Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a protein (transcription factor). Nrf2 increases the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.
Substances that stimulate the Nrf2 pathway are being studied for the treatment of diseases that are caused by oxidative stress.
It responds to injury and inflammation [R].
It's better to have this gene increased most of the time.
Transcription activator that binds to antioxidant response (ARE) elements in the promoter regions of target genes. Important for the coordinated up-regulation of genes in response to oxidative stress. May be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region.
- RS10183914 (NFE2L2) ??
- RS16865105 (NFE2L2) ??
- RS1806649 (NFE2L2) ??
- RS1962142 (NFE2L2) ??
- RS2001350 (NFE2L2) ??
- RS2886161 (NFE2L2) ??
- RS35652124 (NFE2L2) ??
- RS6706649 (NFE2L2) ??
- RS6721961 (NFE2L2) ??
- RS6726395 (NFE2L2) ??
- RS7557529 (NFE2L2) ??
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Top Gene-Substance Interactions
Gene Interacts with Diseases
|Disease||Inference Score||References/Inference chemicals|
Top Ways to Increase Nrf2:
- Exercise (R)
- Calorie Restriction (R)
- Ketosis (R)
- LLLT (R)
- Fish oil/DHA (R)
- Vitamin D (R)
- Sulforaphane/Broccoli sprouts (R) -and other Isothiocyanates from cruciferous vegetables (R)
- Lipoic Acid
- Butyrate (R)
- Garlic (R)
- Curcumin (R)
Other Ways to Activate Nrf2:
- PGC-1a (R)
- Molecular Hydrogen (R),
- Thyroid hormones (R)
- Luteolin (R) “ luteolin is ideal because it inhibits Nrf2 in many cancer cells (R),
- Berberine (R),
- PQQ (R),
- Cinnamaldehyde (R),
- Anthocyanins (R, R2)
- Carnitine (R),
- Andrographolide/Andrographis (R),
- Black Cumin Oil (R),
- EGCG (R),
- Astaxanthin (R),
- Lycopene (R),
- Tocopherols and tocotrienols (R),
- Quercetin (R),
- Naringenin (R),
- Chlorella (R),
- Cocoa (R),
- Schisandra (R),
- Licorice (R),
- Chinese Skullcap - Baicalin (R), Baicalein (R, R2) and Wogonin (R)
- Citrus Flavanoids/Citrus Bioflavonoids (R),
- Withanolide A/Ashwagandha (R),
- Pau Darco (R),
- Ginkgolide B (prevents suppression)/Ginkgo (R),
- Oleanolic acid (R)
- Apigenin (R)
- Melatonin (R)
- Ginger/6-Shigoal (R)
- Pterostilbene (R),
- Hops (R)
- High-dose Vitamin C (R)
- Celastrol found in Thunder God Vine Extract (R)
- Artemisia (R)
- Kaempferol (R),
- Genistein (R), Soy Isoflavones (R),
- Bilirubin (R),
- Betanin/Beets (R),
- Chlorogenic acid (R),
- Carnosic acid/Rosemary (R)
- Grapes (R)
- Propolis (Brazilian green) (R)
- Kiwi peel (R), Geranium (R),
Inhibitors of Nrf2: SIRT1 decreases Nrf2-related gene production since acetylation allows Nrf2 to bind to DNA better and produce antioxidant genes (R). This is a downside of SIRT1.
All Ways to Increase Gene
|Sulforaphane||Increases expression||Danio rerio (R)||Consumable Natural Treatments, Substances of Biological Interest, Beneficial Substances, Important Natural Compounds|
|1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole||Increases expression||Humans (R)||Obscure Chemicals|
|Tobacco Smoke Pollution||Increases expression||Humans (R)||Substances of Biological Interest|
|2-tert-butylhydroquinone||Increases reaction||Humans (R)||Obscure Chemicals, Food Toxin, Household Toxin, Pesticide, Synthetic Toxin|
|Tetrachlorodibenzodioxin||Increases expression||Danio rerio (R)||Substances of Biological Interest, Airborne Pollutant, Industrial/Workplace Toxin, Pollutant, Synthetic Toxin|
|Sodium arsenite||Increases activity||Chickens (R)||Substances of Biological Interest, Airborne Pollutant, Industrial/Workplace Toxin, Pollutant, Synthetic Toxin|
|Cadmium Chloride||Increases reaction||Cows (R)||Substances of Biological Interest, Airborne Pollutant, Food Toxin, Household Toxin, Industrial/Workplace Toxin, Pesticide, Pollutant, Synthetic Toxin|
|Acetaminophen||Increases expression||Humans (R)||Drug, Substances of Biological Interest, Food Toxin, Synthetic Toxin|
|Cobaltiprotoporphyrin||Increases reaction||Humans (R)||Substances of Biological Interest|
|Lipopolysaccharides||Increases expression, Increases reaction||Humans (R) , Humans (R)||Substances of Biological Interest|
All Ways to Decrease Gene
|Sulforaphane||Decreases reaction||Danio rerio (R)||Consumable Natural Treatments, Substances of Biological Interest, Beneficial Substances, Important Natural Compounds|
|Tobacco Smoke Pollution||Decreases reaction||Humans (R)||Substances of Biological Interest|
|2-tert-butylhydroquinone||Decreases reaction||Humans (R)||Obscure Chemicals, Food Toxin, Household Toxin, Pesticide, Synthetic Toxin|
|Resveratrol||Decreases expression||Quails (R)||Consumable Natural Treatments, Substances of Biological Interest, Beneficial Substances, Important Natural Compounds|
|Paraquat||Decreases expression, Decreases reaction||Humans (R) , Humans (R)||Substances of Biological Interest, Toxins|
|Plant Extracts||Decreases reaction||Humans (R)||Substances of Biological Interest, Important Natural Compounds|
|Streptozocin||Decreases abundance||Mice (R)||Drug, Substances of Biological Interest, Synthetic Toxin|
|Lipopolysaccharides||Decreases reaction||Humans (R)||Substances of Biological Interest|
|Arsenic trioxide||Decreases reaction||Humans (R)||Drug, Substances of Biological Interest, Airborne Pollutant, Food Toxin, Household Toxin, Industrial/Workplace Toxin, Pesticide, Pollutant, Synthetic Toxin, Important Natural Compounds|
|Lithocholic Acid||Decreases activity, Decreases expression||Humans (R) , Humans (R)||Substances of Biological Interest, Animal Toxin, Natural Toxin|
Read: About NRF2 and Natural Ways to Increase It.
