Moi, P., Chan, K., Asunis, I., Cao, A. & Kan, Y. W. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc. Natl Acad. Sci. USA 91, 9926–9930 (1994). This article describes the identification of NRF2 as a member of the human CNC basic-region leucine zipper transcription factor family.
Itoh, K. et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313–322 (1997). This paper describes the identification of NRF2 as the transcription factor that mediates the expression of cytoprotective genes through AREs.
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).
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).
Itoh, K. et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76–86 (1999). This article describes the identification of KEAP1 as the main negative regulator of NRF2.
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).
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).
Kobayashi, A. et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol. 24, 7130–7139 (2004). Refs 6–8 describe that KEAP1 functions as a substrate adaptor protein for CUL3-dependent ubiquitylation of NRF2.
Cuadrado, A. et al. Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach. Pharmacol. Rev. 70, 348–383 (2018). This article presents the first attempt to address the role of NRF2 in human chronic disease from a systems medicine perspective and includes a map of disease mechanisms underlined by NRF2 alterations, the NRF2-diseasome and a connectivity map of NRF2 with other physically or functionally associated proteins, the NRF2-interactome.
Yamamoto, M., Kensler, T. W. & Motohashi, H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol. Rev. 98, 1169–1203 (2018).
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.
Rojo de la Vega, M., Chapman, E. & Zhang, D. D. NRF2 and the hallmarks of cancer. Cancer Cell 34, 21–43 (2018).
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).
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.
Takaya, K. et al. Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic. Biol. Med. 53, 817–827 (2012).
Saito, R. et al. Characterizations of three major cysteine sensors of Keap1 in stress response. Mol. Cell. Biol. 36, 271–284 (2015).
Sihvola, V. & Levonen, A. L. Keap1 as the redox sensor of the antioxidant response. Arch. Biochem. Biophys. 617, 94–100 (2017).
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).
Dinkova-Kostova, A. T. et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl Acad. Sci. USA 99, 11908–11913 (2002). This paper describes the finding that cysteine sensors in KEAP1 regulate NRF2-dependent gene expression.
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).
Crunkhorn, S. Deal watch: Abbott boosts investment in NRF2 activators for reducing oxidative stress. Nat. Rev. Drug Discov. 11, 96 (2012).
Sies, H., Berndt, C. & Jones, D. P. Oxidative stress. Annu. Rev. Biochem. 86, 715–748 (2017).
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.
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).
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).
Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012). This paper describes the role of NRF2 in regulating the pentose phosphate pathway in cancer cells and provides the basis to understand how NRF2 participates in the metabolic alterations of cancer cells.
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).
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).
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).
Sedlak, T. W. et al. Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc. Natl Acad. Sci. USA 106, 5171–5176 (2009).
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.
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).
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.
Jain, A. et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 285, 22576–22591 (2010).
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.
Lee, Y. et al. Keap1/Cullin3 modulates p62/SQSTM1 activity via UBA domain ubiquitination. Cell Rep. 19, 188–202 (2017).
Ichimura, Y. et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol. Cell 51, 618–631 (2013).
Taguchi, K. et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc. Natl Acad. Sci. USA 109, 13561–13566 (2012).
Pajares, M. et al. Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A. Autophagy 14, 1310–1322 (2018).
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.
Dayalan Naidu, S. et al. Transcription factors NRF2 and HSF1 have opposing functions in autophagy. Sci. Rep. 7, 11023 (2017).
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.
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).
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).
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).
Bolanos, J. P. Bioenergetics and redox adaptations of astrocytes to neuronal activity. J. Neurochem. 139 (Suppl. 2), 115–125 (2016).
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).
Thimmulappa, R. K. et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J. Clin. Invest. 116, 984–995 (2006). This paper presents one of the first studies showing the anti-inflammatory role of NRF2.
Braun, S. et al. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol. Cell. Biol. 22, 5492–5505 (2002).
