{"gene":"NFE2L3","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1999,"finding":"Nrf3 heterodimerizes with MafK and the resulting complex binds to the Maf recognition element (MARE) in the chicken beta-globin enhancer and activates transcription, establishing Nrf3 as a CNC-family bZIP transcription factor that functions through small Maf protein heterodimerization.","method":"In vitro transcription/translation, EMSA (bandshift), co-immunoprecipitation, transfection-based transcriptional activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal in vitro and in vivo methods (EMSA, co-IP, transactivation assays) in the foundational cloning paper","pmids":["10037736"],"is_preprint":false},{"year":2004,"finding":"Nrf3 associates with small Maf proteins to bind the antioxidant response element (ARE) and acts as a negative regulator of ARE-mediated NQO1 gene expression; repression requires the heterodimerization and DNA-binding domains but not the transcriptional activation domain. RNAi knockdown of Nrf3 increases NQO1 expression, confirming endogenous repressive function.","method":"Overexpression in HepG2 cells, deletion mutant analysis, EMSA/supershift assays with in vitro-translated proteins and nuclear extracts, immunoprecipitation, RNA interference","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal approaches (OE, RNAi, EMSA, co-IP, domain deletion) in a single focused study with multiple orthogonal methods","pmids":["15385560"],"is_preprint":false},{"year":2004,"finding":"Human NRF3 dimerizes with MAFG in vivo (yeast two-hybrid and transfection confirmation), and the NRF3/MAFG heterodimer recognizes NF-E2/MARE-type DNA motifs; a strong transcriptional activation domain was mapped to the central region of the NRF3 protein. NRF3 transcript and protein levels are induced by TNF-alpha in JAR choriocarcinoma cells.","method":"Yeast two-hybrid screen, transfection co-expression, EMSA, deletion mapping of transcriptional activation domain, TNF-alpha induction with RT-PCR and western blot","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid plus transfection confirmation plus EMSA and domain mapping; multiple orthogonal methods in one study","pmids":["15388789"],"is_preprint":false},{"year":2007,"finding":"Nrf3 is subject to rapid proteasomal degradation (stabilized by MG-132) and is N-glycosylated, representing the first identification of a post-translational modification of Nrf3; Nrf3 associates with the endoplasmic reticulum.","method":"Cycloheximide chase, proteasome inhibitor (MG-132) treatment, N-glycosylation analysis, cellular fractionation/ER association assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical assays (CHX chase, glycosylation, ER fractionation) in single lab with multiple methods","pmids":["17976382"],"is_preprint":false},{"year":2008,"finding":"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 Asn glycosylation; the c region (residues 24–39) contains a signal peptidase cleavage site generating the ~90-kDa mature glycoprotein from a ~96-kDa precursor. The ~90- and ~80-kDa isoforms localize to the nuclear envelope and the ~70-kDa (non-glycated) isoform to the nucleoplasm. ER stressors tunicamycin and brefeldin A activate Nrf3, and NHB1 is required for this response.","method":"Deletion and point mutants expressed in cells, subcellular fractionation, western blot, glycosylation analysis (glycosidase treatment), ER stress induction","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic mutagenesis of signal peptide domains combined with biochemical fractionation, glycosylation assays, and functional ER-stress response; multiple orthogonal methods in one detailed study","pmids":["19047052"],"is_preprint":false},{"year":2010,"finding":"Nrf3 is required for smooth muscle cell (SMC) differentiation from embryonic stem cells. Nrf3 overexpression dose-dependently enhances SMC differentiation and upregulates the SMC-specific transcription factor myocardin (but not SRF). Nrf3 directly binds to promoters of SMC differentiation genes (ChIP). Nrf3 overexpression enhances NADPH oxidase-dependent ROS production and inhibits antioxidant