Nrf2 increases the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.
Nrf2 is found in the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain (R). Nrf2 stimulates NQO1, which donates electrons and detoxifies a variety of chemicals and drugs.
NQO1 is important for phase 2 detox. I suspect that people sensitive to everything have less NQO1 or less of an electron supply. Nrf2 produces two of the most important rate-limiting steps in glutathione (GSH) production.
The glutathione S-transferase (GST) allow glutathione to bind with drugs and toxins, which then allow the body to eliminate potentially harmful and toxic compounds. GSTs are produced by Nrf2 activation and represent an important route of detoxification.
Sulfiredoxin 1 (SRXN1) and Thioredoxin reductase 1 (TXNRD1) give over electrons to peroxiredoxins, proteins important in the detoxification of hydrogen peroxide and peroxynitrite.
Nrf2 stimulates Heme oxygenase-1. 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 defends against sepsis, hypertension, atherosclerosis, acute lung injury, kidney injury, and pain.
The UDP-glucuronosyltransferase (UGT) family catalyze the conjugation of a glucuronic acid to drugs, chemicals, and toxins, making them more water-soluble and readily excreted. Nrf2 has been shown to induce UGT1A1 and UGT1A6. Bilirubin and Tylenol are examples of substances that are glucuronidated.
My clients are more likely to have higher bilirubin and this can come from less of an ability to glucuronidation enzymes. Multidrug resistance-associated proteins (Mrps) are important membrane transporters that eject various compounds from various organs into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be increased by Nrf2 and alteration in their expression can dramatically alter the pharmacokinetics and toxicity of compounds.
People with CIRS or biotoxin related issues usually have a problem excreting toxins in an efficient way and almost certainly the Nrf2 pathway will help excrete these toxins more easily. Reference.
The Negatives of Nrf2 Activation: Activation of NRF2 may promote the development of cancerous tumors. It can also contribute to the development of heart disease by raising cholesterol levels and cholesterol content in the liver. Having low cholesterol might be an indicator of less Nrf2 function (although there are many other pathways that lower cholesterol). Reference.
Conditions with Increased Gene Activity
|Condition||Change (log2fold)||Comparison||Species||Experimental variables||Experiment name|
Conditions with Decreased Gene Activity
|Condition||Change (log2fold)||Comparison||Species||Experimental variables||Experiment name|
The following transcription factors increase gene production (R):
Widely expressed. Highest expression in adult muscle, kidney, lung, liver and in fetal muscle.
Down-regulated by ENC1 via a proteasomal ubiquitin-independent protein catabolic process.
- Dna Binding
- Protein Domain Specific Binding
- Rna Polymerase Ii Activating Transcription Factor Binding
- Rna Polymerase Ii Distal Enhancer Sequence-Specific Dna Binding
- Transcription Factor Activity, Sequence-Specific Dna Binding
- Transcription Regulatory Region Dna Binding
- Transcription Regulatory Region Sequence-Specific Dna Binding
- Transcriptional Activator Activity, Rna Polymerase Ii Distal Enhancer Sequence-Specific Binding
- Cell Redox Homeostasis
- Cellular Response To Drug
- Cellular Response To Fluid Shear Stress
- Cellular Response To Glucose Starvation
- Cellular Response To Hydrogen Peroxide
- Cellular Response To Laminar Fluid Shear Stress
- Cellular Response To Oxidative Stress
- Cellular Response To Tumor Necrosis Factor
- Endoplasmic Reticulum Unfolded Protein Response
- Inflammatory Response
- Negative Regulation Of Endothelial Cell Apoptotic Process
- Negative Regulation Of Hematopoietic Stem Cell Differentiation
- Negative Regulation Of Hydrogen Peroxide-Induced Cell Death
- Negative Regulation Of Oxidative Stress-Induced Intrinsic Apoptotic Signaling Pathway
- Perk-Mediated Unfolded Protein Response
- Positive Regulation Of Blood Coagulation
- Positive Regulation Of Er-Associated Ubiquitin-Dependent Protein Catabolic Process
- Positive Regulation Of Gene Expression
- Positive Regulation Of Glucose Import
- Positive Regulation Of Glutathione Biosynthetic Process
- Positive Regulation Of Reactive Oxygen Species Metabolic Process
- Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
- Positive Regulation Of Transcription From Rna Polymerase Ii Promoter In Response To Oxidative Stress
- Positive Regulation Of Transcription From Rna Polymerase Ii Promoter In Response To Stress
- Proteasomal Ubiquitin-Independent Protein Catabolic Process
- Proteasome-Mediated Ubiquitin-Dependent Protein Catabolic Process
- Protein Ubiquitination
- Regulation Of Embryonic Development
- Regulation Of Removal Of Superoxide Radicals
- Transcription From Rna Polymerase Ii Promoter