Affinage

NFE2L3

Nuclear factor erythroid 2-related factor 3 · UniProt Q9Y4A8

Length
694 aa
Mass
76.2 kDa
Annotated
2026-04-29
60 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NFE2L3 (NRF3) is a CNC-bZIP transcription factor that integrates ER stress signaling with nuclear gene regulation to control proteasome homeostasis, redox balance, cell proliferation, and differentiation across diverse tissues. It is anchored to the ER membrane via its NHB1 signal peptide, undergoes N-glycosylation and dual-compartment proteasomal degradation (HRD1/VCP-mediated ERAD in the cytoplasm; FBW7- and β-TRCP-dependent ubiquitination in the nucleus, primed by GSK3 phosphorylation), and is released to the nucleus through DDI2 aspartic protease cleavage upon ER stress (PMID:19047052, PMID:28970512, PMID:26306035). In the nucleus, NFE2L3 heterodimerizes with small Maf proteins (MafK, MAFG) to bind ARE/MARE elements, where it represses NRF2-dependent antioxidant genes such as NQO1 while transcriptionally inducing POMP to enhance 20S proteasome assembly, enabling ubiquitin-independent degradation of p53 and Rb, and induces CPEB3 to translationally repress NFE2L1, thereby coordinating proteasome gene expression with its CNC-bZIP paralog (PMID:15385560, PMID:32123008, PMID:32366381). Beyond cancer cell proliferation, NFE2L3 drives vascular smooth muscle differentiation via myocardin and Pla2g7 induction, promotes cardiomyocyte apoptosis by epigenetically silencing Pitx2 through recruitment of an hnRNPK–DNMT1 complex, regulates melanogenesis through macropinocytosis and autophagy gene programs, and shapes the tumor immune microenvironment by controlling IL33 and RAB27A expression (PMID:20093628, PMID:40099370, PMID:36640303, PMID:35091681).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Identification of NFE2L3 as a CNC-bZIP factor that heterodimerizes with small Maf proteins to bind MARE elements established its basic molecular identity as a transcriptional regulator.

    Evidence In vitro transcription/translation, EMSA, and transfection assays with MafK

    PMID:10037736

    Open questions at the time
    • Endogenous target genes unknown
    • In vivo function uncharacterized
    • Subcellular localization not determined
  2. 2004 High

    Demonstrating that NFE2L3 represses NRF2-driven ARE-mediated NQO1 expression by competing for ARE binding via Maf heterodimerization revealed its antagonistic relationship with NRF2 in antioxidant gene regulation.

    Evidence Overexpression, deletion mutagenesis, EMSA/supershift, RNAi in HepG2 cells; independently confirmed MAFG interaction via yeast two-hybrid

    PMID:15385560 PMID:15388789

    Open questions at the time
    • Genome-wide target repertoire unknown
    • Mechanism of selective repression versus activation not resolved
    • Physiological contexts for NRF2 antagonism not tested in vivo
  3. 2007 High

    Discovery that NFE2L3 is ER-associated, N-glycosylated, and subject to rapid proteasomal turnover revealed an unexpected membrane-tethered lifecycle for a transcription factor, raising the question of how it reaches the nucleus.

    Evidence Cycloheximide chase, MG-132 treatment, glycosylation assays, subcellular fractionation

    PMID:17976382

    Open questions at the time
    • Mechanism of ER-to-nucleus transit unknown
    • Identity of the protease releasing NRF3 not established
    • E3 ligase responsible for degradation not identified
  4. 2008 High

    Mapping the NHB1 tripartite signal peptide as the ER-targeting and glycosylation-directing domain, and showing that ER stress agents trigger NRF3 nuclear accumulation, established the regulated ER-to-nucleus signaling paradigm for this factor.

    Evidence NHB1 mutagenesis, subcellular fractionation, immunofluorescence, ER stress treatment (tunicamycin, brefeldin A) in mouse cells

    PMID:19047052

    Open questions at the time
    • Identity of the protease cleaving NRF3 from the ER unknown
    • Specific ER stress sensor upstream of NRF3 release not identified
  5. 2010 High

    Showing that NFE2L3 promotes vascular smooth muscle differentiation by inducing myocardin and directly binding SMC gene promoters revealed a physiological non-cancer role and its capacity to regulate lineage-specific gene programs.

