{"gene":"NFE2L2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2016,"finding":"NFE2L2/NRF2 directly regulates transcription of autophagy-related genes by binding antioxidant response elements (AREs) in their promoters. ChIP assays and qRT-PCR on human and mouse cells validated 12 AREs in 9 autophagy genes (including SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5, GABARAPL1). Loss of NFE2L2 in knockout MEFs reduced autophagy gene expression and impaired autophagy flux under oxidative stress, rescued by NFE2L2-expressing lentivirus.","method":"ChIP (ENCODE database + experimental), qRT-PCR, NFE2L2 knockout MEFs, lentiviral rescue, autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, qRT-PCR, KO + rescue), replicated across human and mouse cells","pmids":["27427974"],"is_preprint":false},{"year":2018,"finding":"NFE2L2/NRF2 transcriptionally regulates LAMP2A by binding two validated ARE sequences in the LAMP2 gene, thereby controlling chaperone-mediated autophagy (CMA) activity. NFE2L2 deficiency reduced lysosomal LAMP2A levels and CMA activity in hepatocytes; overexpression or pharmacological activation (sulforaphane, dimethyl fumarate) increased both LAMP2A and CMA activity.","method":"ChIP, qRT-PCR, NFE2L2 KO hepatocytes, NFE2L2 overexpression, pharmacological activation, CMA activity assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss of function with multiple orthogonal methods, validated ARE binding sites","pmids":["29950142"],"is_preprint":false},{"year":2020,"finding":"SQSTM1/p62 activates NFE2L2 through a noncanonical pathway: SQSTM1 facilitates AMPK-ULK1 interaction, leading to ULK1 phosphorylation, macroautophagy induction, and autophagic KEAP1 degradation, thereby releasing NFE2L2. Demonstrated in hepatocytes under lipotoxic conditions and confirmed in sqstm1-knockout mice.","method":"Co-immunoprecipitation, phosphorylation assays, sqstm1 conventional and liver-specific KO mice, autophagic flux assays, Western blot","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established in vitro and confirmed in multiple KO mouse models with orthogonal methods","pmids":["31913745"],"is_preprint":false},{"year":2019,"finding":"SQSTM1 Ser351 phosphorylation is required for KEAP1-SQSTM1 interaction and NFE2L2 activation. ALS-FTLD-linked mutation SQSTM1G427R abolishes Ser351 phosphorylation, disrupts the KEAP1-SQSTM1 interaction, and diminishes NFE2L2-targeted gene expression under oxidative stress. TBK1 and ULK1 coordinately phosphorylate SQSTM1 to promote selective autophagy and NFE2L2 signaling.","method":"Immunoprecipitation, phosphorylation assays with mutant constructs, gene expression analysis, neuronal overexpression experiments","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific mutagenesis combined with Co-IP and functional reporter assays in multiple cell types","pmids":["31362587"],"is_preprint":false},{"year":2013,"finding":"In microglia, fractalkine signaling activates AKT, inhibits GSK-3β, and upregulates NFE2L2/NRF2 and its target gene heme oxygenase 1 (HMOX1). NRF2-knockout and fractalkine receptor-knockout mice failed to express HMOX1 in microglia and showed increased microgliosis/astrogliosis in response to neuronal TAU(P301L), establishing NRF2 as a required component of the fractalkine anti-inflammatory pathway.","method":"Genetic KO mouse models (Nrf2-KO, CX3CR1-KO), AAV-TAU(P301L) hippocampal injection, immunohistochemistry, Western blot","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established with two independent KO mouse lines, replicated in human AD tissue","pmids":["24277722"],"is_preprint":false},{"year":2022,"finding":"ALKBH5-mediated m6A demethylation at two m6A residues in the 3'-UTR of NFE2L2 mRNA leads to post-transcriptional inhibition of NFE2L2/NRF2. m6A-dependent stabilization of NFE2L2 mRNA requires the reader protein IGF2BP2. Knockdown of ALKBH5 increases NFE2L2 expression and ferroptosis resistance in hypopharyngeal squamous cell carcinoma cells.","method":"m6A-seq (MeRIP-seq), RNA-seq, RIP-seq, MeRIP-qPCR, RIP-qPCR, dual-luciferase reporter assay, ALKBH5 knockdown","journal":"Journal of clinical laboratory analysis","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — transcriptome-wide m6A mapping plus functional validation with multiple orthogonal methods in a single study","pmids":["35689537"],"is_preprint":false},{"year":2024,"finding":"USP13 deubiquitinase interacts with and catalyzes deubiquitination of NFE2L2, stabilizing its protein levels. USP13 depletion promotes an autophagy-to-ferroptosis switch through the NFE2L2-SQSTM1/p62-KEAP1 axis in KRAS-mutant lung adenocarcinoma cells and xenograft models.","method":"DUB screen (85 enzymes), Co-IP, ubiquitination assays, USP13 KD in vitro and xenograft mouse models, NFE2L2 protein stability assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical deubiquitination assay plus in vivo xenograft validation with multiple orthogonal methods","pmids":["39360581"],"is_preprint":false},{"year":2024,"finding":"ES-Cu (elesclomol plus copper) increases NFE2L2 protein stability, leading to upregulation of GCLM and GCLC (rate-limiting enzymes in GSH synthesis). Elevated GSH is then transported into mitochondria via SLC25A39 to inhibit cuproptosis. Genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis in PDAC cells and mouse tumor models.","method":"NFE2L2 protein stability assays, gene expression analysis, genetic inhibition (KO/KD), cell culture cuproptosis assays, mouse tumor models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic inhibition in vitro and in vivo, but NFE2L2 stabilization mechanism not fully biochemically dissected","pmids":["39609608"],"is_preprint":false},{"year":2024,"finding":"SPOP E3 ubiquitin ligase adaptor binds SQSTM1 and induces non-degradative ubiquitination at Lys420, which suppresses SQSTM1 body formation and KEAP1 sequestration, thereby inhibiting NFE2L2 activation. Cancer-associated SPOP mutants lose the capacity to ubiquitinate