page
  50. Rushworth, S. A. et al. The high Nrf2 expression in human acute myeloid leukemia is driven by NF-kappaB and underlies its chemo-resistance. Blood 120, 5188–5198 (2012). · DOI · Paper page
  51. Cuadrado, A., Martin-Moldes, Z., Ye, J. & Lastres-Becker, I. Transcription factors NRF2 and NF-kappaB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation. J. Biol. Chem. 289, 15244–15258 (2014). · DOI · Paper page
  52. Kim, S. W., Lee, H. K., Shin, J. H. & Lee, J. K. Up-down regulation of HO-1 and iNOS gene expressions by ethyl pyruvate via recruiting p300 to Nrf2 and depriving It from p65. Free Radic. Biol. Med. 65, 468–476 (2013). · DOI
  53. Kim, J. E. et al. Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. Cell Signal 22, 1645–1654 (2010). · DOI · Paper page
  54. Ishii, T. & Mann, G. E. Redox status in mammalian cells and stem cells during culture in vitro: critical roles of Nrf2 and cystine transporter activity in the maintenance of redox balance. Redox Biol. 2, 786–794 (2014). · DOI
  55. Harvey, C. J. et al. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci. Transl Med. 3, 78ra32 (2011). This paper presents one of the first studies to show the beneficial effects of NRF2 targeting in human lung disease. · DOI · Paper page
  56. Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF3 inflammatory axis. Nature 556, 501–504 (2018). · DOI · Paper page
  57. Olagnier, D. et al. Activation of Nrf2 signaling augments vesicular stomatitis virus oncolysis via autophagy-driven suppression of antiviral immunity. Mol. Ther. 25, 1900–1916 (2017). This study finds that NRF2 suppresses antiviral immunity, which can be exploited therapeutically in oncolytic infection. · DOI
  58. Cho, H. Y. Genomic structure and variation of nuclear factor (erythroid-derived 2)-like 2. Oxid Med. Cell Longev. 2013, 286524 (2013). This study is an analysis of polymorphisms in NFE2L2 , the gene encoding NRF2, that are associated with human disease.
  59. von Otter, M. et al. Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer’s disease and age-related cataract. Mech. Ageing Dev. 131, 105–110 (2010). · DOI
  60. von Otter, M. et al. Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson’s disease. BMC Med. Genet. 11, 36 (2010). · DOI
  61. Alam, J. et al. Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. J. Biol. Chem. 275, 27694–27702 (2000). · DOI · Paper page
  62. Al-Huseini, L. M. et al. Nuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2) modulates dendritic cell immune function through regulation of p38 MAPK-cAMP-responsive element binding protein/activating transcription factor 1 signaling. J. Biol. Chem. 288, 22281–22288 (2013). · DOI
  63. Johnson, D. A., Amirahmadi, S., Ward, C., Fabry, Z. & Johnson, J. A. The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol. Sci. 114, 237–246 (2010). · DOI · Paper page
  64. Pareek, T. K. et al. Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Sci. Rep. 1, 201 (2011). · DOI
  65. Li, B. et al. Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp. Neurol. 250, 239–249 (2013). · DOI
  66. Croze, E., Yamaguchi, K. D., Knappertz, V., Reder, A. T. & Salamon, H. Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis. Pharmacogenomics J. 13, 443–451 (2013). · DOI
  67. Bruck, J., Dringen, R., Amasuno, A., Pau-Charles, I. & Ghoreschi, K. A review of the mechanisms of action of dimethylfumarate in the treatment of psoriasis. Exp. Dermatol. 27, 611–624 (2018). · DOI · Paper page
  68. Ma, Q., Battelli, L. & Hubbs, A. F. Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am. J. Pathol. 168, 1960–1974 (2006). · DOI · Paper page
  69. Zhao, M. et al. Nuclear factor erythroid 2-related factor 2 deficiency exacerbates lupus nephritis in B6/lpr mice by regulating Th17 cell function. Sci. Rep. 6, 38619 (2016).