Long, M. et al. An essential role of NRF2 in diabetic wound healing. Diabetes 65, 780–793 (2016).
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).
Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016). This study reports a novel mechanism of NRF2 in repressing the expression of pro-inflammatory genes.
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).
Innamorato, N. G. et al. The transcription factor Nrf2 is a therapeutic target against brain inflammation. J. Immunol. 181, 680–689 (2008).
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).
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).
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).
Lin, W. et al. Sulforaphane suppressed LPS-induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway. Biochem. Pharmacol. 76, 967–973 (2008).
Arisawa, T. et al. Nrf2 gene promoter polymorphism is associated with ulcerative colitis in a Japanese population. Hepatogastroenterology 55, 394–397 (2008).
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.
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).
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).
Kovac, S. et al. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim. Biophys. Acta 1850, 794–801 (2014).
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).
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).
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).
Lee, D. F. et al. KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol. Cell 36, 131–140 (2009).
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).
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).
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.
Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018). This article describes the mechanism by which an endogenous electrophile connects immunometabolism with upregulation of NRF2 and suppression of inflammation in macrophages.
Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF3 inflammatory axis. Nature 556, 501–504 (2018).
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.
Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018).
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.
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).
von Otter, M. et al. Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson’s disease. BMC Med. Genet. 11, 36 (2010).
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).
Ma, Q. Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 53, 401–426 (2013).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Rangasamy, T. et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J. Clin. Invest. 114, 1248–1259 (2004).
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).
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).
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).
Goven, D. et al. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax 63, 916–924 (2008).
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).
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).
Wise, R. A. et al. Lack of effect of oral sulforaphane administration on Nrf2 expression in COPD: a randomized, double-blind, placebo controlled trial. PLOS ONE 11, e0163716 (2016).
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).
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).
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).
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).
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).
Khor, T. O. et al. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res. 66, 11580–11584 (2006).
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.
Arisawa, T. et al. Nrf2 gene promoter polymorphism and gastric carcinogenesis. Hepatogastroenterology 55, 750–754 (2008).
Aleksunes, L. M. & Manautou, J. E. Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol. Pathol. 35, 459–473 (2007).
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).
Lamle, J. et al. Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134, 1159–1168 (2008).
Wakabayashi, N. et al. Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci. Signal 3, ra52 (2010).
Kim, J. H. et al. NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation. J. Clin. Invest. 124, 730–741 (2014).
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).
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).
Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).
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).
Uruno, A. et al. Nrf2-mediated regulation of skeletal muscle glycogen metabolism. Mol. Cell. Biol. 36, 1655–1672 (2016).
Uruno, A., Yagishita, Y. & Yamamoto, M. The Keap1-Nrf2 system and diabetes mellitus. Arch. Biochem. Biophys. 566, 76–84 (2015).
Jiang, T. et al. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59, 850–860 (2010).
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.
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).
Zheng, H. et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 60, 3055–3066 (2011).
Jimenez-Osorio, A. S. et al. Nrf2 and redox status in prediabetic and diabetic patients. Int. J. Mol. Sci. 15, 20290–20305 (2014).
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).
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).
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).
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).
Chowdhry, S. et al. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic. Biol. Med. 48, 357–371 (2010).
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).
Reccia, I. et al. Non-alcoholic fatty liver disease: a sign of systemic disease. Metabolism 72, 94–108 (2017).
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).
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).
Harrison, D., Griendling, K. K., Landmesser, U., Hornig, B. & Drexler, H. Role of oxidative stress in atherosclerosis. Am. J. Cardiol. 91, 7A–11A (2003).
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).
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.
Calvert, J. W. et al. Genetic and pharmacologic hydrogen sulfide therapy attenuates ischemia-induced heart failure in mice. Circulation 122, 11–19 (2010).
Li, J. et al. Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler. Thromb. Vasc. Biol. 29, 1843–1850 (2009).
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).