SQSTM1 and instead enhance NFE2L2 activation in a dominant-negative manner.","method":"Binding assays, ubiquitination assays, SQSTM1 Lys420 mutant constructs, liquid phase condensation assays, SQSTM1 dimerization assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ubiquitination with functional readout, single lab, multiple complementary methods","pmids":["35438056"],"is_preprint":false},{"year":2024,"finding":"Metabolic stress induces a double-positive feedback loop: SQSTM1 phosphorylation (at S24 and S226 by MAP3K7/TAK1) activates both AMPK (by facilitating AXIN-STK11-AMPK complex on lysosomal membrane) and NFE2L2 (via autophagic KEAP1 degradation). AMPK activity in turn drives SQSTM1 expression through TFEB/TFE3 dephosphorylation. This synergizes antioxidant defense in NSCLC.","method":"Co-IP, phosphorylation mapping with phospho-specific antibodies, SQSTM1 phospho-mutant constructs, autophagy flux assays, MEF experiments, lysosomal fractionation","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including site-specific mutagenesis, Co-IP, and epistasis in multiple cell lines","pmids":["38953910"],"is_preprint":false},{"year":2022,"finding":"In Drosophila, disruption of ubiquitinated protein autophagy (ref(2)P/SQSTM1 mutation that prevents Atg8a binding) causes polyubiquitinated aggregate accumulation that co-sequesters Keap1, thereby activating the cnc/NFE2L2/Nrf2 antioxidant pathway. This activation increases oxidative stress tolerance and reduces mitochondrial superoxide, compensating for lost autophagy.","method":"Drosophila genetic model, ref(2)P point mutant (disrupted LIR motif), Keap1 co-sequestration assay, oxidative stress tolerance assay, mitochondrial superoxide measurement","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila ortholog, genetic model with mechanistic readout, single lab","pmids":["35184662"],"is_preprint":false},{"year":2021,"finding":"NFE2L2 mutation (Nrf2E79Q) activates Nrf2, confers radioresistance in HNSCC cells, and promotes recruitment of PMN-MDSCs while reducing M1-polarized macrophages in immunocompetent but not immunocompromised mice. Glutaminase inhibition (CB-839) overcomes this radioresistance by reversing CXCL1/CXCL3/CSF3 upregulation via TLR4.","method":"HNSCC cell lines with Nrf2E79Q/E79K mutants, syngeneic immunocompetent vs. immunocompromised mouse tumors, flow cytometry, CB-839 pharmacological treatment, cytokine expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic mutant comparison in vivo with immune cell phenotyping, single study","pmids":["36652552"],"is_preprint":false},{"year":2021,"finding":"Patient-derived NFE2L2 mutants (L30P and R34P) are directly oncogenic in mouse liver: co-expression of any two members of the mutant β-catenin–YAPS127A–NFE2L2-mutant triad is sufficient to drive hepatoblastoma growth, establishing NFE2L2 oncogenicity independent of its co-drivers.","method":"Hydrodynamic transfection into murine liver, tumor growth measurement, transcriptomic analysis, survival correlation in human HB datasets","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with pairwise combination testing, single lab","pmids":["33618031"],"is_preprint":false},{"year":2022,"finding":"In Trp53/p16-deficient mice, activation of the NRF2E79Q mutation is associated with increased incidence of pure-SCLC (P-SCLC) but not combined-SCLC (C-SCLC), suggesting a tumor-type-specific oncogenic role for NRF2 activation in small cell lung cancer development.","method":"Genetically engineered mouse model (GEMM), Cre-induced LSL-Nrf2E79Q recombination, histopathology, IHC, NRF2 pathway signature analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GEMM with conditional allele activation, single lab, histological phenotyping","pmids":["35577980"],"is_preprint":false},{"year":2011,"finding":"Cyclosporine-A (CsA)-stimulated HO-1 expression in human gingival fibroblasts is mediated through ERK-dependent nuclear translocation of NFE2L2/NRF2. siRNA knockdown of Nrf-2 (but not NF-κB inhibition) reduced CsA-stimulated HO-1 mRNA expression; ERK inhibition decreased NRF2 nuclear translocation and HO-1 expression.","method":"siRNA knockdown, kinase inhibitors, nuclear translocation assay, qRT-PCR, sulforaphane pretreatment","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with mechanistic pathway dissection, single lab, multiple inhibitors","pmids":["21622902"],"is_preprint":false},{"year":2005,"finding":"The nrf-2 gene is required for induction of antioxidant enzymes in gastric mucosal cells exposed to oxidative stress. Sulforaphane stimulates nrf-2-gene-dependent antioxidant enzyme activities, protecting gastric cells from oxidative injury during H. pylori infection.","method":"Cell-based antioxidant enzyme activity assays, nrf-2 gene manipulation, sulforaphane treatment, mucosal cell protection assays","journal":"Inflammopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic claim from abstract lacks full experimental detail; single lab, limited methodological specifics","pmids":["16259730"],"is_preprint":false}],"current_model":"NFE2L2/NRF2 is a master transcription factor that, under basal and stress conditions, translocates to the nucleus and binds antioxidant response elements (AREs) to drive expression of antioxidant, detoxification, autophagy, and iron-handling genes; its activity is principally controlled by KEAP1-mediated ubiquitination and proteasomal degradation, which is relieved by electrophilic/oxidative stress, by SQSTM1/p62-mediated autophagic degradation of KEAP1 (noncanonical pathway), by deubiquitination via USP13, and by m6A-dependent mRNA stabilization through the ALKBH5-IGF2BP2 axis; gain-of-function mutations in NFE2L2 hotspot residues constitutively activate the pathway, conferring oncogenicity, chemoresistance, and radioresistance in multiple cancer types."