  70. Wu, W. J. et al. S-Propargyl-cysteine attenuates inflammatory response in rheumatoid arthritis by modulating the Nrf2-ARE signaling pathway. Redox Biol. 10, 157–167 (2016). · DOI
  71. van Wietmarschen, H. et al. Systems biology guided by Chinese medicine reveals new markers for sub-typing rheumatoid arthritis patients. J. Clin. Rheumatol. 15, 330–337 (2009). · DOI
  72. Guan, C. P. et al. The susceptibility to vitiligo is associated with NF-E2-related factor2 (Nrf2) gene polymorphisms: a study on Chinese Han population. Exp. Dermatol. 17, 1059–1062 (2008). · DOI
  73. Song, P. et al. Genetic polymorphism of the Nrf2 promoter region is associated with vitiligo risk in Han Chinese populations. J. Cell. Mol. Med. 20, 1840–1850 (2016). · DOI
  74. Natarajan, V. T. et al. Transcriptional upregulation of Nrf2-dependent phase II detoxification genes in the involved epidermis of vitiligo vulgaris. J. Invest. Dermatol. 130, 2781–2789 (2010). · DOI
  75. van Eeden, S. F. & Sin, D. D. Oxidative stress in chronic obstructive pulmonary disease: a lung and systemic process. Can. Respir. J. 20, 27–29 (2013). · DOI
  76. Rangasamy, T. et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J. Clin. Invest. 114, 1248–1259 (2004). · DOI · Paper page
  77. Rangasamy, T. et al. Cigarette smoke-induced emphysema in A/J mice is associated with pulmonary oxidative stress, apoptosis of lung cells, and global alterations in gene expression. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L888–900 (2009). · DOI
  78. Sussan, T. E. et al. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc. Natl Acad. Sci. USA 106, 250–255 (2009). · DOI · Paper page
  79. Blake, D. J. et al. Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation. Am. J. Respir. Cell. Mol. Biol. 42, 524–536 (2010). · DOI
  80. Goven, D. et al. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax 63, 916–924 (2008). · DOI · Paper page
  81. Hua, C. C. et al. Functional haplotypes in the promoter region of transcription factor Nrf2 in chronic obstructive pulmonary disease. Dis. Markers 28, 185–193 (2010). · DOI
  82. Bewley, M. A. et al. Opsonic phagocytosis in chronic obstructive pulmonary disease is enhanced by Nrf2 agonists. Am. J. Respir. Crit. Care Med. 198, 739–750 (2018). · DOI
  83. Markart, P. et al. Alveolar oxidative stress is associated with elevated levels of nonenzymatic low-molecular-weight antioxidants in patients with different forms of chronic fibrosing interstitial lung diseases. Antioxid. Redox Signal 11, 227–240 (2009). · DOI
  84. Biasi, F., Leonarduzzi, G., Oteiza, P. I. & Poli, G. Inflammatory bowel disease: mechanisms, redox considerations, and therapeutic targets. Antioxid. Redox Signal 19, 1711–1747 (2013). · DOI · Paper page
  85. Benson, A. M., Hunkeler, M. J. & Talalay, P. Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. Proc. Natl Acad. Sci. USA 77, 5216–5220 (1980). · DOI · Paper page
  86. McMahon, M. et al. The Cap’n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res. 61, 3299–3307 (2001).
  87. Kumar, V. et al. Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells. J. Med. Chem. 54, 4147–4159 (2011). · DOI · Paper page
  88. Khor, T. O. et al. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res. 66, 11580–11584 (2006). · DOI · Paper page
  89. Baillie, J. K. et al. Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease. PLOS Genet. 13, e1006641 (2017). This study demonstrates the significance of NRF2 in human IBD. · DOI
  90. Arisawa, T. et al. Nrf2 gene promoter polymorphism and gastric carcinogenesis. Hepatogastroenterology 55, 750–754 (2008).
