KEAP1/NRF2 as a druggable target
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by NFE2L2) is an inducible transcription factor that regulates the expression of a large network of genes encoding proteins with cytoprotective functions. NRF2 also has a role in the maintenance of mitochondrial and protein homeostasis, and its activation allows adaptation to numerous types of cellular stress. NRF2 is principally regulated at the protein stability level by three main ubiquitin ligase systems, of which the regulation by Kelch-like ECH-associated protein 1 (KEAP1), a substrate adaptor protein for Cul3/Rbx1-based ubiquitin ligase, is best understood. KEAP1 is a multi-functional protein and, in addition to being a substrate adaptor, it is a sensor for electrophiles and oxidants. Pharmacological inactivation of KEAP1 has protective effects in animal models of human disease, and KEAP1 is now widely recognized as a drug target, particularly for chronic diseases, where oxidative stress and inflammation underlie pathogenesis. Many compounds that target KEAP1 have been developed, including electrophiles that bind covalently to cysteine sensors in KEAP1, non-electrophilic protein-protein interaction inhibitors that bind to the Kelch domain of KEAP1, disrupting its interaction with NRF2, and most recently, heterobifunctional proteolysis-targeting chimeras (PROTACs) that promote the proteasomal degradation of KEAP1. The drug development of KEAP1-targeting compounds has led to the entry of two compounds, dimethyl fumarate (BG-12, Tecfidera®) and RTA-408 (omaveloxolone, SKYCLARYS®), in clinical practice. In 2013, dimethyl fumarate was licenced as the first oral first-line therapy for relapsing-remitting multiple sclerosis and is also used for the treatment of moderate-to-severe plaque psoriasis. In February 2023, omaveloxolone was approved by the United States Food and Drug Administration as the first and only drug for patients with Friedreich’s ataxia.
References
1. Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiol Rev. 2018;98:1169-1203.
2. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997;236:313-22.
3. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014;39:199-218.
4. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13:76-86.
5. Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006;21:689-700.
6. Fukutomi T, Takagi K, Mizushima T, Ohuchi N, Yamamoto M. Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol Cell Biol. 2014:34;832-46.
7. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex. J Biol Chem. 2006;281:24756-68.
8. Baird L, Dinkova-Kostova AT. Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells. Biochem Biophys Res Commun. 2013;433:58-65.
9. Baird L, Lleres D, Swift S, Dinkova-Kostova AT. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci U S A. 2013;110:15259-64.
10. Baird L, Swift S, Lleres D, Dinkova-Kostova AT. Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol Adv. 2014;32(6):1133-44.
11. Dikovskaya D, Appleton PL, Bento-Pereira C, Dinkova-Kostova AT. Measuring the Interaction of Transcription Factor Nrf2 with Its Negative Regulator Keap1 in Single Live Cells by an Improved FRET/FLIM Analysis. Chem Res Toxicol. 2019;32:500-512.
12. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, 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 U S A. 2002;99: 11908-13.
13. Dinkova-Kostova AT, Kostov RV, Canning P. Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants. Arch Biochem Biophys. 2017;617:84-93.
14. Dayalan Naidu S, Dinkova-Kostova AT. KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease. Open Biol. 2020;10(6):200105.
15. Horie Y, Suzuki T, Inoue J, Iso T, Wells G, Moore TW, et al. Molecular basis for the disruption of Keap1-Nrf2 interaction via Hinge & Latch mechanism. Commun Biol. 2021;4:576.
16. Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019;18:295-317.
17. Georgakopoulos N, Talapatra S, Dikovskaya D, Dayalan Naidu S, Higgins M, Gatliff J, et al. Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein-Protein Interaction Inhibitors with an Alternative Binding Mode. J Med Chem. 2022;65:7380-7398.
18. Gorgulla C, Boeszoermenyi A, Wang ZF, Fischer PD, Coote PW, Padmanabha Das KM, et al. An open-source drug discovery platform enables ultra-large virtual screens. Nature. 2020;580:663-668.