},"narrative":{"mechanistic_narrative":"NFE2L2/NRF2 is a stress-responsive transcription factor that binds antioxidant response elements (AREs) in target gene promoters to coordinate antioxidant defense, detoxification, autophagy, and iron/redox metabolism [PMID:27427974]. Beyond classical antioxidant enzymes, NFE2L2 directly drives a transcriptional program supporting autophagy: it binds validated AREs in autophagy genes including SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5, and GABARAPL1, with NFE2L2 loss impairing autophagy flux under oxidative stress [PMID:27427974], and it transactivates LAMP2 to control chaperone-mediated autophagy [PMID:29950142]. Its activity is governed principally at the protein-stability level through KEAP1: SQSTM1/p62 sequesters KEAP1 into condensates and promotes its autophagic degradation, thereby releasing NFE2L2, a noncanonical activation route that requires SQSTM1 Ser351 phosphorylation by TBK1/ULK1 for the KEAP1-SQSTM1 interaction [PMID:31362587] and that is reinforced by AMPK-coupled feedback driving SQSTM1 expression under metabolic stress [PMID:31913745, PMID:38953910]. This SQSTM1-KEAP1 node is further tuned by ubiquitin machinery — SPOP imposes non-degradative ubiquitination on SQSTM1 to restrain NFE2L2 activation [PMID:35438056], while the deubiquitinase USP13 directly stabilizes NFE2L2 to govern an autophagy-to-ferroptosis switch [PMID:39360581]. NFE2L2 output also includes a GSH-synthesis program (GCLM/GCLC) feeding mitochondrial glutathione import to suppress cuproptosis [PMID:39609608]. Gain-of-function hotspot mutations (E79Q, L30P, R34P) constitutively activate NFE2L2, conferring oncogenicity, radioresistance, immune remodeling, and tumor-type-specific tumorigenesis across hepatoblastoma, HNSCC, and small cell lung cancer [PMID:36652552, PMID:33618031, PMID:35577980]. In a separate physiological context, NFE2L2 acts downstream of microglial fractalkine-AKT-GSK3β signaling to induce HMOX1 and limit neuroinflammation [PMID:24277722].","teleology":[{"year":2005,"claim":"Established that NRF2 is required for stress-induced antioxidant enzyme induction, framing it as a protective redox effector.","evidence":"nrf-2 gene manipulation and sulforaphane treatment in gastric mucosal cells under H. pylori-associated oxidative injury","pmids":["16259730"],"confidence":"Low","gaps":["Abstract-level mechanistic claim lacking experimental detail","No direct target genes or binding sites defined","Single system, not independently confirmed here"]},{"year":2011,"claim":"Identified the signaling route to NRF2 activation in a stress context, showing ERK-dependent nuclear translocation drives HO-1.","evidence":"siRNA knockdown, kinase inhibitors, and nuclear translocation assays in cyclosporine-A-treated gingival fibroblasts","pmids":["21622902"],"confidence":"Medium","gaps":["Does not establish direct ARE binding at HMOX1","Mechanism of ERK-NRF2 coupling not defined","Single cell type"]},{"year":2013,"claim":"Placed NRF2 within an anti-inflammatory neuronal signaling axis, showing it is a required effector downstream of fractalkine in microglia.","evidence":"Nrf2-KO and CX3CR1-KO mice with AAV-TAU(P301L) injection, IHC, Western blot","pmids":["24277722"],"confidence":"High","gaps":["Direct NRF2 targets in microglia beyond HMOX1 not enumerated","Does not resolve KEAP1-dependence in this context"]},{"year":2016,"claim":"Reframed NRF2 as a direct transcriptional driver of autophagy, not just antioxidant enzymes, by mapping AREs in core autophagy genes.","evidence":"ChIP, qRT-PCR, NFE2L2 KO MEFs with lentiviral rescue, autophagy flux assays in human and mouse cells","pmids":["27427974"],"confidence":"High","gaps":["Does not address feedback via SQSTM1 it transcribes","Quantitative contribution of each ARE not dissected"]},{"year":2018,"claim":"Extended NRF2 transcriptional control to chaperone-mediated autophagy by identifying LAMP2 as a direct target.","evidence":"ChIP, qRT-PCR, NFE2L2 KO hepatocytes, gain-of-function and pharmacological activation, CMA activity assays","pmids":["29950142"],"confidence":"High","gaps":["LAMP2A-specific isoform regulation mechanism not fully resolved","Single tissue context"]},{"year":2019,"claim":"Defined the molecular requirement for noncanonical NRF2 activation, showing SQSTM1 Ser351 phosphorylation gates the KEAP1-SQSTM1 interaction.","evidence":"Co-IP, site-specific phospho-mutant constructs, ALS-FTLD SQSTM1 mutant, gene expression assays in neuronal cells","pmids":["31362587"],"confidence":"High","gaps":["Relative contributions of TBK1 vs ULK1 not quantified","Structural basis of phospho-dependent binding not solved"]},{"year":2020,"claim":"Established the epistatic logic of noncanonical activation: SQSTM1 drives AMPK-ULK1-dependent autophagic KEAP1 degradation to release NRF2.","evidence":"Co-IP, phosphorylation assays, sqstm1 conventional and liver-specific KO mice under lipotoxic conditions","pmids":["31913745"],"confidence":"High","gaps":["Does not quantify KEAP1 turnover kinetics","Generality beyond hepatic lipotoxicity"]},{"year":2021,"claim":"Demonstrated that NRF2 hotspot mutations are intrinsically oncogenic and remodel the tumor immune microenvironment.","evidence":"Nrf2E79Q HNSCC lines and syngeneic vs immunocompromised mice with flow cytometry; hydrodynamic transfection of L30P/R34P mutants in murine liver","pmids":["36652552","33618031"],"confidence":"Medium","gaps":["Direct transcriptional targets mediating immune remodeling only partly defined","Single-lab in vivo models"]},{"year":2022,"claim":"Identified post-transcriptional control of NRF2 via m6A, showing ALKBH5 demethylation destabilizes NFE2L2 mRNA in an IGF2BP2-dependent manner.","evidence":"MeRIP-seq, RIP-seq, dual-luciferase reporter, ALKBH5 knockdown in hypopharyngeal carcinoma cells","pmids":["35689537"],"confidence":"High","gaps":["In vivo relevance not tested","Stoichiometry of the two 3'-UTR m6A sites unresolved"]},{"year":2022,"claim":"Showed in Drosophila that loss of selective autophagy activates the NRF2 ortholog via Keap1 co-sequestration, providing cross-species support for the SQSTM1-KEAP1 axis.","evidence":"ref(2)P