  91. Aleksunes, L. M. & Manautou, J. E. Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol. Pathol. 35, 459–473 (2007). · DOI · Paper page
  92. Okawa, H. et al. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun. 339, 79–88 (2006). · DOI · Paper page
  93. Lamle, J. et al. Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134, 1159–1168 (2008). · DOI · Paper page
  94. Wakabayashi, N. et al. Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci. Signal 3, ra52 (2010). · DOI · Paper page
  95. Kim, J. H. et al. NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation. J. Clin. Invest. 124, 730–741 (2014). · DOI
  96. Duarte, T. L. et al. Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis. Redox Biol. 11, 157–169 (2017). · DOI
  97. Wasik, U., Milkiewicz, M., Kempinska-Podhorodecka, A. & Milkiewicz, P. Protection against oxidative stress mediated by the Nrf2/Keap1 axis is impaired in primary biliary cholangitis. Sci. Rep. 7, 44769 (2017). · DOI
  98. Meakin, P. J. et al. Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance. Mol. Cell. Biol. 34, 3305–3320 (2014). · DOI · Paper page
  99. Jiang, T. et al. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59, 850–860 (2010). · DOI · Paper page
  100. Sharma, R. S. et al. Experimental nonalcoholic steatohepatitis and liver fibrosis are ameliorated by pharmacologic activation of Nrf2 (NF-E2 p45-related factor 2). Cell. Mol. Gastroenterol. Hepatol. 5, 367–398 (2018). This study finds that pharmacological activation of NRF2 in obese and insulin-resistant mice reversed insulin resistance and suppressed hepatic steatosis and fibrosis and that these protective effects were due to inhibition of endoplasmic reticulum, inflammatory and oxidative stress. · DOI · Paper page
  101. Axelsson, A. S. et al. Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Sci. Transl Med. 9, eaah4477 (2017). · DOI · Paper page
  102. Jimenez-Osorio, A. S. et al. Nrf2 and redox status in prediabetic and diabetic patients. Int. J. Mol. Sci. 15, 20290–20305 (2014). · DOI
  103. Wang, X. et al. Association between the NF-E2 related factor 2 gene polymorphism and oxidative stress, anti-oxidative status, and newly-diagnosed type 2 diabetes mellitus in a chinese population. Int. J. Mol. Sci. 16, 16483–16496 (2015). · DOI
  104. Xu, X. et al. Genetic variants of nuclear factor erythroid-derived 2-like 2 associated with the complications in Han descents with type 2 diabetes mellitus of Northeast China. J. Cell. Mol. Med. 20, 2078–2088 (2016). · DOI
  105. Jimenez-Osorio, A. S. et al. Association of nuclear factor-erythroid 2-related factor 2, thioredoxin interacting protein, and heme oxygenase-1 gene polymorphisms with diabetes and obesity in Mexican patients. Oxid Med. Cell Longev. 2016, 7367641 (2016).
  106. Palsamy, P., Ayaki, M., Elanchezhian, R. & Shinohara, T. Promoter demethylation of Keap1 gene in human diabetic cataractous lenses. Biochem. Biophys. Res. Commun. 423, 542–548 (2012). · DOI
  107. Chowdhry, S. et al. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic. Biol. Med. 48, 357–371 (2010). · DOI · Paper page
  108. Sugimoto, H. et al. Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G283–G294 (2010). · DOI · Paper page
  109. Reccia, I. et al. Non-alcoholic fatty liver disease: a sign of systemic disease. Metabolism 72, 94–108 (2017). · DOI · Paper page
  110. Slocum, S. L. et al. Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet. Arch. Biochem. Biophys. 591, 57–65 (2016). · DOI
  111. Takahashi, Y. et al. Does hepatic oxidative stress enhance activation of nuclear factor-E2-related factor in patients with nonalcoholic steatohepatitis? Antioxid. Redox Signal 20, 538–543 (2014). · DOI
  112. Harrison, D., Griendling, K. K., Landmesser, U., Hornig, B. & Drexler, H. Role of oxidative stress in atherosclerosis. Am. J. Cardiol. 91, 7A–11A (2003). · DOI · Paper page
  113. Katsumata, Y. et al. Endogenous prostaglandin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2. Hypertension 63, 80–87 (2014). · DOI
  114. Ashrafian, H. et al. Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metab. 15, 361–371 (2012). This study demonstrates the beneficial effects of targeting NRF2 for cardioprotection. · DOI · Paper page
  115. Calvert, J. W. et al. Genetic and pharmacologic hydrogen sulfide therapy attenuates ischemia-induced heart failure in mice. Circulation 122, 11–19 (2010). · DOI · Paper page
