NFE2L2 (NRF2): Master Regulator of Antioxidant and Cytoprotective Responses
Key transcription factor in oxidative stress, inflammation, and cancer biology
Gene Information Card
| Symbol | NFE2L2 |
|---|---|
| Full Name | Nuclear Factor, Erythroid 2 Like 2 |
| Gene Type | Protein coding |
| Chromosomal Location | 2q31.2 |
| NCBI Gene ID | 4780 ncbi.nlm.nih.gov/gene/4780 |
| Ensembl ID | ENSG00000116044 |
| UniProt ID | Q16236 |
| OMIM ID | 600492 |
| HGNC ID | 7782 |
| Aliases | NRF2, HEBP1, IMDDHH |
Description
NFE2L2 (NRF2) encodes a basic leucine zipper (bZIP) transcription factor that regulates the expression of antioxidant proteins and phase II detoxifying enzymes. Under basal conditions, NRF2 is sequestered in the cytoplasm by KEAP1 and targeted for ubiquitin-mediated degradation. Upon oxidative or electrophilic stress, NRF2 is stabilized, translocates to the nucleus, and binds to antioxidant response elements (AREs) in the promoters of target genes. NRF2 plays a critical role in cellular protection against oxidative damage, inflammation, and carcinogenesis. Somatic gain-of-function mutations in NFE2L2 are frequently found in various cancers, leading to constitutive activation of the antioxidant response and therapy resistance.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Squamous cell carcinoma (lung, head and neck, esophagus) | Gain-of-function mutations in the DLG or ETGE motifs impair KEAP1 binding, leading to constitutive NRF2 activation and enhanced cell survival under oxidative stress. | COSMIC; ClinVar |
| Breast cancer | NFE2L2 amplification or overexpression correlates with poor prognosis and chemoresistance. | NCBI Gene; COSMIC |
| Hepatocellular carcinoma | Somatic mutations and KEAP1 inactivation result in NRF2 accumulation, promoting tumor growth. | COSMIC; OMIM |
| Immunodeficiency, developmental delay, and hypohyperpigmentation (IMDDHH) | Biallelic loss-of-function mutations in NFE2L2 cause impaired antioxidant response, leading to immune dysfunction and developmental abnormalities. | OMIM #617744; ClinVar |
| Chronic obstructive pulmonary disease (COPD) | Reduced NRF2 activity in lung epithelial cells contributes to oxidative stress and inflammation. | NCBI Gene; OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lung | 12.5 | Medium |
| Liver | 10.8 | Medium |
| Kidney | 9.2 | Medium |
| Brain | 6.4 | Low |
| Heart | 5.1 | Low |
| Skeletal Muscle | 4.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| A549 (lung carcinoma) | 15.2 | High NRF2 activity due to KEAP1 mutation |
| HepG2 (hepatocellular carcinoma) | 11.0 | Moderate expression |
| MCF7 (breast cancer) | 8.5 | Moderate expression |
| HEK293 (embryonic kidney) | 7.3 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.101G>A (p.Gly34Glu) | Missense | 1.2% in lung squamous cell carcinoma | Gain-of-function; disrupts KEAP1 binding |
| c.94C>T (p.Arg32Cys) | Missense | 0.8% in head and neck squamous cell carcinoma | Gain-of-function; reduces KEAP1 affinity |
| c.241G>A (p.Glu81Lys) | Missense | 0.5% in esophageal squamous cell carcinoma | Gain-of-function; impairs KEAP1 interaction |
| c.1A>G (p.Met1Val) | Missense | Rare | Loss-of-function; start codon loss, reduced protein expression |
Mutation functional classification
Loss of Function (LOF)
Rare biallelic mutations cause IMDDHH syndrome with impaired antioxidant response.
Gain of Function (GOF)
Common in cancers; mutations in DLG/ETGE motifs prevent KEAP1-mediated degradation, leading to constitutive NRF2 activation.
Dominant Negative (DN)
Not well documented for NFE2L2.
View complete mutation data：
Gene Ontology (GO)
| • GO:0003700 - DNA-binding transcription factor activity | • GO:0008134 - transcription factor binding |
| • GO:0046983 - protein dimerization activity | • GO:0005515 - protein binding |
| • GO:0000978 - RNA polymerase II cis-regulatory region sequence-specific DNA binding | • GO:0042493 - response to drug |
| • GO:0006979 - response to oxidative stress | • GO:0045944 - positive regulation of transcription by RNA polymerase II |
| • GO:0032869 - cellular response to insulin stimulus | • GO:0005737 - cytoplasm |
| • GO:0005634 - nucleus |
Pathways
• KEAP1-NRF2 pathway (Reactome R-HSA-9759194)
• Oxidative stress response (KEGG hsa04216)
• Cytoprotection by NRF2 (WikiPathways WP2884)
• NRF2-ARE signaling (BioCarta)
Protein Summary
NRF2 (NFE2L2) is a 605-amino acid transcription factor with a conserved bZIP domain and multiple regulatory motifs, including the DLG and ETGE motifs that mediate KEAP1 binding. Under normal conditions, NRF2 is rapidly degraded via the ubiquitin-proteasome system. Upon oxidative stress, KEAP1 is inactivated, allowing NRF2 to accumulate and translocate to the nucleus, where it heterodimerizes with small MAF proteins and activates ARE-driven genes such as NQO1, GCLC, and HMOX1. NRF2 is a master regulator of cellular redox homeostasis, detoxification, and survival. Its dysregulation is implicated in cancer progression, chemoresistance, and neurodegenerative diseases.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NFE2L2 Knockout HEK293 Cell Line | EDC90189 | Human | 4780 | Details Get a Quote |
| NFE2L2 Knockout A-549 Cell Line | EDC90777 | Human | 4780 | Details Get a Quote |
| NFE2L2 Knockout HCT 116 Cell Line | EDJ-KQ44611 | Human | 4780 | Details Get a Quote |
| NFE2L2 Knockout HeLa Cell Line | EDJ-KQ44612 | Human | 4780 | Details Get a Quote |
| NFE2L2 Knockout Hep-G2 Cell Line | EDJ-KZ361 | Human | 4780 | Details Get a Quote |
| Nfe2l2 Knockout RAW 264.7 Cell Line | EDJ-KZ362 | Mouse | 18024 | Details Get a Quote |
| NFE2L2 Knockout THP-1 Cell Line | EDJ-KZ363 | Human | 4780 | Details Get a Quote |
| NFE2L2 (p.P477=) Point Mutation in HAP1 Cell Line | EDC03563 | Human | 4780 | Details Get a Quote |
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