signaling, and Nrf3 is involved in ER stressor-induced SMC differentiation.","method":"Knockdown and overexpression in ESC differentiation model, qRT-PCR/western blot for markers, chromatin immunoprecipitation (ChIP), NADPH oxidase/ROS assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function combined with ChIP and mechanistic ROS pathway dissection; multiple orthogonal methods in a single focused study","pmids":["20093628"],"is_preprint":false},{"year":2012,"finding":"Nrf3 directly binds to the promoter regions of the Pla2g7 (platelet-activating factor acetylhydrolase) gene and regulates its expression; Pla2g7 activity mediates SRF binding to SMC differentiation gene promoters and is required for SMC differentiation, placing Nrf3 upstream of Pla2g7 in a pathway controlling vascular smooth muscle differentiation.","method":"ChIP assay, promoter reporter assay, knockdown/overexpression of Pla2g7 and Nrf3 in ESC differentiation model, enzymatic activity assay, ROS measurements","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown/OE, single lab","pmids":["22247257"],"is_preprint":false},{"year":2015,"finding":"NFE2L3 is ubiquitinated and degraded via the SCF-FBW7 E3 ubiquitin ligase complex. GSK3 phosphorylates NFE2L3 and this phosphorylation is required for FBW7-dependent ubiquitination and degradation. Dimerization of FBW7 is required for NFE2L3 degradation. FBW7 abrogates NFE2L3-mediated repression of the NQO1 ARE.","method":"Co-immunoprecipitation, ubiquitination assay, kinase assay (GSK3 phosphorylation), FBW7 mutant overexpression, NQO1-ARE reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct ubiquitination assay, kinase assay, co-IP, and functional reporter in one study with multiple orthogonal methods","pmids":["26306035"],"is_preprint":false},{"year":2017,"finding":"Under basal conditions NRF3 is rapidly degraded in the cytoplasm by the ER-associated degradation (ERAD) ubiquitin ligase HRD1 and VCP (valosin-containing protein). Nuclear NRF3 is separately degraded by β-TRCP, an adaptor for the SCF ubiquitin ligase. Nuclear translocation of NRF3 from the ER requires the aspartic protease DDI2 but does not require inhibition of HRD1-VCP-mediated degradation. NRF3 induces expression of UHMK1 (U2AF homology motif kinase 1) to promote cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, DDI2 knockdown, subcellular fractionation, gene expression profiling, cell proliferation assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical methods (co-IP, ubiquitination, fractionation, knockdown) in a single comprehensive study","pmids":["28970512"],"is_preprint":false},{"year":2019,"finding":"NRF3 specifically enhances assembly of the 20S proteasome by directly inducing transcription of POMP (proteasome maturation protein chaperone), leading to ubiquitin-independent proteolysis of the tumor suppressors p53 and Rb, thereby promoting cancer cell proliferation, tumorigenesis, and metastasis.","method":"ChIP assay (NRF3 binding to POMP promoter), siRNA knockdown, protein stability assay with 20S proteasome inhibitor (bortezomib) vs. E1 inhibitor (TAK-243), western blot for p53/Rb, cell viability assays, xenograft tumor models","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct ChIP, pharmacological dissection of ubiquitin-independent vs. ubiquitin-dependent proteolysis, in vitro and in vivo tumor models; multiple orthogonal methods","pmids":["32123008"],"is_preprint":false},{"year":2019,"finding":"The RELA subunit of NF-κB directly regulates NFE2L3 expression in colon cancer cells. NFE2L3 knockdown increases levels of DUX4, which functions as a direct CDK1 inhibitor, thereby decreasing colon cancer cell proliferation in vitro and tumor growth in vivo.","method":"ChIP assay, siRNA/shRNA knockdown, luciferase reporter assay, cell proliferation assays, xenograft mouse model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional KD with defined phenotypic readout and in vivo validation; multiple orthogonal methods","pmids":["31693889"],"is_preprint":false},{"year":2019,"finding":"The β-catenin/TCF4 complex directly binds a conserved WRE (TCF/LEF