Ruotsalainen, A. K. et al. The absence of macrophage Nrf2 promotes early atherogenesis. Cardiovasc. Res. 98, 107–115 (2013).
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).
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).
Freigang, S. et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur. J. Immunol. 41, 2040–2051 (2011).
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).
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).
Xie, L. et al. Hydrogen sulfide induces Keap1 S-sulfhydration and suppresses diabetes-accelerated atherosclerosis via Nrf2 activation. Diabetes 65, 3171–3184 (2016).
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).
Harvey, P. A. & Leinwand, L. A. The cell biology of disease: cellular mechanisms of cardiomyopathy. J. Cell Biol. 194, 355–365 (2011).
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).
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).
Kannan, S. et al. Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy. Cardiovasc. Res. 100, 63–73 (2013).
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).
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).
Jo, C. et al. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat. Commun. 5, 3496 (2014).
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.
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).
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).
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.
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).
Lastres-Becker, I. et al. Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis. Brain 137, 78–91 (2014).
Skibinski, G. et al. Nrf2 mitigates LRRK2- and alpha-synuclein-induced neurodegeneration by modulating proteostasis. Proc. Natl Acad. Sci. USA 114, 1165–1170 (2017).
Clark, L. N. et al. Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology 67, 1786–1791 (2006).
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).
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).
Innamorato, N. G., Lastres-Becker, I. & Cuadrado, A. Role of microglial redox balance in modulation of neuroinflammation. Curr. Opin. Neurol. 22, 308–314 (2009).
Rojo, A. I. et al. Redox control of microglial function: molecular mechanisms and functional significance. Antioxid. Redox Signal 21, 1766–1801 (2014).
Rojo, A. I. et al. Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia 58, 588–598 (2010).
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).
Schipper, H. M., Song, W., Zukor, H., Hascalovici, J. R. & Zeligman, D. Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement. J. Neurochem. 110, 469–485 (2009).
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).
Bergstrom, P. et al. Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 130–137 (2014).
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).
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).
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).
Paupe, V. et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLOS ONE 4, e4253 (2009).
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).
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).
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).
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).
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).
Abeti, R. et al. Targeting lipid peroxidation and mitochondrial imbalance in Friedreich’s ataxia. Pharmacol. Res. 99, 344–350 (2015).
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).
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).
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).
DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).
DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).
Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23, 1362–1368 (2017).
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.
Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385 (2018).
Kerins, M. J. & Ooi, A. A catalogue of somatic NRF2 gain-of-function mutations in cancer. Sci. Rep. 8, 12846 (2018).
Bar-Peled, L. et al. Chemical proteomics identifies druggable vulnerabilities in a genetically defined cancer. Cell 171, 696–709 (2017).
Sanchez-Vega, F. et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 173, 321–337 (2018).
Taguchi, K. et al. Genetic analysis of cytoprotective functions supported by graded expression of Keap1. Mol. Cell. Biol. 30, 3016–3026 (2010).
Best, S. A. et al. Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment. Cell Metab. 27, 935–943 (2018). This study demonstrates that mice with constitutive NRF2 activation do not develop spontaneous tumours, but the combined activation of the PI3K pathway and NRF2 promotes the development of lung cancer characterized by an immunosuppressive microenvironment, which can be therapeutically exploited by use of immune checkpoint inhibitors.
DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011). This paper describes how NRF2 is activated by oncogenes to promote ROS detoxification.
Chartoumpekis, D. V. et al. Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice. JCI Insight 3, 97735 (2018).
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).
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).
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).
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).
Kensler, T. W. & Wakabayashi, N. Nrf2: friend or foe for chemoprevention? Carcinogenesis 31, 90–99 (2010).
Linker, R. A. et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134, 678–692 (2011).
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).
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).
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).
Chen, H. et al. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE. J. Clin. Invest. 124, 2188–2192 (2014).
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.
Zhang, D. D. & Hannink, M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol. Cell. Biol. 23, 8137–8151 (2003). This paper presents the first study that identified C151 as a major sensor cysteine in KEAP1.