LIR-motif point mutant, Keap1 co-sequestration assay, oxidative stress and mitochondrial superoxide measurements","pmids":["35184662"],"confidence":"Medium","gaps":["Ortholog system; human equivalence not directly shown","Single lab"]},{"year":2024,"claim":"Resolved ubiquitin-machinery control of the SQSTM1-KEAP1-NRF2 node from both directions: SPOP restrains it via non-degradative SQSTM1 ubiquitination, while USP13 directly deubiquitinates and stabilizes NRF2.","evidence":"SPOP binding/ubiquitination assays with SQSTM1 K420 mutants and condensation assays; DUB screen, Co-IP, ubiquitination assays, USP13 KD in vitro and xenografts","pmids":["35438056","39360581"],"confidence":"Medium","gaps":["USP13 deubiquitination established High; SPOP node Medium/single lab","Crosstalk between SPOP and USP13 on NRF2 not tested together"]},{"year":2024,"claim":"Connected NRF2 output to metabolic cell-death control via a GSH-synthesis program and integrated it into an AMPK feedback loop.","evidence":"NFE2L2 stability assays with GCLM/GCLC and SLC25A39 in PDAC cuproptosis models; SQSTM1 phospho-mapping (S24/S226 by TAK1) with AMPK and TFEB/TFE3 readouts in NSCLC","pmids":["39609608","38953910"],"confidence":"Medium","gaps":["NFE2L2 stabilization mechanism by ES-Cu not biochemically dissected","Generality of the double-positive feedback loop beyond NSCLC"]},{"year":2024,"claim":"Refined oncogenic context-dependence, showing NRF2 hotspot activation promotes specific tumor subtypes.","evidence":"Trp53/p16-deficient GEMM with conditional LSL-Nrf2E79Q activation, histopathology and pathway signature analysis","pmids":["35577980"],"confidence":"Medium","gaps":["Mechanism of subtype selectivity (P-SCLC vs C-SCLC) unexplained","Single GEMM"]},{"year":null,"claim":"How the multiple layers of NRF2 control — KEAP1 sequestration, m6A mRNA stabilization, USP13/SPOP ubiquitin editing, and AMPK feedback — are integrated and prioritized within a single cell under graded stress remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of relative flux through each regulatory layer","Structural basis of NRF2-ARE selectivity across antioxidant vs autophagy targets not defined","Therapeutic exploitation of activating mutations beyond glutaminase inhibition untested broadly"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,4,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,12,13]}],"complexes":[],"partners":["KEAP1","SQSTM1","USP13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16236","full_name":"Nuclear factor erythroid 2-related factor 2","aliases":["Nuclear factor, erythroid derived 2, like 2"],"length_aa":605,"mass_kda":67.8,"function":"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 neutralizing reactive electrophiles (PubMed:11035812, PubMed:19489739, PubMed:29018201, PubMed:31398338). In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex (PubMed:11035812, PubMed:15601839, PubMed:29018201). In response to oxidative stress, electrophile metabolites inhibit activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes (PubMed:19489739, PubMed:29590092). 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 (PubMed:20452972). The NFE2L2/NRF2 pathway is also activated during the unfolded protein response (UPR), contributing to redox homeostasis and cell survival following endoplasmic reticulum stress (By similarity). 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 (PubMed:7937919). Also plays an important role in the regulation of the innate immune response and antiviral cytosolic DNA sensing. It is a critical regulator of the innate immune response and survival during sepsis by maintaining redox homeostasis and restraint of the dysregulation of pro-inflammatory signaling pathways like MyD88-dependent and -independent and TNF signaling (By similarity). Suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6 (By similarity). Binds to the proximity of pro-inflammatory genes in macrophages and inhibits RNA Pol II recruitment. The inhibition is independent of the NRF2-binding motif and reactive oxygen species level (By similarity). Represses antiviral cytosolic DNA sensing by suppressing the expression of the adapter protein STING1 and decreasing responsiveness to STING1 agonists while increasing susceptibility to infection with DNA viruses (PubMed:30158636). Once activated, limits the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and to virus-derived ligands through a mechanism that involves inhibition of IRF3 dimerization. Also inhibits both SARS-CoV-2 replication, as well as the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism (PubMed:33009401)","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q16236/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NFE2L2","classification":"Not Classified","n_dependent_lines":166,"n_total_lines":1208,"dependency_fraction":0.13741721854304637},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NFE2L2","total_profiled":1310},"omim":[{"mim_id":"621451","title":"SMALL NUCLEOLAR RNA HOST GENE 12; SNHG12","url":"https://www.omim.org/entry/621451"},{"mim_id":"618190","title":"LUNG CANCER-ASSOCIATED TRANSCRIPT 1, NONCODING; LUCAT1","url":"https://www.omim.org/entry/618190"},{"mim_id":"617744","title":"IMMUNODEFICIENCY, DEVELOPMENTAL DELAY, AND HYPOHOMOCYSTEINEMIA; IMDDHH","url":"https://www.omim.org/entry/617744"},{"mim_id":"616009","title":"COP9 SIGNALOSOME, SUBUNIT 7A; COPS7A","url":"https://www.omim.org/entry/616009"},{"mim_id":"614939","title":"PHOSPHOGLYCERATE MUTASE FAMILY, MEMBER 5; PGAM5","url":"https://www.omim.org/entry/614939"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NFE2L2"},"hgnc":{"alias_symbol":["NRF2","NRF-2"],"prev_symbol":[]},"alphafold":{"accession":"Q16236","domains":[{"cath_id":"1.10.880.10","chopping":"455-534","consensus_level":"medium","plddt":93.0745,"start":455,"end":534}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16236","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16236-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16236-F1-predicted_aligned_error_v6.png","plddt_mean":60.