    Evidence shRNA KD, overexpression, ChIP on SMC promoters, ROS measurement, in vitro stem cell differentiation

    PMID:20093628

    Open questions at the time
    • In vivo vascular phenotype of NRF3 loss not yet tested
    • Whether NRF3 binds SMC promoters directly or via Maf partners unresolved
  6. 2015 High

    Identification of FBW7 as the E3 ligase for nuclear NFE2L3, with GSK3-dependent phosphodegron priming, resolved how nuclear NFE2L3 protein levels are controlled and linked its stability to a major tumor suppressor pathway.

    Evidence Co-IP, ubiquitination assays, phosphorylation assays, FBW7 dimerization mutants, ARE reporter in mammalian cells

    PMID:26306035

    Open questions at the time
    • Cytoplasmic degradation pathway not yet defined
    • Relationship between ER-tethered and nuclear degradation routes unclear
  7. 2017 High

    Identification of HRD1/VCP as the cytoplasmic ERAD machinery and DDI2 aspartic protease as the enzyme releasing NFE2L3 from the ER completed the dual-compartment degradation model and revealed the ER-to-nucleus transit mechanism.

    Evidence siRNA KD of HRD1, VCP, DDI2, β-TRCP; nuclear fractionation; proliferation assays identifying UHMK1 as target gene

    PMID:28970512

    Open questions at the time
    • DDI2 cleavage site on NRF3 not mapped
    • Signal connecting ER stress to DDI2 activation uncharacterized
  8. 2018 High

    Demonstrating that NRF3-deficient keratinocytes resist UV-induced apoptosis due to enhanced integrin-FAK signaling established NRF3 as a pro-apoptotic factor that regulates cell adhesion, expanding its roles beyond transcription of metabolic/proteasome genes.

    Evidence Nrf3 KO mouse keratinocytes, UV irradiation in vitro/in vivo, integrin staining, FAK phosphorylation, focal adhesion imaging

    PMID:29487353

    Open questions at the time
    • Direct transcriptional targets mediating adhesion changes not identified
    • Whether this is Maf-dependent not tested
  9. 2019 High

    Three contemporaneous studies established NFE2L3 as a cancer-promoting transcription factor: it induces POMP to assemble 20S proteasomes for ubiquitin-independent p53/Rb degradation, induces DUX4 downstream of NF-κB to modulate CDK1, and is itself a Wnt/β-catenin target driving GLUT1 and proliferation in colon cancer.

    Evidence ChIP, proteasome activity assays, E1 inhibitor (TAK-243) dissection, xenograft/metastasis models; NF-κB ChIP; Apc-KO mouse organoids and reporter assays

    PMID:31288376 PMID:31693889 PMID:32123008

    Open questions at the time
    • Whether 20S-mediated p53 degradation operates in non-cancer contexts unknown
    • Relative contribution of POMP vs. DUX4 vs. GLUT1 axes to tumor growth not delineated
  10. 2020 High

    Showing that NFE2L3 induces CPEB3 to translationally repress NFE2L1, while both factors complementarily maintain basal proteasome subunit gene expression, revealed a cross-regulatory circuit between CNC-bZIP paralogs governing proteasome homeostasis.

    Evidence Double KD, polysome profiling, RNA immunoprecipitation for CPEB3–NFE2L1 mRNA, proteasome activity assays

    PMID:32366381

    Open questions at the time
    • Whether NFE2L1 reciprocally regulates NFE2L3 not tested
    • Physiological conditions triggering this cross-regulation unknown
  11. 2022 High

    NFE2L3 was shown to directly bind IL33 and RAB27A loci and shape the colorectal tumor immune microenvironment (mast cell and Treg abundance), extending its oncogenic role beyond cell-intrinsic proliferation to tumor–immune crosstalk.

    Evidence ChIP in human CRC cells, Nfe2l3−/− mouse AOM/DSS colitis-cancer model, CIBERSORT deconvolution, digital spatial profiling

    PMID:35091681

    Open questions at the time
    • Whether mast cell recruitment is sufficient or necessary for NRF3-driven tumorigenesis not resolved
    • Direct versus indirect regulation of immune infiltrate composition unclear
  12. 2022 High

    ChIP-seq revealed NFE2L3 coordinates melanogenesis by transcriptionally activating the core melanogenic gene circuit (Mitf, Tyr, Tyrp1) and macropinocytosis/autophagy genes (Cln3, Ulk2, Gabarapl2), linking NRF3 to vesicular trafficking-dependent pigmentation.