Holmstrom, K. M., Kostov, R. V. & Dinkova-Kostova, A. T. The multifaceted role of Nrf2 in mitochondrial function. Curr. Opin. Toxicol. 1, 80–91 (2016).
Singh, K. et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc. Natl Acad. Sci. USA 111, 15550–15555 (2014).
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).
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).
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).
Cipolla, B. G. et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer Prev. Res. (Phila) 8, 712–719 (2015).
Fahey, J. W. et al. Stabilized sulforaphane for clinical use: phytochemical delivery efficiency. Mol. Nutr. Food Res. 61, 1600766 (2017).
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).
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).
Honda, T. et al. Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages. J. Med. Chem. 43, 4233–4246 (2000).
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.
Shekh-Ahmad, T. et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain 141, 1390–1403 (2018).
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).
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).
Yamaguchi, J., Tanaka, T. & Nangaku, M. Recent advances in understanding of chronic kidney disease. F1000Res https://doi.org/10.12688/f1000research.6970.1 (2015).
Sutendra, G. & Michelakis, E. D. The metabolic basis of pulmonary arterial hypertension. Cell Metab. 19, 558–573 (2014).
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).
Kearney, M., Orrell, R. W., Fahey, M. & Pandolfo, M. Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst. Rev. 4, CD007791 (2012).
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).
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).
Batthyany, C. et al. Reversible post-translational modification of proteins by nitrated fatty acids in vivo. J. Biol. Chem. 281, 20450–20463 (2006).
Kansanen, E. et al. Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism. J. Biol. Chem. 286, 14019–14027 (2011).
Deen, A. J. et al. Regulation of stress signaling pathways by nitro-fatty acids. Nitric Oxide 78, 170–175 (2018).
Rudolph, V. et al. Nitro-fatty acid metabolome: saturation, desaturation, β-oxidation, and protein adduction. J. Biol. Chem. 284, 1461–1473 (2009).
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).
Rodriguez-Duarte, J. et al. Electrophilic nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses. Sci. Rep. 8, 12784 (2018).
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).
Higashi, C. et al. The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. Eur. J. Pharmacol. 802, 76–84 (2017).
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).
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).
Georgakopoulos, N. D. et al. Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy. Sci. Rep. 7, 10303 (2017).
Beamer, L. J., Li, X., Bottoms, C. A. & Hannink, M. Conserved solvent and side-chain interactions in the 1.35 Angstrom structure of the Kelch domain of Keap1. Acta Crystallogr. D Biol. Crystallogr. 61, 1335–1342 (2005).
Padmanabhan, B. et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol. Cell 21, 689–700 (2006).
Tong, K. I. et al. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol. Cell. Biol. 27, 7511–7521 (2007).
Marcotte, D. et al. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg. Med. Chem. 21, 4011–4019 (2013). This paper presents one of the earliest studies describing a small molecule that inhibits the KEAP1–NRF2 PPI.
Jiang, Z. Y. et al. Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J. Med. Chem. 57, 2736–2745 (2014).
Davies, T. G. et al. Monoacidic inhibitors of the Kelch-like ECH-associated protein 1: nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein-protein interaction with high cell potency identified by fragment-based discovery. J. Med. Chem. 59, 3991–4006 (2016).
Hu, L. et al. Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg. Med. Chem. Lett. 23, 3039–3043 (2013). This article presents one of the earliest studies describing a small molecule that inhibits the KEAP1–NRF2 PPI.
Jnoff, E. et al. Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex. ChemMedChem 9, 699–705 (2014).
Satoh, M. et al. Multiple binding modes of a small molecule to human Keap1 revealed by X-ray crystallography and molecular dynamics simulation. FEBS Open Bio. 5, 557–570 (2015).
Bertrand, H. C. et al. Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 Protein-protein interaction. J. Med. Chem. 58, 7186–7194 (2015).