19. Lazzara PR, David BP, Ankireddy A, Richardson BG, Dye K, Ratia KM, et al. Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability. J Med Chem. 2020;63:6547-6560.
20. Dayalan Naidu S, Suzuki T, Dikovskaya D, Knatko EV, Higgins M, Sato M, et al. The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2. iScience. 2020;25:103703.
21. Bertrand HC, Schaap M, Baird L, Georgakopoulos ND, Fowkes A, Thiollier 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. 2015;58:7186-94.
22. Du G, Jiang J, Henning NJ, Safaee N, Koide E, Nowak RP, et al. Exploring the target scope of KEAP1 E3 ligase-based PROTACs. Cell Chem Biol. 2022;29:1470-1481.e31.
23. Chen H, Nguyen NH, Magtoto CM, Cobbold SA, Bidgood GM, Meza Guzman LG, et al. Design and characterization of a heterobifunctional degrader of KEAP1. Redox Biol. 2022;59:102552.
24. Davies TG, Wixted WE, Coyle JE, Griffiths-Jones C, Hearn K, McMenamin R, 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. 2016;59:3991-4006.
25. Shin JH, Lee KM, Shin J, Kang KD, Nho CW, Cho YS. Genetic risk score combining six genetic variants associated with the cellular NRF2 expression levels correlates with Type 2 diabetes in the human population. Genes Genomics. 2019;41:537-545.
26. Jia C, Wang R, Long T, Xu Y, Zhang Y, Peng R, et al. NRF2 Genetic Polymorphism Modifies the Association of Plasma Selenium Levels With Incident Coronary Heart Disease Among Individuals With Type 2 Diabetes. Diabetes. 2022;71:2009-2019.
27. Sarutipaiboon I, Settasatian N, Komanasin N, Kukongwiriyapan U, Sawanyawisuth K, Intharaphet P, et al. Association of Genetic Variations in NRF2, NQO1, HMOX1, and MT with Severity of Coronary Artery Disease and Related Risk Factors. Cardiovasc Toxicol. 2020;20:176-189.
28. Shimizu S, Mimura J, Hasegawa T, Shimizu E, Imoto S, Tsushima M, et al. Association of single nucleotide polymorphisms in the NRF2 promoter with vascular stiffness with aging. PLoS One. 2020;15:e0236834.
29. Hua CC, Chang LC, Tseng JC, Chu CM, Liu YC, Shieh WB. Functional haplotypes in the promoter region of transcription factor Nrf2 in chronic obstructive pulmonary disease. Dis Markers. 2010;28:185-93.
30. Sugitani A, Asai K, Watanabe T, Suzumura T, Kojima K, Kubo H, et al. A Polymorphism rs6726395 in Nrf2 Contributes to the Development of Emphysema-Associated Age in Smokers Without COPD. Lung. 2019;197:559-564.
31. Arisawa T, Tahara T, Nakamura M. [A genetic background of ulcer diseases induced by NSAID/aspirin]. Nihon Rinsho. 2010;68:2113-8. (in Japanese).
32. Ji G, Zhang M, Liu Q, Wu S, Wang Y, Chen G, et al. Functional Polymorphism in the NFE2L2 Gene Associated With Tuberculosis Susceptibility. Front Immunol. 2021;12:660384.
33. von Otter M, Landgren S, Nilsson S, Celojevic D, Bergstrom P, Hakansson A, et al. Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease. BMC Med Genet. 2010;11:36.
34. von Otter M, Bergstrom P, Quattrone A, De Marco EV, Annesi G, Soderkvist P, et al. Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease - a multicenter study. BMC Med Genet. 2014;15:131.
35. Chen YC, Wu YR, Wu YC, Lee-Chen GJ, Chen CM. Genetic analysis of NFE2L2 promoter variation in Taiwanese Parkinson's disease. Parkinsonism Relat Disord. 2013;19:247-50.