consensus element) in the NRF3 gene promoter and induces NRF3 expression in colon cancer cells. NRF3 activation in turn promotes cell proliferation and GLUT1 expression.","method":"ChIP assay (β-catenin/TCF4 binding to NRF3 WRE), reporter assay, NRF3 expression in Apc-deficient mouse intestine and organoids, qRT-PCR, western blot","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct ChIP on the NRF3 promoter, reporter assay, validated in vivo in Apc-KO model; multiple orthogonal methods","pmids":["31288376"],"is_preprint":false},{"year":2020,"finding":"NFE2L3 and NFE2L1 complementarily maintain basal proteasome activity in cancer cells. NFE2L3 represses NFE2L1 translation by inducing CPEB3, which binds the 3' UTR of NFE2L1 mRNA and reduces polysome formation on it. Double knockdown of NFE2L1 and NFE2L3 impairs basal proteasome activity and reduces expression of seven proteasome-related genes (PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, POMP).","method":"Double siRNA knockdown, polysome profiling, RIP (RNA immunoprecipitation for CPEB3 binding to NFE2L1 3' UTR), proteasome activity assays, western blot","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — polysome profiling, RIP, and functional proteasome assays in one study; multiple orthogonal methods","pmids":["32366381"],"is_preprint":false},{"year":2018,"finding":"Nrf3-deficient keratinocytes exhibit stronger cell-cell and cell-matrix adhesion with higher cell-surface integrin levels, enhanced focal adhesion kinase (FAK) activation, more and larger focal adhesions, and higher motility, and are protected from UV- and oxidative stress-induced apoptosis in vitro and in vivo, demonstrating that Nrf3 promotes apoptosis by suppressing integrin-mediated cell adhesion signaling.","method":"Nrf3 KO mouse model, primary keratinocyte culture, UV/oxidative stress treatment, integrin surface expression (flow cytometry), FAK phosphorylation (western blot), focal adhesion staining, live-cell motility assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO model with multiple mechanistic readouts (integrin levels, FAK, focal adhesions, motility) and in vivo confirmation","pmids":["29487353"],"is_preprint":false},{"year":2022,"finding":"NFE2L3 directly binds the regulatory sequences of IL33 and RAB27A loci in human colorectal carcinoma cells (validated by ChIP), and its loss reduces IL33 transcript levels and modulates mast cell numbers and immune checkpoint marker expression in the tumor microenvironment.","method":"ChIP assay, Nfe2l3-/- mouse model with colitis-cancer protocol, toluidine blue staining for mast cells, RNA-seq/CIBERSORT, CD3/FOXP3 immunostaining","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP in human cells plus KO mouse model; single lab but multiple methods","pmids":["35091681"],"is_preprint":false},{"year":2023,"finding":"NRF3 activates mTORC1 in cancer cells in an arginine-dependent manner by inducing expression of SLC38A9 and RagC for lysosomal mTORC1 recruitment, as well as RAB5-mediated macropinocytosis and SLC7A1-mediated arginine transport for arginine loading into lysosomes. Inhibition of the NRF3-mTORC1 axis impairs mitochondrial function and leads to cancer cell apoptosis.","method":"siRNA knockdown, mTORC1 activity assays, amino acid stimulation experiments, ChIP (NRF3 binding to target gene promoters), metabolomics, cell viability assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional mTORC1 pathway assays; single lab","pmids":["36818298"],"is_preprint":false},{"year":2023,"finding":"NFE2L3 promotes HCC cell proliferation by acting as a transcription factor that directly induces expression of proteasome subunit genes and ISG15, enhancing proteasome-dependent degradation of ISGylated p53; ISGylation of p53 reduces p53 stability and facilitates HCC cell growth.","method":"ChIP assay, knockdown/overexpression, proteasome activity assay, western blot for ISGylated p53, cell proliferation assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional assays for ISGylation/p53 degradation; single lab","pmids":["37350063"],"is_preprint":false},{"year":2022,"finding":"Nrf3 