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NFE2L2","jax_strain_url":"https://www.jax.org/strain/search?query=NFE2L2"},"sequence":{"accession":"Q16236","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16236.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16236/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16236"}},"corpus_meta":[{"pmid":"27427974","id":"PMC_27427974","title":"Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27427974","citation_count":331,"is_preprint":false},{"pmid":"31913745","id":"PMC_31913745","title":"SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31913745","citation_count":191,"is_preprint":false},{"pmid":"30236989","id":"PMC_30236989","title":"Regulatory crosstalk between the oxidative stress-related transcription factor Nfe2l2/Nrf2 and mitochondria.","date":"2018","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30236989","citation_count":190,"is_preprint":false},{"pmid":"29950142","id":"PMC_29950142","title":"Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of 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preeclampsia.","date":"2021","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/34237527","citation_count":13,"is_preprint":false},{"pmid":"38087141","id":"PMC_38087141","title":"Chitosan-insulin nano-formulations as critical modulators of inflammatory cytokines and Nrf-2 pathway to accelerate burn wound healing.","date":"2023","source":"Discover nano","url":"https://pubmed.ncbi.nlm.nih.gov/38087141","citation_count":13,"is_preprint":false},{"pmid":"38665580","id":"PMC_38665580","title":"Nrf-2 as a novel target in radiation induced lung injury.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38665580","citation_count":12,"is_preprint":false},{"pmid":"29630901","id":"PMC_29630901","title":"NFE2L2, PPARGC1α, and pesticides and Parkinson's disease risk and progression.","date":"2018","source":"Mechanisms of ageing and 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38449809","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59672,"output_tokens":4425,"usd":0.122695,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12322,"output_tokens":4331,"usd":0.084943,"stage2_stop_reason":"end_turn"},"total_usd":0.207638,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"NFE2L2/NRF2 directly regulates transcription of autophagy-related genes by binding antioxidant response elements (AREs) in their promoters. ChIP assays and qRT-PCR on human and mouse cells validated 12 AREs in 9 autophagy genes (including SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5, GABARAPL1). Loss of NFE2L2 in knockout MEFs reduced autophagy gene expression and impaired autophagy flux under oxidative stress, rescued by NFE2L2-expressing lentivirus.\",\n      \"method\": \"ChIP (ENCODE database + experimental), qRT-PCR, NFE2L2 knockout MEFs, lentiviral rescue, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, qRT-PCR, KO + rescue), replicated across human and mouse cells\",\n      \"pmids\": [\"27427974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NFE2L2/NRF2 transcriptionally regulates LAMP2A by binding two validated ARE sequences in the LAMP2 gene, thereby controlling chaperone-mediated autophagy (CMA) activity. NFE2L2 deficiency reduced lysosomal LAMP2A levels and CMA activity in hepatocytes; overexpression or pharmacological activation (sulforaphane, dimethyl fumarate) increased both LAMP2A and CMA activity.\",\n      \"method\": \"ChIP, qRT-PCR, NFE2L2 KO hepatocytes, NFE2L2 overexpression, pharmacological activation, CMA activity assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss of function with multiple orthogonal methods, validated ARE binding sites\",\n      \"pmids\": [\"29950142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SQSTM1/p62 activates NFE2L2 through a noncanonical pathway: SQSTM1 facilitates AMPK-ULK1 interaction, leading to ULK1 phosphorylation, macroautophagy induction, and autophagic KEAP1 degradation, thereby releasing NFE2L2. Demonstrated in hepatocytes under lipotoxic conditions and confirmed in sqstm1-knockout mice.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, sqstm1 conventional and liver-specific KO mice, autophagic flux assays, Western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established in vitro and confirmed in multiple KO mouse models with orthogonal methods\",\n      \"pmids\": [\"31913745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SQSTM1 Ser351 phosphorylation is required for KEAP1-SQSTM1 interaction and NFE2L2 activation. ALS-FTLD-linked mutation SQSTM1G427R abolishes Ser351 phosphorylation, disrupts the KEAP1-SQSTM1 interaction, and diminishes NFE2L2-targeted gene expression under oxidative stress. TBK1 and ULK1 coordinately phosphorylate SQSTM1 to promote selective autophagy and NFE2L2 signaling.\",\n      \"method\": \"Immunoprecipitation, phosphorylation assays with mutant constructs, gene expression analysis, neuronal overexpression experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific mutagenesis combined with Co-IP and functional reporter assays in multiple cell types\",\n      \"pmids\": [\"31362587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In microglia, fractalkine signaling activates AKT, inhibits GSK-3β, and upregulates NFE2L2/NRF2 and its target gene heme oxygenase 1 (HMOX1). NRF2-knockout and fractalkine receptor-knockout mice failed to express HMOX1 in microglia and showed increased microgliosis/astrogliosis in response to neuronal TAU(P301L), establishing NRF2 as a required component of the fractalkine anti-inflammatory pathway.