  116. Li, J. et al. Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler. Thromb. Vasc. Biol. 29, 1843–1850 (2009). · DOI · Paper page
  117. Collins, A. R. et al. Myeloid deletion of nuclear factor erythroid 2-related factor 2 increases atherosclerosis and liver injury. Arterioscler. Thromb. Vasc. Biol. 32, 2839–2846 (2012). · DOI
  118. Ruotsalainen, A. K. et al. The absence of macrophage Nrf2 promotes early atherogenesis. Cardiovasc. Res. 98, 107–115 (2013). · DOI · Paper page
  119. Sussan, T. E. et al. Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice. PLOS ONE 3, e3791 (2008). · DOI · Paper page
  120. Barajas, B. et al. NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection. Arterioscler. Thromb. Vasc. Biol. 31, 58–66 (2011). · DOI · Paper page
  121. Ruotsalainen, A. K. et al. Nrf2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolemic mice. Cardiovasc. Res. https://doi.org/10.1093/cvr/cvy143 (2018). · DOI
  122. Tan, S. M. et al. Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-associated atherosclerosis and improves diabetic kidney disease. Diabetes 63, 3091–3103 (2014). · DOI
  123. Xie, L. et al. Hydrogen sulfide induces Keap1 S-sulfhydration and suppresses diabetes-accelerated atherosclerosis via Nrf2 activation. Diabetes 65, 3171–3184 (2016). · DOI · Paper page
  124. Quiles, J. L. et al. Curcuma longa extract supplementation reduces oxidative stress and attenuates aortic fatty streak development in rabbits. Arterioscler. Thromb. Vasc. Biol. 22, 1225–1231 (2002). · DOI · Paper page
  125. Harvey, P. A. & Leinwand, L. A. The cell biology of disease: cellular mechanisms of cardiomyopathy. J. Cell Biol. 194, 355–365 (2011). · DOI · Paper page
  126. Pedruzzi, L. M. et al. Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2. J. Nephrol. 28, 495–501 (2015). · DOI
  127. Shimoyama, Y., Mitsuda, Y., Tsuruta, Y., Hamajima, N. & Niwa, T. Polymorphism of Nrf2, an antioxidative gene, is associated with blood pressure and cardiovascular mortality in hemodialysis patients. Int. J. Med. Sci. 11, 726–731 (2014). · DOI
  128. Kannan, S. et al. Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy. Cardiovasc. Res. 100, 63–73 (2013). · DOI
  129. Kanninen, K. et al. Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 106, 16505–16510 (2009). · DOI · Paper page
  130. Joshi, G., Gan, K. A., Johnson, D. A. & Johnson, J. A. Increased Alzheimer’s disease-like pathology in the APP/ PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol. Aging 36, 664–679 (2015). · DOI · Paper page
  131. Rojo, A. I. et al. NRF2 deficiency replicates transcriptomic changes in Alzheimer’s patients and worsens APP and TAU pathology. Redox Biol. 13, 444–451 (2017). This paper presents the first mouse model combining amyloidopathy and tauopathy with the presence or absence of NRF2 and demonstrates that NRF2-deficient mice exhibit pathway alterations common to patients with AD. · DOI · Paper page
  132. Rojo, A. I. et al. Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy. Redox Biol. 18, 173–180 (2018). · DOI
  133. Lastres-Becker, I. et al. α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson’s disease. Hum. Mol. Genet. 21, 3173–3192 (2012). · DOI · Paper page
  134. Lastres-Becker, I. et al. Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s disease. Antioxid. Redox Signal 25, 61–77 (2016). This study provides a preclinical proof of concept indicating that DMF can be repurposed for the treatment of synucleinopathies, such as PD. · DOI · Paper page
  135. Gan, L., Vargas, M. R., Johnson, D. A. & Johnson, J. A. Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the α-synuclein mutant (A53T) mouse model. J. Neurosci. 32, 17775–17787 (2012). · DOI · Paper page
  136. Lastres-Becker, I. et al. Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis. Brain 137, 78–91 (2014). · DOI · Paper page
  137. Skibinski, G. et al. Nrf2 mitigates LRRK2- and alpha-synuclein-induced neurodegeneration by modulating proteostasis. Proc. Natl Acad. Sci. USA 114, 1165–1170 (2017). · DOI
  138. Clark, L. N. et al. Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology 67, 1786–1791 (2006). · DOI · Paper page
  139. Chen, P. C. et al. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: critical role for the astrocyte. Proc. Natl Acad. Sci. USA 106, 2933–2938 (2009). · DOI · Paper page