coordinates the melanogenesis cascade by upregulating the core melanogenic gene circuit (Mitf, Tyr, Tyrp1, Pmel, Oca2) and inducing Cln3 for melanin precursor uptake via macropinocytosis, as well as Ulk2 and Gabarapl2 for autophagosome-mediated melanosome formation and autolysosomal melanosome degradation. The HIV-1 protease inhibitor nelfinavir suppresses this Nrf3-mediated melanin production.","method":"siRNA knockdown, ChIP assay (Nrf3 binding to target promoters), macropinocytosis assay, autophagy/autolysosome assays, melanin production quantification, pharmacological inhibitor (nelfinavir)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP combined with multiple functional assays (macropinocytosis, autophagy, melanin); single lab with multiple orthogonal methods","pmids":["36640303"],"is_preprint":false},{"year":2023,"finding":"NRF3 suppresses squamous carcinogenesis and its tumor-suppressive effect involves interaction with HSPA5 (GRP78/BiP), a key regulator of the unfolded protein response. NRF3 deficiency increases HSPA5 levels, which promotes cancer cell survival and migration; pharmacological or knockdown inhibition of HSPA5 rescues the malignant phenotypes of NRF3-deficient SCC cells.","method":"Immunoprecipitation-mass spectrometry (NRF3 interactome), NRF3-KO mouse skin carcinogenesis model, 3D invasion assay, xenograft, HSPA5 knockdown/inhibitor rescue experiments","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS for interaction plus KO model and rescue experiments; single lab","pmids":["37807968"],"is_preprint":false},{"year":2025,"finding":"Nrf3 promotes cardiomyocyte apoptosis and impairs cardiac function after myocardial infarction by increasing mitochondrial ROS production through suppression of Pitx2 expression. Mechanistically, Nrf3 binds to the Pitx2 promoter and recruits hnRNPK and DNMT1 to increase DNA methylation and thereby inhibit Pitx2 transcription.","method":"Global and CM-specific Nrf3 KO mice (MI/I-R injury models), ChIP-seq (Nrf3 at Pitx2 promoter), IP-mass spectrometry (Nrf3 interactors: hnRNPK, DNMT1), mitochondrial ROS measurement, AAV-mediated CM-specific overexpression/knockdown, MitoParaquat rescue experiment, cardiac function analysis","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-seq, IP-MS, multiple KO models (global and cell-specific), rescue experiments with AAV and MitoParaquat; highly orthogonal evidence in one study","pmids":["40099370"],"is_preprint":false},{"year":2025,"finding":"Nrf3 promotes VSMC proliferation, migration, and inflammatory response leading to neointimal hyperplasia after vascular injury. Mechanistically, ER stress activates Nrf3 expression via ATF4. Nrf3 transcriptionally upregulates Trim5, which in turn enhances autophagy in VSMCs to drive dysfunction and injury-induced neointimal hyperplasia.","method":"Nrf3-/- and VSMC-specific Nrf3-KO mice (wire injury model), porcine carotid stenting model, ChIP assay (Nrf3 binding to Trim5 promoter), transcriptomics, rescue by Nrf3/Trim5 re-expression, Nrf3 inhibitor perivascular delivery","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO models, ChIP, transcriptomics, rescue experiments, and large-animal model validation; multiple orthogonal methods across labs/models","pmids":["40377016"],"is_preprint":false},{"year":2025,"finding":"METTL3-mediated N6-methyladenosine (m6A) modification stabilizes NFE2L3 mRNA, increasing NFE2L3 protein levels, which in turn activates the WNT signaling pathway to maintain cancer stem cell (OV6+) stemness in lung adenocarcinoma.","method":"m6A-RIP, RNA stability assays, METTL3 knockdown/overexpression, western blot, reporter assays, xenograft models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP and RNA stability assays support mechanism; single lab","pmids":["40249818"],"is_preprint":false},{"year":2025,"finding":"NAT10-mediated ac4C acetylation of NFE2L3 mRNA promotes its stability. NFE2L3 then acts as a transcription factor that directly induces LASP1 expression (shown by ChIP-seq), activating the AKT/GSK3β/β-catenin signaling axis in clear cell renal cell carcinoma.","method":"acRIP-seq, RIP, RNA