\",\n      \"method\": \"Genetic KO mouse models (Nrf2-KO, CX3CR1-KO), AAV-TAU(P301L) hippocampal injection, immunohistochemistry, Western blot\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established with two independent KO mouse lines, replicated in human AD tissue\",\n      \"pmids\": [\"24277722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALKBH5-mediated m6A demethylation at two m6A residues in the 3'-UTR of NFE2L2 mRNA leads to post-transcriptional inhibition of NFE2L2/NRF2. m6A-dependent stabilization of NFE2L2 mRNA requires the reader protein IGF2BP2. Knockdown of ALKBH5 increases NFE2L2 expression and ferroptosis resistance in hypopharyngeal squamous cell carcinoma cells.\",\n      \"method\": \"m6A-seq (MeRIP-seq), RNA-seq, RIP-seq, MeRIP-qPCR, RIP-qPCR, dual-luciferase reporter assay, ALKBH5 knockdown\",\n      \"journal\": \"Journal of clinical laboratory analysis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — transcriptome-wide m6A mapping plus functional validation with multiple orthogonal methods in a single study\",\n      \"pmids\": [\"35689537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP13 deubiquitinase interacts with and catalyzes deubiquitination of NFE2L2, stabilizing its protein levels. USP13 depletion promotes an autophagy-to-ferroptosis switch through the NFE2L2-SQSTM1/p62-KEAP1 axis in KRAS-mutant lung adenocarcinoma cells and xenograft models.\",\n      \"method\": \"DUB screen (85 enzymes), Co-IP, ubiquitination assays, USP13 KD in vitro and xenograft mouse models, NFE2L2 protein stability assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical deubiquitination assay plus in vivo xenograft validation with multiple orthogonal methods\",\n      \"pmids\": [\"39360581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ES-Cu (elesclomol plus copper) increases NFE2L2 protein stability, leading to upregulation of GCLM and GCLC (rate-limiting enzymes in GSH synthesis). Elevated GSH is then transported into mitochondria via SLC25A39 to inhibit cuproptosis. Genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis in PDAC cells and mouse tumor models.\",\n      \"method\": \"NFE2L2 protein stability assays, gene expression analysis, genetic inhibition (KO/KD), cell culture cuproptosis assays, mouse tumor models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic inhibition in vitro and in vivo, but NFE2L2 stabilization mechanism not fully biochemically dissected\",\n      \"pmids\": [\"39609608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPOP E3 ubiquitin ligase adaptor binds SQSTM1 and induces non-degradative ubiquitination at Lys420, which suppresses SQSTM1 body formation and KEAP1 sequestration, thereby inhibiting NFE2L2 activation. Cancer-associated SPOP mutants lose the capacity to ubiquitinate SQSTM1 and instead enhance NFE2L2 activation in a dominant-negative manner.\",\n      \"method\": \"Binding assays, ubiquitination assays, SQSTM1 Lys420 mutant constructs, liquid phase condensation assays, SQSTM1 dimerization assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ubiquitination with functional readout, single lab, multiple complementary methods\",\n      \"pmids\": [\"35438056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Metabolic stress induces a double-positive feedback loop: SQSTM1 phosphorylation (at S24 and S226 by MAP3K7/TAK1) activates both AMPK (by facilitating AXIN-STK11-AMPK complex on lysosomal membrane) and NFE2L2 (via autophagic KEAP1 degradation). AMPK activity in turn drives SQSTM1 expression through TFEB/TFE3 dephosphorylation. This synergizes antioxidant defense in NSCLC.\",\n      \"method\": \"Co-IP, phosphorylation mapping with phospho-specific antibodies, SQSTM1 phospho-mutant constructs, autophagy flux assays, MEF experiments, lysosomal fractionation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including site-specific mutagenesis, Co-IP, and epistasis in multiple cell lines\",\n      \"pmids\": [\"38953910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila, disruption of ubiquitinated protein autophagy (ref(2)P/SQSTM1 mutation that prevents Atg8a binding) causes polyubiquitinated aggregate accumulation that co-sequesters Keap1, thereby activating the cnc/NFE2L2/Nrf2 antioxidant pathway. This activation increases oxidative stress tolerance and reduces mitochondrial superoxide, compensating for lost autophagy.\",\n      \"method\": \"Drosophila genetic model, ref(2)P point mutant (disrupted LIR motif), Keap1 co-sequestration assay, oxidative stress tolerance assay, mitochondrial superoxide measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila ortholog, genetic model with mechanistic readout, single lab\",\n      \"pmids\": [\"35184662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NFE2L2 mutation (Nrf2E79Q) activates Nrf2, confers radioresistance in HNSCC cells, and promotes recruitment of PMN-MDSCs while reducing M1-polarized macrophages in immunocompetent but not immunocompromised mice. Glutaminase inhibition (CB-839) overcomes this radioresistance by reversing CXCL1/CXCL3/CSF3 upregulation via TLR4.\",\n      \"method\": \"HNSCC cell lines with Nrf2E79Q/E79K mutants, syngeneic immunocompetent vs. immunocompromised mouse tumors, flow cytometry, CB-839 pharmacological treatment, cytokine expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic mutant comparison in vivo with immune cell phenotyping, single study\",\n      \"pmids\": [\"36652552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Patient-derived NFE2L2 mutants (L30P and R34P) are directly oncogenic in mouse liver: co-expression of any two members of the mutant β-catenin–YAPS127A–NFE2L2-mutant triad is sufficient to drive hepatoblastoma growth, establishing NFE2L2 oncogenicity independent of its co-drivers.\",\n      \"method\": \"Hydrodynamic transfection into murine liver, tumor growth measurement, transcriptomic analysis, survival correlation in human HB datasets\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with pairwise combination testing, single lab\",\n      \"pmids\": [\"33618031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Trp53/p16-deficient mice, activation of the NRF2E79Q mutation is associated with increased incidence of pure-SCLC (P-SCLC) but not combined-SCLC (C-SCLC), suggesting a tumor-type-specific oncogenic role for NRF2 activation in small cell lung cancer development.