Jiang, Z. Y. et al. Structure-activity and structure-property relationship and exploratory in vivo evaluation of the nanomolar Keap1-Nrf2 protein-protein interaction inhibitor. J. Med. Chem. 58, 6410–6421 (2015).
Lu, M. C. et al. An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci. Rep. 6, 26585 (2016).
Shimozono, R. et al. Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model. Mol. Pharmacol. 84, 62–70 (2013).
Yu, S. et al. Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP mice. PLOS ONE 5, e8579 (2010).
Alam, M. M. et al. Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2. J. Biol. Chem. 292, 7519–7530 (2017).
Malloy, M. T. et al. Trafficking of the transcription factor Nrf2 to promyelocytic leukemia-nuclear bodies: implications for degradation of NRF2 in the nucleus. J. Biol. Chem. 288, 14569–14583 (2013).
Sun, Z., Chin, Y. E. & Zhang, D. D. Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response. Mol. Cell. Biol. 29, 2658–2672 (2009).
Rada, P. et al. SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol. Cell. Biol. 31, 1121–1133 (2011). This paper presents one of the earliest studies that describes the regulation of NRF2 by GSK3–β-TrCP-mediated degradation.
Rada, P. et al. Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis. Mol. Cell. Biol. 32, 3486–3499 (2012).
Chowdhry, S. et al. Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32, 3765–3781 (2013).
Wu, T. et al. Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev. 28, 708–722 (2014).
Tebay, L. E. et al. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic. Biol. Med. 88, 108–146 (2015).
Katsuoka, F. & Yamamoto, M. Small Maf proteins (MafF, MafG, MafK): history, structure and function. Gene 586, 197–205 (2016).
Attucks, O. C. et al. Induction of heme oxygenase I (HMOX1) by HPP-4382: a novel modulator of Bach1 activity. PLOS ONE 9, e101044 (2014).
Riedl, M. A., Saxon, A. & Diaz-Sanchez, D. Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway. Clin. Immunol. 130, 244–251 (2009).
Bauman, J. E. et al. Prevention of carcinogen-induced oral cancer by sulforaphane. Cancer Prev. Res. (Phila) 9, 547–557 (2016).
Hammer, A. et al. The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis. Ann. Clin. Transl Neurol. 5, 668–676 (2018).
Egner, P. A. et al. Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage: results of a randomized clinical trial in China. Cancer Prev. Res. (Phila) 7, 813–823 (2014). This study demonstrated that broccoli sprout beverages can be used as frugal medicine to accelerate the detoxification of airborne pollutants in humans.
Kensler, T. W. et al. Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China. Carcinogenesis 33, 101–107 (2012).
Kostov, R. V. et al. Pharmacokinetics and pharmacodynamics of orally administered acetylenic tricyclic bis(cyanoenone), a highly potent Nrf2 activator with a reversible covalent mode of action. Biochem. Biophys. Res. Commun. 465, 402–407 (2015).
Jusko, W. J. Moving from basic toward systems pharmacodynamic models. J. Pharm. Sci. 102, 2930–2940 (2013).
Dayneka, N. L., Garg, V. & Jusko, W. J. Comparison of four basic models of indirect pharmacodynamic responses. J. Pharmacokinet. Biopharm. 21, 457–478 (1993).
Eggler, A. L., Small, E., Hannink, M. & Mesecar, A. D. Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem. J. 422, 171–180 (2009).
Cleasby, A. et al. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLOS ONE 9, e98896 (2014). This study reports the crystal structure of the BTB domain of KEAP1 in complex with a cyanoenone triterpenoid.
Rachakonda, G. et al. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem. Res. Toxicol. 21, 705–710 (2008).
Couch, R. D. et al. Studies on the reactivity of CDDO, a promising new chemopreventive and chemotherapeutic agent: implications for a molecular mechanism of action. Bioorg. Med. Chem. Lett. 15, 2215–2219 (2005).
Zheng, S. et al. Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents. J. Med. Chem. 55, 4837–4846 (2012).