    Evidence ChIP-seq, siRNA KD, overexpression, macropinocytosis and melanin quantification assays

    PMID:36640303

    Open questions at the time
    • Whether NRF3 binds melanogenic promoters directly or via MITF cooperativity not resolved
    • In vivo pigmentation phenotype of Nrf3 KO not reported
  13. 2023 Medium

    Multiple studies expanded NFE2L3's cancer-promoting mechanisms to include ISGylation-mediated p53 degradation in HCC, mTORC1 activation via SLC38A9/RagC/RAB5 induction for arginine sensing, PI3K/AKT pathway activation in TNBC, and a context-dependent tumor-suppressive role in squamous cell carcinoma via HSPA5 restraint.

    Evidence ChIP, protein stability assays in HCC; lysosomal fractionation and macropinocytosis assays; luciferase reporter on p110α promoter; NRF3-deficient mouse SCC models with HSPA5 co-IP and pharmacological rescue

    PMID:36818298 PMID:37350063 PMID:37720674 PMID:37807968

    Open questions at the time
    • Tissue-specific determinants of oncogenic versus tumor-suppressive NRF3 function unresolved
    • Whether ISGylation and 20S proteasome routes to p53 degradation are redundant or tissue-specific unknown
    • Each axis from a single laboratory
  14. 2024 High

    In the heart, NFE2L3 was shown to epigenetically silence Pitx2 by recruiting an hnRNPK–DNMT1 complex to the Pitx2 promoter, increasing DNA methylation and thereby promoting cardiomyocyte apoptosis via mitochondrial ROS after injury — establishing NRF3 as an epigenetic regulator beyond classical transcriptional activation.

    Evidence CM-specific and global Nrf3 KO mice, MI and I/R models, ChIP-seq, IP-mass spectrometry identifying hnRNPK and DNMT1, AAV rescue

    PMID:40099370

    Open questions at the time
    • Whether hnRNPK–DNMT1 recruitment is a general mechanism at other NRF3 targets unknown
    • Role of Maf partners in cardiac context not examined
  15. 2024 High

    In vascular injury, NFE2L3 (induced by ATF4 under ER stress) transcriptionally activates Trim5 to trigger VSMC autophagy and neointimal hyperplasia, validated by VSMC-specific KO and therapeutic perivascular NRF3 inhibition, linking the ER stress–DDI2–NRF3 axis to vascular disease.

    Evidence Global and VSMC-specific Nrf3 KO mice, wire-injury and porcine stenting models, ChIP, transcriptomics, perivascular inhibitor delivery

    PMID:40377016

    Open questions at the time
    • Direct ATF4 binding to Nrf3 promoter not shown by ChIP
    • Whether DDI2 cleavage is required in this vascular context not tested
  16. 2025 Medium

    Post-transcriptional regulation of NFE2L3 mRNA was established: METTL3-mediated m6A modification stabilizes NFE2L3 mRNA to activate Wnt signaling in lung adenocarcinoma, and NAT10-mediated ac4C acetylation stabilizes NFE2L3 mRNA to drive AKT/GSK3β/β-catenin signaling in ccRCC, revealing epitranscriptomic control of NRF3 expression.

    Evidence m6A-RIP-seq, ac4C-RIP-seq, RNA stability assays, KD/OE of METTL3 and NAT10, WNT and AKT pathway assays, xenograft models

    PMID:40169553 PMID:40249818

    Open questions at the time
    • Specific m6A and ac4C sites on NFE2L3 mRNA not mapped at single-nucleotide resolution
    • Whether these modifications operate in non-cancer physiology unknown
    • Each finding from a single laboratory