\",\n      \"method\": \"Genetically engineered mouse model (GEMM), Cre-induced LSL-Nrf2E79Q recombination, histopathology, IHC, NRF2 pathway signature analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GEMM with conditional allele activation, single lab, histological phenotyping\",\n      \"pmids\": [\"35577980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cyclosporine-A (CsA)-stimulated HO-1 expression in human gingival fibroblasts is mediated through ERK-dependent nuclear translocation of NFE2L2/NRF2. siRNA knockdown of Nrf-2 (but not NF-κB inhibition) reduced CsA-stimulated HO-1 mRNA expression; ERK inhibition decreased NRF2 nuclear translocation and HO-1 expression.\",\n      \"method\": \"siRNA knockdown, kinase inhibitors, nuclear translocation assay, qRT-PCR, sulforaphane pretreatment\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with mechanistic pathway dissection, single lab, multiple inhibitors\",\n      \"pmids\": [\"21622902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The nrf-2 gene is required for induction of antioxidant enzymes in gastric mucosal cells exposed to oxidative stress. Sulforaphane stimulates nrf-2-gene-dependent antioxidant enzyme activities, protecting gastric cells from oxidative injury during H. pylori infection.\",\n      \"method\": \"Cell-based antioxidant enzyme activity assays, nrf-2 gene manipulation, sulforaphane treatment, mucosal cell protection assays\",\n      \"journal\": \"Inflammopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic claim from abstract lacks full experimental detail; single lab, limited methodological specifics\",\n      \"pmids\": [\"16259730\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NFE2L2/NRF2 is a master transcription factor that, under basal and stress conditions, translocates to the nucleus and binds antioxidant response elements (AREs) to drive expression of antioxidant, detoxification, autophagy, and iron-handling genes; its activity is principally controlled by KEAP1-mediated ubiquitination and proteasomal degradation, which is relieved by electrophilic/oxidative stress, by SQSTM1/p62-mediated autophagic degradation of KEAP1 (noncanonical pathway), by deubiquitination via USP13, and by m6A-dependent mRNA stabilization through the ALKBH5-IGF2BP2 axis; gain-of-function mutations in NFE2L2 hotspot residues constitutively activate the pathway, conferring oncogenicity, chemoresistance, and radioresistance in multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NFE2L2/NRF2 is a stress-responsive transcription factor that binds antioxidant response elements (AREs) in target gene promoters to coordinate antioxidant defense, detoxification, autophagy, and iron/redox metabolism [#0]. Beyond classical antioxidant enzymes, NFE2L2 directly drives a transcriptional program supporting autophagy: it binds validated AREs in autophagy genes including SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5, and GABARAPL1, with NFE2L2 loss impairing autophagy flux under oxidative stress [#0], and it transactivates LAMP2 to control chaperone-mediated autophagy [#1]. Its activity is governed principally at the protein-stability level through KEAP1: SQSTM1/p62 sequesters KEAP1 into condensates and promotes its autophagic degradation, thereby releasing NFE2L2, a noncanonical activation route that requires SQSTM1 Ser351 phosphorylation by TBK1/ULK1 for the KEAP1-SQSTM1 interaction [#3] and that is reinforced by AMPK-coupled feedback driving SQSTM1 expression under metabolic stress [#2, #9]. This SQSTM1-KEAP1 node is further tuned by ubiquitin machinery — SPOP imposes non-degradative ubiquitination on SQSTM1 to restrain NFE2L2 activation [#8], while the deubiquitinase USP13 directly stabilizes NFE2L2 to govern an autophagy-to-ferroptosis switch [#6]. NFE2L2 output also includes a GSH-synthesis program (GCLM/GCLC) feeding mitochondrial glutathione import to suppress cuproptosis [#7]. Gain-of-function hotspot mutations (E79Q, L30P, R34P) constitutively activate NFE2L2, conferring oncogenicity, radioresistance, immune remodeling, and tumor-type-specific tumorigenesis across hepatoblastoma, HNSCC, and small cell lung cancer [#11, #12, #13]. In a separate physiological context, NFE2L2 acts downstream of microglial fractalkine-AKT-GSK3\\u03b2 signaling to induce HMOX1 and limit neuroinflammation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that NRF2 is required for stress-induced antioxidant enzyme induction, framing it as a protective redox effector.\",\n      \"evidence\": \"nrf-2 gene manipulation and sulforaphane treatment in gastric mucosal cells under H. pylori-associated oxidative injury\",\n      \"pmids\": [\"16259730\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Abstract-level mechanistic claim lacking experimental detail\", \"No direct target genes or binding sites defined\", \"Single system, not independently confirmed here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the signaling route to NRF2 activation in a stress context, showing ERK-dependent nuclear translocation drives HO-1.\",\n      \"evidence\": \"siRNA knockdown, kinase inhibitors, and nuclear translocation assays in cyclosporine-A-treated gingival fibroblasts\",\n      \"pmids\": [\"21622902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish direct ARE binding at HMOX1\", \"Mechanism of ERK-NRF2 coupling not defined\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed NRF2 within an anti-inflammatory neuronal signaling axis, showing it is a required effector downstream of fractalkine in microglia.\",\n      \"evidence\": \"Nrf2-KO and CX3CR1-KO mice with AAV-TAU(P301L) injection, IHC, Western blot\",\n      \"pmids\": [\"24277722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NRF2 targets in microglia beyond HMOX1 not enumerated\", \"Does not resolve KEAP1-dependence in this context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reframed NRF2 as a direct transcriptional driver of autophagy, not just antioxidant enzymes, by mapping AREs in core autophagy genes.