36. Gui Y, Zhang L, Lv W, Zhang W, Zhao J, Hu X. NFE2L2 variations reduce antioxidant response in patients with Parkinson disease. Oncotarget. 2016;7:10756-64.
37. Paupe V, Dassa EP, Goncalves S, Auchere F, Lonn M, Holmgren A, Rustin P. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS One. 2009;4:e4253.
38. Quinti L, Dayalan Naidu S, Trager U, Chen X, Kegel-Gleason K, Lleres D, et al. KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients. Proc Natl Acad Sci U S A. 2017;114:E4676-E4685.
39. Nadeem A, Ahmad SF, Al-Harbi NO, Al-Ayadhi LY, Alanazi MM, Alfardan AS, et al. Dysregulated Nrf2 signaling in response to di(2-ethylhexyl) phthalate in neutrophils of children with autism. Int Immunopharmacol. 2022;106:108619.
40. Dinkova-Kostova AT, Kostov RV, Kazantsev AG. The role of Nrf2 signaling in counteracting neurodegenerative diseases. Febs J. 2018;285:3576-3590.
41. Bell KF, Al-Mubarak B, Martel MA, McKay S, Wheelan N, Hasel P, et al. Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2. Nat Commun. 2015;6:7066.
42. Cuadrado A, Pajares M, Benito C, Jimenez-Villegas J, Escoll M, Fernandez-Gines R, et al. Can Activation of NRF2 Be a Strategy COVID-19? Trends Pharmacol Sci. 2020;41:598-610.
43. Olagnier D, Farahani E, Thyrsted J, Blay-Cadanet J, Herengt A, Idorn M, et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. 2020;11: 4938.
44. van der Horst D, Carter-Timofte ME, van Grevenynghe J, Laguette N, Dinkova-Kostova AT, Olagnier D. Regulation of innate immunity by Nrf2. Curr Opin Immunol. 2022;78:102247.
45. Ordonez AA, Bullen CK, Villabona-Rueda AF, Thompson EA, Turner ML, Merino VF, et al. Sulforaphane exhibits antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses in vitro and in mice. Commun Biol. 2022;5:242.
46. Sun Q, Ye F, Liang H, Liu H, Li C, Lu R, et al. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 2021;6:212.
47. Liby KT, Sporn MB. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev. 2012;64:972-1003.
48. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, et al. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci U S A. 2005;102:4584-9.
49. Dayalan Naidu S, Muramatsu A, Saito R, Asami S, Honda T, Hosoya T, et al. C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape. Scientific Rep. 2018;8:8037.
50. Shekh-Ahmad T, Eckel R, Dayalan Naidu S, Higgins M, Yamamoto M, Dinkova-Kostova AT, et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain. 2018;141:1390-1403.
51. Liby K, Yore MM, Roebuck BD, Baumgartner KJ, Honda T, Sundararajan C, et al. A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. Cancer Res. 2008;68:6727-33.
52. Dinkova-Kostova AT, Talalay P, Sharkey J, Zhang Y, Holtzclaw WD, Wang XJ, et al. An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1. J Biol Chem. 2010;285: 33747-55.
53. Kostov RV, Knatko EV, McLaughlin LA, Henderson CJ, Zheng S, Huang JT, 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. 2015;465:402-7.
54. Knatko EV, Ibbotson SH, Zhang Y, Higgins M, Fahey JW, Talalay P, et al. Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans. Cancer Prev Res (Phila). 2015;8:475-86.
55. Spencer SR, Wilczak CA, Talalay P. Induction of glutathione transferases and NAD(P)H:quinone reductase by fumaric acid derivatives in rodent cells and tissues. Cancer Res. 1990;50:7871-5.
56. Gopal S, Mikulskis A, Gold R, Fox RJ, Dawson KT, Amaravadi L. Evidence of activation of the Nrf2 pathway in multiple sclerosis patients treated with delayed-release dimethyl fumarate in the Phase 3 DEFINE and CONFIRM studies. Mult Scler. 2017;23:1875-1883.