stability assay, dual luciferase reporter, ChIP-seq (NFE2L3 at LASP1 locus), NAT10 knockdown/overexpression, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acRIP-seq, ChIP-seq, and RNA stability assays; single lab with multiple orthogonal methods","pmids":["40169553"],"is_preprint":false},{"year":2019,"finding":"ChIP-exo sequencing defined 22 genes transcriptionally regulated specifically by NRF3 in U2OS cells, distinct from the larger NRF1 and NRF2 target sets, with all three NRFs binding ARE motifs but with different flanking sequence preferences (NRF2 prefers GC-rich flanks; NRF1 prefers AT-rich flanks).","method":"ChIP-exo sequencing combined with RNA-seq in U2OS cells expressing each NRF member","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — high-resolution ChIP-exo plus RNA-seq; single study defining genome-wide binding and transcriptional targets","pmids":["31628195"],"is_preprint":false},{"year":2021,"finding":"NFE2L3 promotes mevalonate/cholesterol biosynthesis by inducing SREBP2 and HMGCR gene expression, reduces intracellular levels of neural fatty acids by inducing GGPS1, and promotes macropinocytosis for cholesterol uptake by inducing RAB5 gene expression.","method":"ChIP assay, gene expression analysis (qRT-PCR/western blot), macropinocytosis assay, lipid metabolomics (referenced from prior studies summarized in the review)","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review summarizing prior data; individual experimental details not fully described in this abstract","pmids":["34884489"],"is_preprint":false},{"year":2022,"finding":"NFE2L3 directly binds the promoter region of IL-6 and transcriptionally regulates IL-6 expression, thereby promoting radioresistance in esophageal squamous cell carcinoma cells via IL-6/STAT3 signaling.","method":"Dual luciferase reporter gene assay, RNA-seq, qRT-PCR, western blot, clonogenic survival assay, xenograft radiosensitivity model","journal":"Computer methods and programs in biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay for direct promoter binding combined with in vivo xenograft validation; single lab","pmids":["36108571"],"is_preprint":false},{"year":2023,"finding":"Nrf3 directly binds the p110α (PIK3CA) promoter and activates PI3K/AKT/mTOR signaling to promote proliferation and migration of triple-negative breast cancer cells.","method":"Luciferase reporter assay, ChIP assay, PI3K inhibitor rescue experiment, overexpression/knockdown studies, xenograft model","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assay for direct p110α promoter binding; single lab","pmids":["37720674"],"is_preprint":false},{"year":2019,"finding":"NRF3 inhibited breast cancer cell proliferation and metastasis at least in part by inactivating the AKT signaling pathway, reducing ID3 expression; exogenous ID3 expression reversed NRF3's inhibitory effects on invasion.","method":"NRF3 overexpression/silencing, western blot for AKT phosphorylation and ID3, Transwell invasion assay, MTT/colony formation assay","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement based on western blot without direct mechanistic link (e.g., ChIP or reporter) between NRF3 and AKT/ID3","pmids":["31114245"],"is_preprint":false},{"year":2026,"finding":"NFE2L3 protein binds the promoter region of BHLHE40 and directly regulates its transcriptional activity in TNBC cells; NFE2L3 regulates BHLHE40 at both transcriptional and translational levels, and BHLHE40 requires NFE2L3 for cell proliferation and migration.","method":"Luciferase reporter assay, siRNA/plasmid transfection, qRT-PCR, western blot, cell proliferation and migration assays","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase reporter assay demonstrating NFE2L3 binding to BHLHE40 promoter, plus functional rescue; single lab","pmids":["41613788"],"is_preprint":false},{"year":2048,"finding":"NFE2L3 protein is mutually regulated with VCP (valosin-containing protein): VCP knockdown dramatically increases NRF3 protein expression, and NRF3 overexpression reciprocally decreases VCP expression. NRF3 protein promotes ROS accumulation and inhibits ERK