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: (1) the structural basis for DDI2-mediated NRF3 cleavage and how ER stress activates DDI2; (2) what determines whether NRF3 acts as an oncogene or tumor suppressor in different tissue contexts; (3) whether the hnRNPK–DNMT1 epigenetic silencing mechanism generalizes beyond the Pitx2 locus; and (4) a comprehensive ChIP-seq-defined cistrome across tissues to unify the diverse transcriptional programs attributed to NRF3.
  • No crystal or cryo-EM structure of NRF3 or NRF3–DDI2 complex
  • No systematic loss-of-function screen across tissues to define context-dependent gene programs
  • No Mendelian disease association established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 11 GO:0140110 transcription regulator activity 9
Localization
GO:0005654 nucleoplasm 2 GO:0005783 endoplasmic reticulum 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
DDI2FBW7HNRNPKHRD1HSPA5MAFGMAFKVCP
Complex memberships
NRF3–small Maf heterodimer (MafK, MAFG, MAFF)hnRNPK–DNMT1–NRF3 epigenetic silencing complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 NRF3 (NFE2L3) heterodimerizes with small Maf proteins (e.g., MafK) and the resulting complex binds to Maf recognition elements (MARE) in the chicken β-globin enhancer to activate transcription. In vitro transcription/translation, EMSA (bandshift), in vivo transfection assays The Journal of biological chemistry High 10037736
2004 NRF3 acts as a negative regulator of ARE-mediated NQO1 gene expression by associating with small Maf proteins to compete for ARE binding, requiring its heterodimerization and DNA-binding domains but not its transcriptional activation domain. Overexpression, deletion mutagenesis, EMSA/supershift, immunoprecipitation, RNA interference in HepG2 cells The Journal of biological chemistry High 15385560
2004 Human NRF3 heterodimerizes with MAFG (identified by in vivo protein-protein interaction screen), and the NRF3/MAFG heterodimer binds NF-E2/MARE-type DNA elements; a strong transcriptional activation domain was mapped to the center region of NRF3. Yeast two-hybrid screen using full-length MAFG as bait, transfection confirmation, functional transcriptional activation assays Molecular endocrinology High 15388789
2007 NRF3 protein undergoes rapid proteasomal turnover and is N-linked glycosylated; it is associated with the endoplasmic reticulum. Cycloheximide chase, proteasome inhibitor (MG-132) treatment, glycosylation assays, subcellular fractionation FEBS letters High 17976382
2008 Mouse NRF3 is targeted to the ER through its N-terminal NHB1 sequence, which functions as a tripartite signal peptide (n, h, c regions). The h region (residues 12-23) directs ER targeting and is required for N-glycosylation. Proteolytic processing generates ~90, ~80, and ~70 kDa isoforms; the ~90 kDa glycoprotein and ~80 kDa form localize to the nuclear envelope, while the ~70 kDa isoform is detected primarily in the nucleoplasm. NHB1 is required for ER stress-induced (tunicamycin, brefeldin A) activation. Mutagenesis of NHB1, subcellular fractionation, immunofluorescence, deglycosylation assays, ER stress treatment The Journal of biological chemistry High 19047052
2010 NRF3 promotes smooth muscle cell (SMC) differentiation from stem cells by upregulating the SMC-specific transcription factor myocardin, increasing binding of SRF and myocardin to SMC differentiation gene promoters, and directly binding SMC gene promoters. NRF3 also promotes NADPH oxidase-derived ROS production and suppresses antioxidant signaling during SMC differentiation. shRNA knockdown, overexpression, chromatin immunoprecipitation (ChIP), promoter binding, ROS measurement, in vitro differentiation assays Circulation research High 20093628
2012 NRF3 directly binds to the promoter of Pla2g7 (phospholipase A2, group 7) to regulate its expression during SMC differentiation; Pla2g7 in turn increases ROS generation and SRF binding to SMC gene promoters, linking NRF3-Pla2g7 axis to SMC differentiation. ChIP assay on Pla2g7 promoter, knockdown/overexpression of Pla2g7, ROS measurements, SRF binding assays Arteriosclerosis, thrombosis, and vascular biology Medium 22247257
2015 NFE2L3 is ubiquitinated and degraded by the SCF E3 ubiquitin ligase component FBW7, requiring dimerization of FBW7. GSK3 phosphorylates NFE2L3 to prime it for FBW7-dependent ubiquitination. FBW7 abrogates NFE2L3-mediated repression of the NQO1 ARE. Co-immunoprecipitation, ubiquitination assays, phosphorylation assays, FBW7 dimerization mutants, functional ARE reporter assay The Journal of biological chemistry High 26306035