  140. Vargas, M. R., Johnson, D. A., Sirkis, D. W., Messing, A. & Johnson, J. A. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28, 13574–13581 (2008). · DOI · Paper page
  141. Innamorato, N. G., Lastres-Becker, I. & Cuadrado, A. Role of microglial redox balance in modulation of neuroinflammation. Curr. Opin. Neurol. 22, 308–314 (2009). · DOI
  142. Rojo, A. I. et al. Redox control of microglial function: molecular mechanisms and functional significance. Antioxid. Redox Signal 21, 1766–1801 (2014). · DOI · Paper page
  143. Rojo, A. I. et al. Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia 58, 588–598 (2010). · DOI · Paper page
  144. van Muiswinkel, F. L. et al. Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol. Aging 25, 1253–1262 (2004). · DOI
  145. Cuadrado, A., Moreno-Murciano, P. & Pedraza-Chaverri, J. The transcription factor Nrf2 as a new therapeutic target in Parkinson’s disease. Expert Opin. Ther. Targets 13, 319–329 (2009). · DOI
  146. Bergstrom, P. et al. Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 130–137 (2014). · DOI
  147. LoGerfo, A. et al. Lack of association between nuclear factor erythroid-derived 2-like 2 promoter gene polymorphisms and oxidative stress biomarkers in amyotrophic lateral sclerosis patients. Oxid Med. Cell Longev. 2014, 432626 (2014). · DOI
  148. von Otter, M. et al. Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson’s disease - a multicenter study. BMC Med. Genet. 15, 131 (2014). · DOI
  149. Chen, Y. C., Wu, Y. R., Wu, Y. C., Lee-Chen, G. J. & Chen, C. M. Genetic analysis of NFE2L2 promoter variation in Taiwanese Parkinson’s disease. Parkinsonism Relat. Disord. 19, 247–250 (2013). · DOI
  150. Paupe, V. et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLOS ONE 4, e4253 (2009). · DOI · Paper page
  151. D’Oria, V. et al. Frataxin deficiency leads to reduced expression and impaired translocation of NF-E2-related factor (Nrf2) in cultured motor neurons. Int. J. Mol. Sci. 14, 7853–7865 (2013). · DOI
  152. Shan, Y. et al. Frataxin deficiency leads to defects in expression of antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich’s ataxia YG8R mouse model. Antioxid. Redox Signal 19, 1481–1493 (2013). · DOI · Paper page
  153. Quinti, L. et al. SIRT2- and NRF2-targeting thiazole-containing compound with therapeutic activity in Huntington’s disease models. Cell Chem. Biol. 23, 849–861 (2016). · DOI
  154. Ellrichmann, G. et al. Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington’s disease. PLOS ONE 6, e16172 (2011). · DOI
  155. Stack, C. et al. Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington’s disease. Free Radic. Biol. Med. 49, 147–158 (2010). · DOI · Paper page
  156. Abeti, R. et al. Targeting lipid peroxidation and mitochondrial imbalance in Friedreich’s ataxia. Pharmacol. Res. 99, 344–350 (2015). · DOI
  157. Abeti, R., Baccaro, A., Esteras, N. & Giunti, P. Novel Nrf2-inducer prevents mitochondrial defects and oxidative stress in Friedreich’s ataxia models. Front. Cell Neurosci. 12, 188 (2018). · DOI
  158. Kalra, S. et al. Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): implications for protection against UV radiation during thiopurine therapy. Cancer Prev. Res. (Phila) 5, 973–981 (2012). · DOI
  159. Yang, L. et al. Reduced formation of depurinating estrogen-DNA adducts by sulforaphane or KEAP1 disruption in human mammary epithelial MCF-10A cells. Carcinogenesis 34, 2587–2592 (2013). · DOI
  160. DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015). · DOI · Paper page
  161. Sayin, V. I. et al. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife 6, e28083 (2017). This article describes the mechanism by which activation of NRF2 promotes KRAS-driven lung carcinogenesis and results in dependence on glutaminolysis, which can be therapeutically exploited. · DOI · Paper page
  162. Taguchi, K. et al. Genetic analysis of cytoprotective functions supported by graded expression of Keap1. Mol. Cell. Biol. 30, 3016–3026 (2010). · DOI · Paper page
  163. Chartoumpekis, D. V. et al. Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice. JCI Insight 3, 97735 (2018). · DOI
  164. Knatko, E. V. et al. Whole-exome sequencing validates a preclinical mouse model for the prevention and treatment of cutaneous squamous cell carcinoma. Cancer Prev. Res. (Phila) 10, 67–75 (2017). · DOI