phosphorylation to suppress TNBC cell metastasis.","method":"Co-expression western blot, siRNA knockdown, flow cytometry (ROS), Transwell assay, NAC (ROS scavenger) rescue experiment","journal":"Histology and histopathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single set of western blot and knockdown experiments without direct mechanistic link (no co-IP, ChIP, or direct binding assay)","pmids":["39005145"],"is_preprint":false},{"year":2025,"finding":"NFE2L3 regulates colitis-related gene expression in vivo: Nfe2l3-/- mice show reduced DSS-induced upregulation of Stat1, Hmox1, and Slc7a11 proteins, and elevated basal pSTAT1 and SLC7A11, consistent with NFE2L3 priming a pro-inflammatory state. ENCODE ChIP data (MAFF and MAFK binding partners) support NFE2L3 binding near these loci.","method":"Nfe2l3-/- mouse DSS colitis model, histological analysis, qRT-PCR, western blot, cross-reference with ENCODE ChIP data","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KO mouse with western blot readout; direct NFE2L3 ChIP in the colitis context not performed (ENCODE data used for binding partner inference); single lab","pmids":["40360021"],"is_preprint":false}],"current_model":"NFE2L3/NRF3 is an ER-anchored, N-glycosylated CNC-family bZIP transcription factor that is held inactive at the ER under basal conditions through HRD1/VCP-mediated ERAD degradation and GSK3/FBW7-mediated nuclear degradation; upon ER stress or other signals, the aspartic protease DDI2 enables NRF3 nuclear translocation, where it heterodimerizes with small Maf proteins (MafK, MAFG) to bind antioxidant response elements (AREs/MAREs) and regulate target genes—including acting as a direct repressor of NQO1, an inducer of POMP (driving ubiquitin-independent 20S proteasome assembly to degrade p53 and Rb), an inducer of CPEB3 (translationally repressing NFE2L1), an activator of UHMK1 (promoting cell proliferation), an inducer of Pitx2 suppression via hnRNPK/DNMT1 recruitment (promoting mitochondrial ROS and cardiomyocyte apoptosis), and a direct activator of Trim5 (driving VSMC autophagy and neointimal hyperplasia), placing NRF3 as a context-dependent regulator of proteasome homeostasis, redox balance, cell differentiation, and tumor biology."},"narrative":{"mechanistic_narrative":"NFE2L3/NRF3 is a CNC-family bZIP transcription factor that heterodimerizes with small Maf proteins (MafK, MAFG) to bind antioxidant/Maf recognition elements (ARE/MARE) and regulate transcription, functioning as a context-dependent controller of proteasome homeostasis, redox balance, cell differentiation, and tumor biology [PMID:10037736, PMID:15388789, PMID:31628195]. Its activity is set largely by stringent post-translational control: NRF3 is an N-glycosylated protein targeted to the ER through an N-terminal NHB1 tripartite signal peptide, processed to mature ~90/80-kDa isoforms that distribute between the nuclear envelope and nucleoplasm, with ER stressors (tunicamycin, brefeldin A) triggering its activation [PMID:17976382, PMID:19047052]. Under basal conditions NRF3 is rapidly degraded—cytoplasmically by the ERAD ligase HRD1 with VCP, and in the nucleus by SCF adaptors (β-TRCP, and FBW7 following GSK3 phosphorylation)—while the aspartic protease DDI2 enables its nuclear translocation [PMID:26306035, PMID:28970512]. As a transcription factor NRF3 acts as a direct repressor of NQO1 [PMID:15385560] and a direct activator of POMP, driving ubiquitin-independent 20S proteasome assembly to degrade the tumor suppressors p53 and Rb [PMID:32123008]; it further controls a proteasome program in concert with NFE2L1, which it represses translationally by inducing CPEB3 [PMID:32366381]. Across tissues NRF3 directs distinct programs: it promotes smooth muscle differentiation via myocardin and Pla2g7 [PMID:20093628, PMID:22247257], coordinates melanogenesis [PMID:36640303], drives cardiomyocyte apoptosis after infarction by recruiting hnRNPK and DNMT1 to methylate and silence the Pitx2 promoter [PMID:40099370], and promotes injury-induced neointimal hyperplasia by transactivating Trim5 downstream of ATF4/ER stress [PMID:40377016]. In