2017 Under physiological conditions NRF3 is degraded by the ER-associated degradation (ERAD) ubiquitin ligase HRD1 and VCP (valosin-containing protein) in the cytoplasm, and in the nucleus by β-TRCP (adaptor for SCF ubiquitin ligase). Nuclear translocation of NRF3 from the ER requires the aspartic protease DDI2 but is independent of HRD1-VCP inhibition. NRF3 induces UHMK1 gene expression to promote cancer cell proliferation. Co-immunoprecipitation, proteasome inhibitor assays, siRNA knockdown of HRD1/VCP/DDI2/β-TRCP, nuclear fractionation, gene expression analysis Scientific reports High 28970512
2018 NRF3 promotes UV-induced apoptosis in keratinocytes by suppressing cell-cell and cell-matrix adhesion; NRF3-deficient keratinocytes show higher surface integrin levels, enhanced focal adhesion kinase activation, more/larger focal adhesions, and higher motility. NRF3 knockout mouse model, UV irradiation in vitro and in vivo, integrin surface staining, focal adhesion kinase phosphorylation assay, focal adhesion imaging Cell death and differentiation High 29487353
2019 NFE2L3 expression in colon cancer cells is regulated by the RELA subunit of NF-κB; NFE2L3 in turn activates expression of DUX4, which functions as a direct inhibitor of CDK1, thereby modulating colon cancer cell proliferation. ChIP, siRNA knockdown, overexpression, in vitro proliferation assays, in vivo tumor xenograft Cell reports High 31693889
2019 NRF3 specifically enhances 20S proteasome assembly in cancer cells by transcriptionally inducing POMP (proteasome maturation protein), leading to ubiquitin-independent proteolysis of tumor suppressors p53 and retinoblastoma (Rb) protein. Transcriptional reporter assays, ChIP, proteasome activity assays, protein stability assays using 20S-specific inhibitor (bortezomib) and E1 inhibitor (TAK-243), KD/KO in cancer cells, in vivo xenograft and metastasis models Molecular and cellular biology High 32123008
2019 The β-catenin/TCF4 complex directly binds a conserved WRE (TCF/LEF consensus element) in the NRF3 gene promoter to induce NRF3 expression in colon cancer cells; this axis drives cell proliferation and GLUT1 expression and was validated in Apc-deficient mouse intestine and organoids. ChIP, luciferase reporter assay, conditional Apc-knockout mouse intestine/organoids, gene expression analysis International journal of molecular sciences High 31288376
2020 NFE2L3 represses NFE2L1 translation by inducing the expression of CPEB3, a translational regulator that binds the NFE2L1 3′ UTR and decreases polysome formation on NFE2L1 mRNA. Together NFE2L1 and NFE2L3 complementarily maintain basal expression of seven proteasome-related genes (PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, POMP) and proteasome activity in cancer cells. Double knockdown, polysome profiling, RIP (RNA immunoprecipitation), gene expression analysis, proteasome activity assays Molecular and cellular biology High 32366381
2022 NFE2L3 directly binds the regulatory sequences of IL33 and RAB27A loci in human colorectal carcinoma cells (ChIP-validated), regulating mast cell-related gene expression and tumor microenvironment composition including mast cell abundance and immunosuppressive Treg levels in vivo. ChIP in human colorectal carcinoma cells, Nfe2l3-/- mouse model of inflammation-induced colorectal cancer, histological analysis, CIBERSORT immune cell deconvolution, digital spatial profiling Oncogene High 35091681
2022 NRF3 regulates macropinocytosis and autophagy to coordinate the melanogenesis cascade: NRF3 transcriptionally upregulates the core melanogenic gene circuit (Mitf, Tyr, Tyrp1, Pmel, Oca2) and induces Cln3 (autophagosome-related factor) for melanin precursor uptake by macropinocytosis, as well as Ulk2 and Gabarapl2 for melanosome formation and autolysosomal degradation. ChIP-seq, siRNA knockdown, overexpression, macropinocytosis assays, melanin quantification, gene expression analysis Cell reports High 36640303
2023 NRF3 promotes HCC cell proliferation by transcriptionally inducing proteasome genes and ISG15, which causes ISGylation of p53 and its subsequent proteasome-dependent degradation. ChIP, gene expression analysis, protein stability assays, knockdown/overexpression in HCC cells Cancer science Medium 37350063
