# NFE2L2

Source: https://onco.cc/targets/nfe2l2/  
OnCo record `nfe2l2` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

NFE2L2 (Nuclear factor erythroid 2-related factor 2) is a protein that switches other genes on and off. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Lung cancer, Hepatocellular carcinoma, Head and neck squamous cell carcinoma and 5 more.

## Summary

Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response (ARE) elements present in the promoter region of many cytoprotective genes, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralising reactive electrophiles. In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex. In response to oxidative stress, electrophile metabolites inhibit activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, heterodimerisation with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes.

CIViC holds 10 clinical evidence items and 0 assertions across 8 variants, naming Sapanisertib and Platinum Doublet. Open Targets scores its association with cancer at 0.80 (direct and indirect evidence; datatypes clinical 0.14, affected pathway 0.33, literature 1.00, genetic association 0.07, somatic mutation 0.94, animal model 0.53). IntOGen calls it a driver in 18 cohorts (16 activating, 2 loss-of-function), covering Bladder Urothelial Carcinoma, Cervical Squamous Cell Carcinoma, Oesophageal Adenocarcinoma, Hepatocellular Carcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma and others.

## Fields

- Kind: Target
- Last checked: 2026-09-23
- Also known as: NFE2 like bZIP transcription factor 2; Nuclear factor erythroid 2-related factor 2; NRF2; NRF-2
- Tags: cancer-genes-wave
- Symbol: NFE2L2
- Class: transcription
- Biology: Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response (ARE) elements present in the promoter region of many cytoprotective genes, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralising reactive electrophiles. In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex. In response to oxidative stress, electrophile metabolites inhibit activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, heterodimerisation with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes. The NFE2L2/NRF2 pathway is also activated in response to selective autophagy: autophagy promotes interaction between KEAP1 and SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1) complex, leading to NFE2L2/NRF2 nuclear accumulation and expression of cytoprotective genes. The NFE2L2/NRF2 pathway is also activated during the unfolded protein response (UPR), contributing to redox homeostasis and cell survival following endoplasmic reticulum stress. May also 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. Location: Cytoplasm, cytosol; Nucleus (UniProt). Locus 2q31.2 (HGNC).
- Where found: Lung cancer: Open Targets association 0.71 with lung cancer (MONDO_0008903); Hepatocellular carcinoma: Open Targets association 0.61 with hepatocellular carcinoma (MONDO_0007256); IntOGen driver in 4 cohorts (HCC); Head and neck squamous cell carcinoma: Open Targets association 0.62 with head and neck squamous cell carcinoma (MONDO_0010150); IntOGen driver in 2 cohorts (HNSC); Bladder & urothelial cancer: Open Targets association 0.55 with urinary bladder cancer (MONDO_0001187); IntOGen driver in 3 cohorts (BLCA); Oesophageal cancer: Open Targets association 0.60 with oesophageal cancer (MONDO_0007576); IntOGen driver in 1 cohort (ESCA); Endometrial cancer: Open Targets association 0.54 with endometrial cancer (MONDO_0011962); IntOGen driver in 1 cohort (UCEC); Non-small-cell lung cancer: hotspot mutation in the keap1-binding degrons 12-15%

## Notes

- Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: Open Targets known-drug datatype score 0.14; IntOGen calls it an activating (Act) driver in 16 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 2 cohorts; CIViC holds 10 clinical evidence items on its variants. Evidence tier "clinical-evidence" is the strongest of those signals.
- Prevalence not recorded: none of the sources gives a positivity rate.
- Diseases the sources name that have no OnCo cancer page yet, so they are not linked: Squamous Cell Carcinoma.
- Lung cancer: hotspot mutated in 12 to 15% of squamous tumours and 3.2% of adenocarcinomas, and the mutations cluster in the two degron motifs KEAP1 grips (E79Q, R34G, R34Q, D29H, G31A, L30F), which is a cleaner signature of positive selection than KEAP1 truncation is (cBioPortal). With KEAP1 and CUL3 the pathway is altered in 34% of squamous cancers (Cancer Genome Atlas Research Network 2012).

## Sources

- HGNC HGNC:7782: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7782
- UniProt Q16236: https://www.uniprot.org/uniprotkb/Q16236/entry
- NCBI Gene 4780: https://www.ncbi.nlm.nih.gov/gene/4780
- Ensembl ENSG00000116044: https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116044

## Connected records

- collections: [CIViC](https://onco.cc/collections/civic/), [IntOGen](https://onco.cc/collections/intogen/), [Open Targets Platform](https://onco.cc/collections/open-targets/)
- cancers: [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Cervical cancer](https://onco.cc/cancers/cervical/), [Endometrial cancer](https://onco.cc/cancers/endometrial/), [Head and neck squamous cell carcinoma](https://onco.cc/cancers/head-and-neck/), [Hepatocellular carcinoma](https://onco.cc/cancers/hcc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Oesophageal cancer](https://onco.cc/cancers/esophageal/), [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- pathways: [Drug efflux pumps (ABC transporters)](https://onco.cc/pathways/drug-efflux-pumps/), [Hepatocellular carcinoma (KEGG map)](https://onco.cc/pathways/hepatocellular-carcinoma-signalling/), [KEAP1-NRF2 antioxidant pathway](https://onco.cc/pathways/keap1-nrf2/)
- key papers: [Comprehensive genomic characterization of squamous cell lung cancers](https://onco.cc/key-papers/paper-tcga-lung-squamous-nature-2012/), [Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer](https://onco.cc/key-papers/paper-arbour-kras-co-mutation-outcomes-ccr-2018/), [Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate](https://onco.cc/key-papers/paper-pandey-gallbladder-elf3-nat-commun-2020/)

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