Bradshaw, J. M. et al. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat. Chem. Biol. 11, 525–531 (2015).
Kobayashi, M. et al. The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol. Cell. Biol. 29, 493–502 (2009).
Dayalan Naidu, S. et al. C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape. Sci. Rep. 8, 8037 (2018).
Hayes, J. D. & Dinkova-Kostova, A. T. Oncogene-stimulated congestion at the KEAP1 stress signaling hub allows bypass of NRF2 and induction of NRF2-target genes that promote tumor survival. Cancer Cell 32, 539–541 (2017).
van der Worp, H. B. et al. Can animal models of disease reliably inform human studies? PLOS Med. 7, e1000245 (2010).
Suh, J. H. et al. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc. Natl Acad. Sci. USA 101, 3381–3386 (2004).
Corenblum, M. J. et al. Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period. Aging Cell 15, 725–736 (2016).
Tarantini, S. et al. Nrf2 deficiency exacerbates obesity-induced oxidative stress, neurovascular dysfunction, blood-brain barrier disruption, neuroinflammation, amyloidogenic gene expression, and cognitive decline in mice, mimicking the aging phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 73, 853–863 (2018).
Yates, M. S. et al. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 30, 1024–1031 (2009). This paper presents one of the earliest studies showing that NRF2 regulates genes involved in lipid metabolism.
Probst, B. L., McCauley, L., Trevino, I., Wigley, W. C. & Ferguson, D. A. Cancer cell growth is differentially affected by constitutive activation of NRF2 by KEAP1 deletion and pharmacological activation of NRF2 by the synthetic triterpenoid, RTA 405. PLOS ONE 10, e0135257 (2015).
Pakpoor, J. et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol. Neuroimmunol. Neuroinflamm. 2, e158 (2015).
Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018).
Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015).
Ki, S. H., Cho, I. J., Choi, D. W. & Kim, S. G. Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression. Mol. Cell. Biol. 25, 4150–4165 (2005).
Wang, X. J., Hayes, J. D., Henderson, C. J. & Wolf, C. R. Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc. Natl Acad. Sci. USA 104, 19589–19594 (2007). This article presents one of the first studies to identify an NRF2 inhibitor.
Wang, H. et al. RXRalpha inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res. 73, 3097–3108 (2013).
Ren, D. et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc. Natl Acad. Sci. USA 108, 1433–1438 (2011).
Vartanian, S. et al. Application of mass spectrometry profiling to establish brusatol as an inhibitor of global protein synthesis. Mol. Cell Proteom. 15, 1220–1231 (2016).
Harder, B. et al. Brusatol overcomes chemoresistance through inhibition of protein translation. Mol. Carcinog. 56, 1493–1500 (2017).
Tsuchida, K. et al. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. Free Radic. Biol. Med. 103, 236–247 (2017).
Tang, X. et al. Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic. Biol. Med. 50, 1599–1609 (2011).
Zuo, Q. et al. The dietary flavone luteolin epigenetically activates the Nrf2 pathway and blocks cell transformation in human colorectal cancer HCT116 cells. J. Cell Biochem. 119, 9573–9582 (2018).
Ashaari, Z. et al. The flavone luteolin improves central nervous system disorders by different mechanisms: a review. J. Mol. Neurosci. 65, 491–506 (2018).
Zhong, Y. et al. Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response. Mol. Carcinog. 52, 824–834 (2013).
Khan, N. M. et al. Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human osteoarthritis chondrocytes. Free Radic. Biol. Med. 106, 288–301 (2017).
Boettler, U. et al. Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression. J. Nutr. Biochem. 22, 426–440 (2011).
Arlt, A. et al. Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 32, 4825–4835 (2013).
Singh, A. et al. Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem. Biol. 11, 3214–3225 (2016).
Manna, A. et al. The variable chemotherapeutic response of Malabaricone-A in leukemic and solid tumor cell lines depends on the degree of redox imbalance. Phytomedicine 22, 713–723 (2015).