2023 NRF3 contributes to cancer cell viability through mTORC1 activation in response to arginine by inducing SLC38A9 and RagC expression for arginine-dependent mTORC1 lysosomal recruitment, and by inducing RAB5 to enhance macropinocytosis and SLC7A1 for arginine transport into lysosomes. ChIP, gene expression analysis, mTORC1 activity assays, lysosomal fractionation, macropinocytosis assays, siRNA knockdown, xenograft tumor models iScience Medium 36818298
2023 NRF3 deficiency promotes malignant progression of squamous cell carcinoma cells through upregulation of HSPA5 (a key unfolded protein response regulator); NRF3 was identified as an interactor of HSPA5, and pharmacological or knockdown inhibition of HSPA5 rescued the malignant features of NRF3-deficient SCC cells. NRF3-deficient mouse skin tumor models, 3D invasion cultures, xenograft formation, Co-immunoprecipitation (NRF3-HSPA5 interaction), pharmacological HSPA5 inhibition, siRNA knockdown EMBO molecular medicine Medium 37807968
2023 NRF3 promotes TNBC cell proliferation by directly binding to the p110α promoter and transcriptionally activating the PI3K/AKT/mTOR signaling pathway. ChIP assay, luciferase reporter assay, overexpression/knockdown, PI3K inhibitor treatment, proliferation/migration assays Oncology letters Medium 37720674
2024 NRF3 promotes injury-induced cardiomyocyte apoptosis and cardiac dysfunction by increasing mitochondrial ROS production through suppression of Pitx2: NRF3 binds the Pitx2 promoter and increases DNA methylation by recruiting hnRNPK and DNMT1 complex, thereby inhibiting Pitx2 expression. CM-specific and global Nrf3 KO mice, MI/ischemia-reperfusion models, ChIP-seq, IP-mass spectrometry, AAV-mediated cardiac-specific overexpression, MitoParaquat ROS augmentation Circulation High 40099370
2024 NRF3 promotes VSMC dysfunction and neointimal hyperplasia by transcriptionally activating Trim5, which in turn triggers autophagy in VSMCs; Nrf3 expression is induced by ER stress via ATF4; Nrf3-/- and VSMC-specific knockout mice show attenuated injury-induced neointimal hyperplasia. Global and VSMC-specific Nrf3 KO mice, wire-injury and porcine carotid stenting models, transcriptomics, ChIP, Co-immunoprecipitation, perivascular Nrf3 inhibitor delivery Cardiovascular research High 40377016
2024 NRF3 promotes neuroprotection and long-distance axon regeneration after optic nerve injury when virally expressed in retinal ganglion cells in vivo; Nfe2l3 expression peaks in developing but not adult projection neurons and is not upregulated after injury. Viral vector (AAV) delivery of Nfe2l3 to retinal ganglion cells, optic nerve crush model, axon regeneration quantification, scRNA-seq expression profiling Experimental neurology Medium 38395216
2025 METTL3 stabilizes NFE2L3 mRNA via N6-methyladenosine (m6A) modification, which upregulates NFE2L3 protein levels and activates intrinsic WNT signaling to maintain cancer stem cell stemness in lung adenocarcinoma. m6A-RIP sequencing, RNA stability assays, METTL3 knockdown/overexpression, WNT pathway activity assays, cancer stem cell functional assays Science advances Medium 40249818
2025 NAT10 mediates ac4C acetylation of NFE2L3 mRNA, promoting its mRNA stability; NFE2L3 in turn binds to LASP1 genomic loci (ChIP-seq) to regulate its expression and activates the AKT/GSK3β/β-catenin signaling axis in ccRCC. acRIP-seq, RIP, RNA stability assays, dual luciferase reporter, ChIP-seq, NAT10 KD/OE, xenograft models Cell death & disease Medium 40169553
2025 NFE2L3 induces mevalonate biosynthesis and reduces intracellular neutral fatty acid levels by inducing SREBP2 and HMGCR gene expression and inducing GGPS1 gene expression; NFE2L3 also induces RAB5 gene expression to promote macropinocytosis for cholesterol uptake. Transcriptional target analysis, gene expression, ChIP (referenced in review context from primary study) International journal of molecular sciences Low 34884489
2022 NFE2L3 regulates colitis-related gene expression by controlling STAT1, HMOX1, and SLC7A11 protein levels in DSS-treated colon; Nfe2l3-/- mice show reduced induction of these proteins upon DSS treatment, suggesting NFE2L3 primes a pro-inflammatory state. NFE2L3 binding partners MAFF and MAFK (from ENCODE ChIP data) were used to identify these targets. Nfe2l3-/- mouse DSS colitis model, Western blot for pSTAT1, HMOX1, SLC7A11, ENCODE ChIP data cross-reference Biochimica et biophysica acta. Molecular cell research Medium 40360021