  165. Knatko, E. V., Higgins, M., Fahey, J. W. & Dinkova-Kostova, A. T. Loss of Nrf2 abrogates the protective effect of Keap1 downregulation in a preclinical model of cutaneous squamous cell carcinoma. Sci. Rep. 6, 25804 (2016). · DOI
  166. Satoh, H. et al. NRF2 intensifies host defense systems to prevent lung carcinogenesis, but after tumor initiation accelerates malignant cell growth. Cancer Res. 76, 3088–3096 (2016). · DOI
  167. Satoh, H., Moriguchi, T., Takai, J., Ebina, M. & Yamamoto, M. Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 73, 4158–4168 (2013). · DOI · Paper page
  168. Kensler, T. W. & Wakabayashi, N. Nrf2: friend or foe for chemoprevention? Carcinogenesis 31, 90–99 (2010). · DOI · Paper page
  169. Spencer, S. R., Wilczak, C. A. & Talalay, P. Induction of glutathione transferases and NAD(P)H:quinone reductase by fumaric acid derivatives in rodent cells and tissues. Cancer Res. 50, 7871–7875 (1990).
  170. Fox, R. J. et al. Efficacy and tolerability of delayed-release dimethyl fumarate in Black, Hispanic, and Asian patients with relapsing-remitting multiple sclerosis: post Hoc integrated analysis of DEFINE and CONFIRM. Neurol. Ther. 6, 175–187 (2017). · doi:10.1007/s40120-017-0077-5
  171. Fernandez, O. et al. Efficacy and safety of delayed-release dimethyl fumarate for relapsing-remitting multiple sclerosis in prior interferon users: an integrated analysis of DEFINE and CONFIRM. Clin. Ther. 39, 1671–1679 (2017). · DOI
  172. Chen, H. et al. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE. J. Clin. Invest. 124, 2188–2192 (2014). · DOI · Paper page
  173. Zhang, Y., Talalay, P., Cho, C. G. & Posner, G. H. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc. Natl Acad. Sci. USA 89, 2399–2403 (1992). This article presents the first study describing the identification of SFN as a highly potent naturally occurring inducer of cytoprotective enzymes. · DOI · Paper page
  174. Singh, K. et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc. Natl Acad. Sci. USA 111, 15550–15555 (2014). · DOI · Paper page
  175. Fahey, J. W., Zhang, Y. & Talalay, P. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc. Natl Acad. Sci. USA 94, 10367–10372 (1997). · DOI · Paper page
  176. Shapiro, T. A., Fahey, J. W., Wade, K. L., Stephenson, K. K. & Talalay, P. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol. Biomarkers Prev. 7, 1091–1100 (1998).
  177. Fahey, J. W. et al. Protection of humans by plant glucosinolates: efficiency of conversion of glucosinolates to isothiocyanates by the gastrointestinal microflora. Cancer Prev. Res. (Phila) 5, 603–611 (2012). · DOI · Paper page
  178. Cipolla, B. G. et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer Prev. Res. (Phila) 8, 712–719 (2015). · DOI
  179. Fahey, J. W. et al. Stabilized sulforaphane for clinical use: phytochemical delivery efficiency. Mol. Nutr. Food Res. 61, 1600766 (2017). · DOI
  180. Bent, S. et al. Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Mol. Autism 9, 35 (2018). · DOI
  181. Sporn, M. B. et al. New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J. Nat. Prod. 74, 537–545 (2011). · DOI · Paper page
  182. Dinkova-Kostova, A. T. et al. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc. Natl Acad. Sci. USA 102, 4584–4589 (2005). This article presents one of the earliest studies that identified the cyanoenone triterpenoids as extremely potent NRF2 activators. · DOI · Paper page
  183. Shekh-Ahmad, T. et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain 141, 1390–1403 (2018). · DOI
  184. Ruiz, S., Pergola, P. E., Zager, R. A. & Vaziri, N. D. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 83, 1029–1041 (2013). · DOI · Paper page
  185. Ding, Y. et al. The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells. Kidney Int. 83, 845–854 (2013). · DOI
  186. Yamaguchi, J., Tanaka, T. & Nangaku, M. Recent advances in understanding of chronic kidney disease. F1000Res https://doi.org/10.12688/f1000research.6970.1 (2015). · DOI
  187. Sutendra, G. & Michelakis, E. D. The metabolic basis of pulmonary arterial hypertension. Cell Metab. 19, 558–573 (2014). · DOI · Paper page
  188. Chung, L. et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res. (Hoboken) 66, 489–495 (2014). · doi:10.1002/acr.22121
  189. Kearney, M., Orrell, R. W., Fahey, M. & Pandolfo, M. Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst. Rev. 4, CD007791 (2012).