Marin-Kuan, M. et al. A toxicogenomics approach to identify new plausible epigenetic mechanisms of ochratoxin a carcinogenicity in rat. Toxicol. Sci. 89, 120–134 (2006).
Bollong, M. J. et al. A small molecule inhibits deregulated NRF2 transcriptional activity in cancer. ACS Chem. Biol. 10, 2193–2198 (2015).
Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).
Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).
Bagger, F. O. et al. BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis. Nucleic Acids Res. 44, D917–D924 (2016).
Mrowietz, U., Christophers, E. & Altmeyer, P. Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German multicentre study. Br. J. Dermatol. 138, 456–460 (1998).
Reilly, J. F. et al. CAT-4001 improves mitochondrial function in a Friedreich’s ataxia model. catabasis https://www.catabasis.com/CATB-2017-IARC-Poster-Reilly.pdf (2017).
Nakagami, Y. et al. Novel Nrf2 activators from microbial transformation products inhibit blood-retinal barrier permeability in rabbits. Br. J. Pharmacol. 172, 1237–1249 (2015).
Swanson, H. I. & Perdew, G. H. Half-life of aryl hydrocarbon receptor in Hepa 1 cells: evidence for ligand-dependent alterations in cytosolic receptor levels. Arch. Biochem. Biophys. 302, 167–174 (1993).
Sandoval, P. C. et al. Proteome-wide measurement of protein half-lives and translation rates in vasopressin-sensitive collecting duct cells. J. Am. Soc. Nephrol. 24, 1793–1805 (2013).
Emi, Y., Omura, S., Ikushiro, S. & Iyanagi, T. Accelerated degradation of mislocalized UDP-glucuronosyltransferase family 1 (UGT1) proteins in Gunn rat hepatocytes. Arch. Biochem. Biophys. 405, 163–169 (2002).
Fukuda, Y. et al. Conserved intramolecular disulfide bond is critical to trafficking and fate of ATP-binding cassette (ABC) transporters ABCB6 and sulfonylurea receptor 1 (SUR1)/ABCC8. J. Biol. Chem. 286, 8481–8492 (2011).
Schwanhausser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
Kato, H., Sakaki, K. & Mihara, K. Ubiquitin-proteasome-dependent degradation of mammalian ER stearoyl-CoA desaturase. J. Cell Sci. 119, 2342–2353 (2006).
Srivastava, K. K., Cable, E. E., Donohue, S. E. & Bonkovsky, H. L. Molecular basis for heme-dependent induction of heme oxygenase in primary cultures of chick embryo hepatocytes. Demonstration of acquired refractoriness to heme. Eur. J. Biochem. 213, 909–917 (1993).
Ding, B., Gibbs, P. E., Brookes, P. S. & Maines, M. D. The coordinated increased expression of biliverdin reductase and heme oxygenase-2 promotes cardiomyocyte survival: a reductase-based peptide counters beta-adrenergic receptor ligand-mediated cardiac dysfunction. FASEB J. 25, 301–313 (2011).
Crooks, D. R., Ghosh, M. C., Haller, R. G., Tong, W. H. & Rouault, T. A. Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood 115, 860–869 (2010).
Katoh, Y. et al. Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch. Biochem. Biophys. 433, 342–350 (2005).
McMahon, M., Thomas, N., Itoh, K., Yamamoto, M. & Hayes, J. D. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J. Biol. Chem. 279, 31556–31567 (2004).
Massey, A. C., Follenzi, A., Kiffin, R., Zhang, C. & Cuervo, A. M. Early cellular changes after blockage of chaperone-mediated autophagy. Autophagy 4, 442–456 (2008).
Bjorkoy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).
Ferrington, D. A. & Gregerson, D. S. Immunoproteasomes: structure, function, and antigen presentation. Prog. Mol. Biol. Transl Sci. 109, 75–112 (2012).