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3. The Journal of biological chemistry 252 10037736
2004 Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. The Journal of biological chemistry 92 15385560
2011 NFE2L3 (NRF3): the Cinderella of the Cap'n'Collar transcription factors. Cellular and molecular life sciences : CMLS 89 21687990
2004 Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus. Molecular and cellular biology 85 15060151
2010 Crucial role of nrf3 in smooth muscle cell differentiation from stem cells. Circulation research 81 20093628
2019 NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor. Cell reports 72 31693889
2017 Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation. Scientific reports 68 28970512
2019 Differential and overlapping targets of the transcriptional regulators NRF1, NRF2, and NRF3 in human cells. The Journal of biological chemistry 67 31628195
2008 The Nrf3 transcription factor is a membrane-bound glycoprotein targeted to the endoplasmic reticulum through its N-terminal homology box 1 sequence. The Journal of biological chemistry 64 19047052
2020 Defining the Functional Targets of Cap'n'collar Transcription Factors NRF1, NRF2, and NRF3. Antioxidants (Basel, Switzerland) 57 33096892
2012 Nrf3-Pla2g7 interaction plays an essential role in smooth muscle differentiation from stem cells. Arteriosclerosis, thrombosis, and vascular biology 54 22247257
2010 Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma. Blood 43 21148084
2020 NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression. Molecular and cellular biology 42 32366381
2007 Endoplasmic reticulum association and N-linked glycosylation of the human Nrf3 transcription factor. FEBS letters 40 17976382
2004 Functional and placental expression analysis of the human NRF3 transcription factor. Molecular endocrinology (Baltimore, Md.) 40 15388789
2020 NRF3-POMP-20S Proteasome Assembly Axis Promotes Cancer Development via Ubiquitin-Independent Proteolysis of p53 and Retinoblastoma Protein. Molecular and cellular biology 39 32123008
2020 NFE2L3 promotes malignant behavior and EMT of human hepatocellular carcinoma (HepG2) cells via Wnt/β‑catenin pathway. Journal of Cancer 39 33123284
2019 β-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells. International journal of molecular sciences 38 31288376
2020 Roles of NRF3 in the Hallmarks of Cancer: Proteasomal Inactivation of Tumor Suppressors. Cancers 36 32962187
2019 New addiction to the NRF2-related factor NRF3 in cancer cells: Ubiquitin-independent proteolysis through the 20S proteasome. Cancer science 34 31742837
2019 NRF3 suppresses breast cancer cell metastasis and cell proliferation and is a favorable predictor of survival in breast cancer. OncoTargets and therapy 29 31114245
2025 Nrf3-Mediated Mitochondrial Superoxide Promotes Cardiomyocyte Apoptosis and Impairs Cardiac Functions by Suppressing Pitx2. Circulation 27 40099370
2022 Loss of NFE2L3 protects against inflammation-induced colorectal cancer through modulation of the tumor microenvironment. Oncogene 27 35091681
2015 Stringent Control of NFE2L3 (Nuclear Factor, Erythroid 2-Like 3; NRF3) Protein Degradation by FBW7 (F-box/WD Repeat-containing Protein 7) and Glycogen Synthase Kinase 3 (GSK3). The Journal of biological chemistry 25 26306035
2021 MicroRNA-1246 Mediates Drug Resistance and Metastasis in Breast Cancer by Targeting NFE2L3. Frontiers in oncology 22 34926237
2018 Nrf3 promotes UV-induced keratinocyte apoptosis through suppression of cell adhesion. Cell death and differentiation 22 29487353
2019 NFE2L3 Inhibition Induces Cell Cycle Arrest at the G0/G1 Phase in Colorectal Cancer Cells through Downregulating CCND1 and pRb1-ser807/811. Disease markers 16 31191746
2023 NFE2L3 drives hepatocellular carcinoma cell proliferation by regulating the proteasome-dependent degradation of ISGylated p53. Cancer science 14 37350063
2005 The cap 'n' collar family member NF-E2-related factor 3 (Nrf3) is expressed in mesodermal derivatives of the avian embryo. The International journal of developmental biology 12 15906252
2023 NRF3 activates mTORC1 arginine-dependently for cancer cell viability. iScience 11 36818298
2021 Nrf3 Promotes 5-FU Resistance in Colorectal Cancer Cells via the NF-κB/BCL-2 Signaling Pathway In Vitro and In Vivo. Journal of oncology 11 34795760