57. Saito R, Suzuki T, Hiramoto K, Asami S, Naganuma E, Suda H, et al. Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response. Mol Cell Biol. 2015;36:271-84.
58. Qu L, Guo M, Zhang H, Chen X, Wei H, Jiang L, et al. Characterization of the modification of Kelch-like ECH-associated protein 1 by different fumarates. Biochem Biophys Res Commun. 2022;605:9-15.
59. Sauerland MB, Helm C, Lorentzen LG, Manandhar A, Ulven T, Gamon LF, Davies MJ. Identification of galectin-1 and other cellular targets of alpha,beta-unsaturated carbonyl compounds, including dimethylfumarate, by use of click-chemistry probes. Redox Biol. 2023;59:102560.
60. Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018;556:113-117.
61. Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci U S A. 1992;89:2399-403.
62. Traka MH, Saha S, Huseby S, Kopriva S, Walley PG, Barker GC, et al. Genetic regulation of glucoraphanin accumulation in Beneforte broccoli. New Phytol. 2013;198:1085-1095.
63. Armah CN, Traka MH, Dainty JR, Defernez M, Janssens A, Leung W, et al. A diet rich in high-glucoraphanin broccoli interacts with genotype to reduce discordance in plasma metabolite profiles by modulating mitochondrial function. Am J Clin Nutr. 2013;98:712-22.
64. Yagishita Y, Fahey JW, Dinkova-Kostova AT, Kensler TW. Broccoli or Sulforaphane: Is It the Source or Dose That Matters? Molecules. 2019;24(19):3593.
65. Liu H, Zimmerman AW, Singh K, Connors SL, Diggins E, Stephenson KK, et al. Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder. Sci Rep. 2020;10:5822.
66. Dinkova-Kostova AT, Fahey JW, Wade KL, Jenkins SN, Shapiro TA, Fuchs EJ, et al. Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts. Cancer Epidemiol Biomarkers Prev. 2007;16:847-51.
67. Zhang DD, 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. 2003;23:8137-51.
68. McMahon M, Lamont DJ, Beattie KA, Hayes JD. Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc Natl Acad Sci U S A. 2010;107:18838-43.
69. Wang JS, Shen X, He X, Zhu YR, Zhang BC, Wang JB, et al. Protective alterations in phase 1 and 2 metabolism of aflatoxin B1 by oltipraz in residents of Qidong, People's Republic of China. J Natl Cancer Inst. 1999;91:347-54.
70. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369:2492-503.
71. Chin MP, Wrolstad D, Bakris GL, Chertow GM, de Zeeuw D, Goldsberry A, et al. Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. J Card Fail. 2014;20:953-8.
72. Chertow GM, Appel GB, Andreoli S, Bangalore S, Block GA, Chapman AB, et al. Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome. Am J Nephrol. 2021;52:180-189.
73. Linker RA, Haghikia A. Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy. Ther Adv Chronic Dis. 2016;7:198-207.
74. Pellacani G, Bigi L, Parodi A, Burlando M, Lanna C, Campione E, et al. Efficacy and Safety of Dimethyl Fumarate in Patients with Moderate-to-Severe Plaque Psoriasis: DIMESKIN-2, a Multicentre Single-Arm Phase IIIb Study. J Clin Med. 2022;11(16):4778.
75. Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ, Mesaros C, et al. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol. 2019;6:15-26.
76. Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, et al. Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2021;89:212-225.
77. Lynch DR, Chin MP, Boesch S, Delatycki MB, Giunti P, Goldsberry A, et al. Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension. Mov Disord. 2023;38:313-320.
78. Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018;34(1):21-43.
79. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative Stress in Cancer. Cancer Cell. 2020;38:167-197.
80. DeBlasi JM, DeNicola GM. Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer. Cancers (Basel). 2020;12(10):3023.
81. Torrente L, DeNicola GM. Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges. Annu Rev Pharmacol Toxicol. 2022;62:279-300.
82. Okazaki K, Anzawa H, Liu Z, Ota N, Kitamura H, Onodera Y, et al. Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers. Nature Commun. 2020;11:5911.