cancer NRF3 is both oncogenic and tumor-suppressive depending on context—promoting proliferation through targets such as UHMK1, PIK3CA, IL33, and mTORC1-pathway genes [PMID:28970512, PMID:37720674, PMID:35091681, PMID:36818298], yet suppressing squamous carcinogenesis through interaction with HSPA5/GRP78 [PMID:37807968].","teleology":[{"year":1999,"claim":"Established the fundamental molecular identity of NRF3 as a CNC-bZIP factor that requires small Maf heterodimerization to bind DNA and activate transcription.","evidence":"In vitro transcription/translation, EMSA, co-IP, and transactivation assays on the chicken beta-globin MARE","pmids":["10037736"],"confidence":"High","gaps":["Endogenous target genes not yet defined","No data on regulation of NRF3 activity or localization"]},{"year":2004,"claim":"Defined NRF3 as functionally bidirectional—a repressor at the NQO1 ARE yet bearing a strong activation domain—answering whether a CNC factor can negatively regulate ARE genes.","evidence":"Overexpression/RNAi in HepG2 and JAR cells, EMSA/supershift, domain deletion, MAFG yeast two-hybrid and TNF-alpha induction","pmids":["15385560","15388789"],"confidence":"High","gaps":["Mechanism distinguishing repressed vs activated targets unresolved","Signals controlling activation domain usage unknown"]},{"year":2008,"claim":"Resolved how NRF3 is spatially controlled, showing it is an ER-targeted N-glycoprotein whose NHB1 signal peptide governs processing, isoform distribution, and ER-stress responsiveness.","evidence":"Signal-peptide mutagenesis, subcellular fractionation, glycosidase assays, and ER-stress induction (extending CHX-chase/MG-132 findings)","pmids":["19047052","17976382"],"confidence":"High","gaps":["Protease/machinery releasing NRF3 from ER not identified at this stage","Functional consequence of each isoform unclear"]},{"year":2015,"claim":"Identified a nuclear degradation route, showing GSK3 phosphorylation primes NRF3 for SCF-FBW7 ubiquitination and relieves ARE repression.","evidence":"Co-IP, ubiquitination and kinase assays, FBW7 dimerization mutants, NQO1-ARE reporter","pmids":["26306035"],"confidence":"High","gaps":["Stimuli regulating GSK3-FBW7 axis on NRF3 not defined","Relationship to ER-associated degradation not yet integrated"]},{"year":2017,"claim":"Unified NRF3 turnover into compartment-specific pathways and identified DDI2 as the protease enabling nuclear translocation, while linking NRF3 to proliferation via UHMK1.","evidence":"Co-IP, ubiquitination assays, DDI2 knockdown, fractionation, expression profiling, proliferation assays","pmids":["28970512"],"confidence":"High","gaps":["Trigger activating DDI2-dependent release unknown","Direct vs indirect UHMK1 regulation not fully resolved"]},{"year":2020,"claim":"Defined NRF3's central role in proteasome homeostasis—directly inducing POMP for ubiquitin-independent 20S assembly to degrade p53/Rb, and repressing NFE2L1 translation through CPEB3.","evidence":"ChIP, pharmacological dissection (bortezomib vs TAK-243), xenografts, polysome profiling, RIP, double knockdown proteasome assays","pmids":["32123008","32366381"],"confidence":"High","gaps":["Conditions favoring proteasome induction vs other programs unclear","In vivo p53/Rb degradation contribution not quantified"]},{"year":2019,"claim":"Placed NRF3 within oncogenic signaling networks, showing it is induced by NF-kB (RELA) and Wnt/β-catenin-TCF4 and feeds proliferative outputs in colon cancer.","evidence":"ChIP, reporter assays, siRNA/shRNA, Apc-deficient organoids/intestine, xenografts (with genome-wide ChIP-exo defining NRF3-specific targets)","pmids":["31693889","31288376","31628195"],"confidence":"High","gaps":["Integration of upstream NF-kB/Wnt inputs with ER-anchored regulation unclear","Tissue specificity of the 22-gene NRF3 program not mapped"]},{"year":2018,"claim":"Established physiological roles in adhesion and stress-induced apoptosis, with Nrf3 promoting apoptosis by suppressing integrin-mediated adhesion signaling in keratinocytes.","evidence":"Nrf3 KO mice, primary keratinocytes, UV/oxidative stress, integrin flow cytometry, FAK