Nuclear factor (erythroid-derived 2)-like 2
Symbols NFE2L2; NRF2
External IDs OMIM600492 MGI108420 HomoloGene2412 GeneCards: NFE2L2 Gene
RNA expression pattern
PBB GE NFE2L2 201146 at tn.png
More reference expression data
Species Human Mouse
Entrez 4780 18024
Ensembl ENSG00000116044 ENSMUSG00000015839
UniProt Q16236 Q05DU7
RefSeq (mRNA) NM_001145412.1 NM_010902.3
RefSeq (protein) NP_001138884.1 NP_035032.1
Location (UCSC) Chr 2:
178.09 – 178.26 Mb
Chr 2:
75.51 – 75.54 Mb
PubMed search [1] [2]

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene.[1] NFE2L2 induces the expression of various genes including those that encode for several antioxidant enzymes, and it may play a physiological role in the regulation of oxidative stress. Investigational drugs that target NFE2L2 are of interest as potential therapeutic interventions for oxidative-stress related pathologies.



NFE2, NFE2L1, and NFE2L2 (this protein) comprise a family of human genes encoding basic leucine zipper (bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other.[2][3]

Under normal or unstressed conditions, Nrf2 is tethered in the cytoplasm by another protein called Kelch like-ECH-associated protein 1 (Keap1).[4] Keap1 acts as a substrate adaptor protein for Cullin 3-based ubiquitination, which results in the proteasomal degradation of Nrf2, and under normal conditions Nrf2 has a half-life of only 20 minutes.[5] Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, resulting in a disruption of the Keap1-Cul3 ubiquitination system and a build-up of Nrf2 in the cytoplasm.[6][7] Unbound Nrf2 is then able to translocate into the nucleus, where it will heterodimerize with a small Maf protein and bind to the Antioxidant Response Element (ARE) in the upstream promoter region of many antioxidative genes, where it will initiate their transcription.[8]

Target Genes

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

  • NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical Nrf2 target gene that catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and oxidative stress.[9]
  • Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM) subunits form a heterodimer, which is the rate-limiting step in the synthesis of glutathione (GSH), a very powerful endogenous antioxidant. Both Gclc and Gclm are characteristic Nrf2 target genes, which establish Nrf2 as a regulator of glutathione, one of the most important antioxidants in the body.[10]
  • Heme oxygenase-1 (HMOX1, HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin, the anti-inflammatory agent carbon monoxide, and iron. HO-1 is a Nrf2 target gene that has been shown to protect from a variety of pathologies, including sepsis, hypertension, atherosclerosis, acute lung injury, kidney injury, and pain.[11]
  • The glutathione S-transferase (GST) family includes cytosolic, mitochondrial, and microsomal enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic electrophiles. After detoxification by GSH conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds. GSTs are induced by Nrf2 activation and represent an important route of detoxification.[12]
  • The UDP-glucuronosyltransferase (UGT) family catalyze the conjugation of a glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water soluble and readily excreted. Important substrates for glucuronidation include bilirubin and acetaminophen. Nrf2 has been shown to induce UGT1A1 and UGT1A6.[13]
  • Multidrug resistance-associated proteins (Mrps) are important membrane transporters that efflux various compounds from various organs and into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be upregulated by Nrf2 and alteration in their expression can dramatically alter the pharamacokinetics and toxicity of compounds.[14][15]


Nrf2 is a basic leucine zipper (bZip) transcription factor with a Cap “n” Collar (CNC) structure.[1]

Nrf2 possesses six highly conserved domains called Nrf2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins.[16] The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.[17] The Neh3 domain may play a role in Nrf2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.[18] The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CBP), which possesses intrinsic histone acetyltransferase activity.[17] The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.[19]

Tissue distribution

Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.[1]

Nrf2 as a drug target

Investigational drugs that target NFE2L2 have been evaluated in animal models as therapeutic interventions for oxidative-stress related pathologies. One such compound, bardoxolone methyl, is undergoing testing in human clinical trials.

The dithiolethiones are a class of organosulfur compounds, of which, oltipraz is the most well-studied. Oltipraz has been shown to inhibit cancer formation in a variety of rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.[20] However, clinical trials involving oltipraz have demonstrated significant side-effects with no or questionable chemopreventive efficacy.[20] In one clinical study, side-effects after 8 weeks of treatment included numbness, tingling, and pain in the extremities. In another study, side-effects after 4 weeks included gastrointestinal toxicity. Oltipraz has also been shown to generate superoxide radical, which can be quite toxic.[21]

A series of synthetic oleane triterpenoid compounds that are Nrf2 activators and referred to as antioxidant inflammation modulators (AIMs), are in clinical development at Reata Pharmaceuticals. The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), has completed Phase 2 clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus. Data indicate that bardoxolone methyl improves markers of kidney function, including producing a significant increase in estimated glomerular filtration rate that correlates with changes in blood urea nitrogen, serum phosphorus, uric acid, and magnesium. Improvements were sustained over 6 months of therapy and remained significant compared to placebo.[citation needed]) A Phase 3 outcomes study (BEACON) is scheduled to begin in mid 2011.[citation needed]) Reata also indicates that it has other Nrf2 inducers in the same class that are in preclinical development for the treatment of CNS and respiratory diseases.[citation needed])


NFE2L2 has been shown to interact with CREB-binding protein,[22] KEAP1,[23][24][25] C-jun,[26] EIF2AK3[23] and Ubiquitin C.[24][27]


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  11. ^ Jarmi T, Agarwal A (February 2009). "Heme oxygenase and renal disease". Curr. Hypertens. Rep. 11 (1): 56–62. doi:10.1007/s11906-009-0011-z. PMID 19146802. 
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  14. ^ Maher JM, Dieter MZ, Aleksunes LM, Slitt AL, Guo G, Tanaka Y, Scheffer GL, Chan JY, Manautou JE, Chen Y, Dalton TP, Yamamoto M, Klaassen CD (November 2007). "Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway". Hepatology 46 (5): 1597–610. doi:10.1002/hep.21831. PMID 17668877. 
  15. ^ Reisman SA, Csanaky IL, Aleksunes LM, Klaassen CD (May 2009). "Altered Disposition of Acetaminophen in Nrf2-null and Keap1-knockdown Mice". Toxicol. Sci. 109 (1): 31–40. doi:10.1093/toxsci/kfp047. PMC 2675638. PMID 19246624. 
  16. ^ Motohashi H, Katsuoka F, Engel JD, Yamamoto M. (April 2004). "Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1–Nrf2 regulatory pathway". Proc Natl Acad Sci U S A. 101 (17): 6379–84. doi:10.1073/pnas.0305902101. PMC 404053. PMID 15087497. 
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  23. ^ a b Cullinan, Sara B; Zhang Donna, Hannink Mark, Arvisais Edward, Kaufman Randal J, Diehl J Alan (Oct. 2003). "Nrf2 Is a Direct PERK Substrate and Effector of PERK-Dependent Cell Survival". Mol. Cell. Biol. (United States) 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. ISSN 0270-7306. PMC 230321. PMID 14517290. 
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  25. ^ Wang, Xiao-Jun; Sun Zheng, Chen Weimin, Li Yanjie, Villeneuve Nicole F, Zhang Donna D (Aug. 2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicol. Appl. Pharmacol. (United States) 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. ISSN 0041-008X. PMC 2610481. PMID 18417180. 
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Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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