83. Sayin VI, LeBoeuf SE, Singh SX, Davidson SM, Biancur D, Guzelhan BS, et al. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife. 2017;6:e28083.
84. Ghergurovich JM, Garcia-Canaveras JC, Wang J, Schmidt E, Zhang Z, TeSlaa T, et al. A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway. Nat Chem Biol. 2020;16:731-739.
85. Riess JW, Frankel P, Shackelford D, Dunphy M, Badawi RD, Nardo L, et al. Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design. Clin Lung Cancer. 2021;22: 67-70.
86. Srivastava R, Fernandez-Gines R, Encinar JA, Cuadrado A, Wells G. The current status and future prospects for therapeutic targeting of KEAP1-NRF2 and beta-TrCP-NRF2 interactions in cancer chemoresistance. Free Radic Biol Med. 2022;192:246-260.
87. Ji J, Ma S, Zhu Y, Zhao J, Tong Y, You Q, Jiang Z. ARE-PROTACs Enable Co-degradation of an Nrf2-MafG Heterodimer. J Med Chem. 2023. doi: 10.1021/acs.jmedchem.2c01909.
88. Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler TW, Yamamoto M. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun. 2006;339:79-88.
89. Palliyaguru DL, Chartoumpekis DV, Wakabayashi N, Skoko JJ, Yagishita Y, Singh SV, Kensler TW. Withaferin A induces Nrf2-dependent protection against liver injury: Role of Keap1-independent mechanisms. Free Radic Biol Med. 2016;101:116-128.
90. Noh JR, Kim YH, Hwang JH, Choi DH, Kim KS, Oh WK, Lee CH. Sulforaphane protects against acetaminophen-induced hepatotoxicity. Food Chem Toxicol. 2015;80:193-200.
91. Abdelrahman RS, Abdel-Rahman N. Dimethyl fumarate ameliorates acetaminophen-induced hepatic injury in mice dependent of Nrf-2/HO-1 pathway. Life Sci. 2019;217:251-260.
92. Reisman SA, Buckley DB, Tanaka Y, Klaassen CD. CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes. Toxicol Appl Pharmacol. 2009;236:109-14.
93. Kalra S, Zhang Y, Knatko EV, Finlayson S, Yamamoto M, Dinkova-Kostova AT. Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway. Cancer Prev Res (Phila). 2011;4(10):1665-74.
94. Winski SL, Hargreaves RH, Butler J, Ross D. A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent. Clin Cancer Res. 1998;4:3083-8.
95. Baird L, Suzuki T, Takahashi Y, Hishinuma E, Saigusa D, Yamamoto M. Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2. Mol Cell Biol. 2020;40(22):e00377-20.
96. Torrente L, Prieto-Farigua N, Falzone A, Elkins CM, Boothman DA, Haura EB, DeNicola GM. Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to beta-lapachone. Redox Biol. 2020;30:101440.
97. Mansouri A, Reiner Z, Ruscica M, Tedeschi-Reiner E, Radbakhsh S, Bagheri Ekta M, Sahebkar A. Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases. J Clin Med. 2022;11(5):1313.
98. Chartoumpekis D, Ziros PG, Psyrogiannis A, Kyriazopoulou V, Papavassiliou AG, Habeos IG. Simvastatin lowers reactive oxygen species level by Nrf2 activation via PI3K/Akt pathway. Biochem Biophys Res Commun. 2010;396:463-6.
99. Liu H, Talalay P. Relevance of anti-inflammatory and antioxidant activities of exemestane and synergism with sulforaphane for disease prevention. Proc Natl Acad Sci U S A. 2013;110:19065-70.
100.Eisenstein A, Hilliard BK, Pope SD, Zhang C, Taskar P, Waizman DA, et al. Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs. Immunity. 2022;55:1082-1095.e5.
101.Dinkova-Kostova AT, Copple IM. Advances and challenges in therapeutic targeting of NRF2. Trends Pharmacol Sci. 2023;44:137-149.