  190. Freeman, B. A., O’Donnell, V. B. & Schopfer, F. J. The discovery of nitro-fatty acids as products of metabolic and inflammatory reactions and mediators of adaptive cell signaling. Nitric Oxide 77, 106–111 (2018). · DOI
  191. Baker, L. M. et al. Nitro-fatty acid reaction with glutathione and cysteine. Kinetic analysis of thiol alkylation by a Michael addition reaction. J. Biol. Chem. 282, 31085–31093 (2007). · DOI · Paper page
  192. Kansanen, E. et al. Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism. J. Biol. Chem. 286, 14019–14027 (2011). · DOI · Paper page
  193. Deen, A. J. et al. Regulation of stress signaling pathways by nitro-fatty acids. Nitric Oxide 78, 170–175 (2018). · DOI
  194. Rudolph, V. et al. Nitro-fatty acid metabolome: saturation, desaturation, β-oxidation, and protein adduction. J. Biol. Chem. 284, 1461–1473 (2009). · DOI
  195. Schopfer, F. J., Vitturi, D. A., Jorkasky, D. K. & Freeman, B. A. Nitro-fatty acids: new drug candidates for chronic inflammatory and fibrotic diseases. Nitric Oxide 79, 31–37 (2018). · DOI
  196. Rodriguez-Duarte, J. et al. Electrophilic nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses. Sci. Rep. 8, 12784 (2018). · DOI
  197. Hirotsu, Y., Katsuoka, F., Itoh, K. & Yamamoto, M. Nrf2 degron-fused reporter system: a new tool for specific evaluation of Nrf2 inducers. Genes Cells 16, 406–415 (2011). · DOI
  198. Higashi, C. et al. The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. Eur. J. Pharmacol. 802, 76–84 (2017). · DOI
  199. Schmoll, D., Engel, C. K. & Glombik, H. The Keap1-Nrf2 protein-protein interaction: a suitable target for small molecules. Drug Discov. Today Technol. 24, 11–17 (2017). · DOI
  200. Pallesen, J. S., Tran, K. T. & Bach, A. Non-covalent small-molecule Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) inhibitors and their potential for targeting central nervous system diseases. J. Med. Chem. 61, 8088–8103 (2018). · DOI

200 of 276 shown

Cited by

See all 1,438

Metadata

Authors
Cuadrado, A., Rojo, A. I., Wells, G., Hayes, J. D., Cousin, S. P., Rumsey, W. L., Attucks, O. C., Franklin, S., Levonen, A.-L., Kensler, T. W., & Dinkova-Kostova, A. T.
Venue
Nature Reviews Drug Discovery
Published
2019-01-04
Volume
18
Issue
4
Pages
295-317
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
OpenAlex
W2907855283
Cited by
1,438
References
51
FWCI
10.70
Type
journal article
Language
en
Open access
green
Licence
www.springer.com/tdm (tdm)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. https://app.cochat.ai/papers/10.1038/s41573-018-0008-x
The paper
Cuadrado, A., Rojo, A. I., Wells, G., Hayes, J. D., Cousin, S. P., Rumsey, W. L., Attucks, O. C., Franklin, S., Levonen, A.-L., Kensler, T. W., & Dinkova-Kostova, A. T. (2019). Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature Reviews Drug Discovery. https://doi.org/10.1038/s41573-018-0008-x

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.