\",\n      \"evidence\": \"ChIP, qRT-PCR, NFE2L2 KO MEFs with lentiviral rescue, autophagy flux assays in human and mouse cells\",\n      \"pmids\": [\"27427974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address feedback via SQSTM1 it transcribes\", \"Quantitative contribution of each ARE not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended NRF2 transcriptional control to chaperone-mediated autophagy by identifying LAMP2 as a direct target.\",\n      \"evidence\": \"ChIP, qRT-PCR, NFE2L2 KO hepatocytes, gain-of-function and pharmacological activation, CMA activity assays\",\n      \"pmids\": [\"29950142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LAMP2A-specific isoform regulation mechanism not fully resolved\", \"Single tissue context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the molecular requirement for noncanonical NRF2 activation, showing SQSTM1 Ser351 phosphorylation gates the KEAP1-SQSTM1 interaction.\",\n      \"evidence\": \"Co-IP, site-specific phospho-mutant constructs, ALS-FTLD SQSTM1 mutant, gene expression assays in neuronal cells\",\n      \"pmids\": [\"31362587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of TBK1 vs ULK1 not quantified\", \"Structural basis of phospho-dependent binding not solved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the epistatic logic of noncanonical activation: SQSTM1 drives AMPK-ULK1-dependent autophagic KEAP1 degradation to release NRF2.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, sqstm1 conventional and liver-specific KO mice under lipotoxic conditions\",\n      \"pmids\": [\"31913745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not quantify KEAP1 turnover kinetics\", \"Generality beyond hepatic lipotoxicity\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that NRF2 hotspot mutations are intrinsically oncogenic and remodel the tumor immune microenvironment.\",\n      \"evidence\": \"Nrf2E79Q HNSCC lines and syngeneic vs immunocompromised mice with flow cytometry; hydrodynamic transfection of L30P/R34P mutants in murine liver\",\n      \"pmids\": [\"36652552\", \"33618031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets mediating immune remodeling only partly defined\", \"Single-lab in vivo models\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-transcriptional control of NRF2 via m6A, showing ALKBH5 demethylation destabilizes NFE2L2 mRNA in an IGF2BP2-dependent manner.\",\n      \"evidence\": \"MeRIP-seq, RIP-seq, dual-luciferase reporter, ALKBH5 knockdown in hypopharyngeal carcinoma cells\",\n      \"pmids\": [\"35689537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance not tested\", \"Stoichiometry of the two 3'-UTR m6A sites unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed in Drosophila that loss of selective autophagy activates the NRF2 ortholog via Keap1 co-sequestration, providing cross-species support for the SQSTM1-KEAP1 axis.\",\n      \"evidence\": \"ref(2)P LIR-motif point mutant, Keap1 co-sequestration assay, oxidative stress and mitochondrial superoxide measurements\",\n      \"pmids\": [\"35184662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog system; human equivalence not directly shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved ubiquitin-machinery control of the SQSTM1-KEAP1-NRF2 node from both directions: SPOP restrains it via non-degradative SQSTM1 ubiquitination, while USP13 directly deubiquitinates and stabilizes NRF2.\",\n      \"evidence\": \"SPOP binding/ubiquitination assays with SQSTM1 K420 mutants and condensation assays; DUB screen, Co-IP, ubiquitination assays, USP13 KD in vitro and xenografts\",\n      \"pmids\": [\"35438056\", \"39360581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"USP13 deubiquitination established High; SPOP node Medium/single lab\", \"Crosstalk between SPOP and USP13 on NRF2 not tested together\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected NRF2 output to metabolic cell-death control via a GSH-synthesis program and integrated it into an AMPK feedback loop.\",\n      \"evidence\": \"NFE2L2 stability assays with GCLM/GCLC and SLC25A39 in PDAC cuproptosis models; SQSTM1 phospho-mapping (S24/S226 by TAK1) with AMPK and TFEB/TFE3 readouts in NSCLC\",\n      \"pmids\": [\"39609608\", \"38953910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NFE2L2 stabilization mechanism by ES-Cu not biochemically dissected\", \"Generality of the double-positive feedback loop beyond NSCLC\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined oncogenic context-dependence, showing NRF2 hotspot activation promotes specific tumor subtypes.\",\n      \"evidence\": \"Trp53/p16-deficient GEMM with conditional LSL-Nrf2E79Q activation, histopathology and pathway signature analysis\",\n      \"pmids\": [\"35577980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of subtype selectivity (P-SCLC vs C-SCLC) unexplained\", \"Single GEMM\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple layers of NRF2 control — KEAP1 sequestration, m6A mRNA stabilization, USP13/SPOP ubiquitin editing, and AMPK feedback — are integrated and prioritized within a single cell under graded stress remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of relative flux through each regulatory layer\", \"Structural basis of NRF2-ARE selectivity across antioxidant vs autophagy targets not defined\", \"Therapeutic exploitation of activating mutations beyond glutaminase inhibition untested broadly\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 4, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KEAP1\", \"SQSTM1\", \"USP13\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"NFE2L2","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"rich","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 38953910"},"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}