2021 Pathophysiological Potentials of NRF3-Regulated Transcriptional Axes in Protein and Lipid Homeostasis. International journal of molecular sciences 11 34884489
2021 Elevated expression of NFE2L3 promotes the development of gastric cancer through epithelial-mesenchymal transformation. Bioengineered 10 34783304
2023 NRF3 suppresses squamous carcinogenesis, involving the unfolded protein response regulator HSPA5. EMBO molecular medicine 9 37807968
2022 The CNC-family transcription factor Nrf3 coordinates the melanogenesis cascade through macropinocytosis and autophagy regulation. Cell reports 9 36640303
2021 miR-23b-3p Inhibits the Oncogenicity of Colon Adenocarcinoma by Directly Targeting NFE2L3. Journal of oncology 9 34966429
2019 Nuclear factor-erythroid 2-related factor 3 (NRF3) is low expressed in colorectal cancer and its down-regulation promotes colorectal cancer malignance through activating EGFR and p38/MAPK. American journal of cancer research 9 30949407
2024 NRF3 suppresses the malignant progression of TNBC by promoting M1 polarization of macrophages via ROS/HMGB1 axis. Cancer biology & therapy 7 39443820
2024 Nfe2l3 promotes neuroprotection and long-distance axon regeneration after injury in vivo. Experimental neurology 6 38395216
2025 NAT10 promotes the progression of clear cell renal cell carcinoma by regulating ac4C acetylation of NFE2L3 and activating AKT/GSK3β signaling pathway. Cell death & disease 5 40169553
2023 Hypomethylation-Mediated Upregulation of NFE2L3 Promotes Malignant Phenotypes of Clear Cell Renal Cell Carcinoma Cells. Molecular biotechnology 5 37071304
2023 Nrf3 promotes the proliferation and migration of triple‑negative breast cancer by activating PI3K/AKT/mTOR and epithelial‑mesenchymal transition. Oncology letters 5 37720674
2022 Multi-Omics Analysis of Molecular Characteristics and Carcinogenic Effect of NFE2L3 in Pan-Cancer. Frontiers in genetics 5 35846126
2022 Transcription factor NFE2L3 promotes the proliferation of esophageal squamous cell carcinoma cells and causes radiotherapy resistance by regulating IL-6. Computer methods and programs in biomedicine 5 36108571
2022 NFE2L3 as a Potential Functional Gene Regulating Immune Microenvironment in Human Kidney Cancer. BioMed research international 5 36337840
2024 NRF3 suppresses the metastasis of triple-negative breast cancer cells by inhibiting ERK activation in a ROS-dependent manner. Histology and histopathology 4 39005145
2024 New insight into the CNC-bZIP member, NFE2L3, in human diseases. Frontiers in cell and developmental biology 4 39149514
2025 A METTL3-NFE2L3 axis mediates tumor stemness and progression in lung adenocarcinoma. Science advances 3 40249818
2025 Novel roles of Nrf3-Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia. Cardiovascular research 3 40377016
2024 Identification roles of NFE2L3 in digestive system cancers. Journal of cancer research and clinical oncology 3 38514488
2023 Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway. Open life sciences 2 38027228
2022 NFE2L3 as a Novel Biomarker Associated With IL-2/STAT5/NLRP3 Signaling Pathway in Malignant Pleural Mesothelioma and Other Cancers. Frontiers in genetics 2 35664314
2025 The CNC-family transcription factor NRF3: A crucial therapeutic target for cancer treatment. Biochimica et biophysica acta. Molecular basis of disease 1 40081618
2025 NFE2L3 regulates inflammation and oxidative stress-related genes in the colon. Biochimica et biophysica acta. Molecular cell research 1 40360021
2026 Emodin induces oxidative stress and Ferroptosis in hepatocellular carcinoma cells through the miR-4465/NFE2L3/HMGCR/GPX4 signaling axis. Life sciences 0 41534777
2026 BHLHE40 Is a Transcriptional Regulatory Target of NFE2L3 in Triple-Negative Breast Cancer. Oncology research 0 41613788
2026 A comprehensive review of the emerging role of NRF3 in ovarian cancer tumorigenesis and progression. Journal of ovarian research 0 41652483
2026 Nrf3: an emerging player in cancer, inflammation, and cellular homeostasis. Molecular biology reports 0 41838283
2022 Nrf3 Functions Reversely as a Tumorigenic to an Antitumorigenic Transcription Factor in Obese Mice. The Tohoku journal of experimental medicine 0 36328531
2020 Correction to: Nrf3 promotes UV-induced keratinocyte apoptosis through suppression of cell adhesion. Cell death and differentiation 0 31641240