western blot, motility assays","pmids":["29487353"],"confidence":"High","gaps":["Direct transcriptional targets controlling integrins not defined","Link to ARE/Maf dimerization in this context untested"]},{"year":2023,"claim":"Demonstrated NRF3 can be tumor-suppressive through a non-transcriptional protein interaction, binding HSPA5/GRP78 to restrain squamous carcinogenesis.","evidence":"IP-MS interactome, NRF3-KO skin carcinogenesis model, 3D invasion, xenografts, HSPA5 rescue","pmids":["37807968"],"confidence":"Medium","gaps":["Reciprocal validation of the HSPA5 interaction limited","Context determining oncogenic vs suppressive role unresolved"]},{"year":2025,"claim":"Extended NRF3 into cardiovascular pathology, showing epigenetic and autophagic mechanisms—hnRNPK/DNMT1-mediated Pitx2 silencing driving cardiomyocyte apoptosis, and ATF4-induced NRF3 transactivating Trim5 to drive neointimal hyperplasia.","evidence":"Global and cell-specific KO mice, ChIP-seq, IP-MS, mitochondrial ROS assays, AAV rescue, porcine stenting model, ChIP","pmids":["40099370","40377016"],"confidence":"High","gaps":["Signals selecting epigenetic-repressor vs activator mode unknown","Generalizability of hnRNPK/DNMT1 recruitment to other targets untested"]},{"year":2025,"claim":"Revealed that NRF3 abundance is itself set by mRNA modifications (METTL3 m6A, NAT10 ac4C) that stabilize NFE2L3 transcript and feed Wnt/AKT stemness programs in cancer.","evidence":"m6A-RIP, acRIP-seq, RNA stability assays, ChIP-seq (LASP1), knockdown/overexpression, xenografts","pmids":["40249818","40169553"],"confidence":"Medium","gaps":["Physiological triggers of these RNA modifications unclear","Interplay with protein-level ERAD/FBW7 control not addressed"]},{"year":null,"claim":"What molecular switch dictates whether NRF3 acts as a transcriptional activator, an ARE repressor, an epigenetic silencer via hnRNPK/DNMT1, or a tumor suppressor via HSPA5 in a given cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking upstream stimulus to choice of target program","Determinants of oncogenic vs tumor-suppressive output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,9,19,23]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,5,9,19,23]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,4,8]},{"term_id":"GO:0005635","term_label":"nuclear 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transcription/translation, EMSA (bandshift), co-immunoprecipitation, transfection-based transcriptional activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal in vitro and in vivo methods (EMSA, co-IP, transactivation assays) in the foundational cloning paper\",\n      \"pmids\": [\"10037736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nrf3 associates with small Maf proteins to bind the antioxidant response element (ARE) and acts as a negative regulator of ARE-mediated NQO1 gene expression; repression requires the heterodimerization and DNA-binding domains but not the transcriptional activation domain. RNAi knockdown of Nrf3 increases NQO1 expression, confirming endogenous repressive function.\",\n      \"method\": \"Overexpression in HepG2 cells, deletion mutant analysis, EMSA/supershift assays with in vitro-translated proteins and nuclear extracts, immunoprecipitation, RNA interference\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal approaches (OE, RNAi, EMSA, co-IP, domain deletion) in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"15385560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human NRF3 dimerizes with MAFG in vivo (yeast two-hybrid and transfection confirmation), and the NRF3/MAFG heterodimer recognizes NF-E2/MARE-type DNA motifs; a strong transcriptional activation domain was mapped to the central region of the NRF3 protein. NRF3 transcript and protein levels are induced by TNF-alpha in JAR choriocarcinoma cells.\",\n      \"method\": \"Yeast two-hybrid screen, transfection co-expression, EMSA, deletion mapping of transcriptional activation domain, TNF-alpha induction with RT-PCR and western blot\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid plus transfection confirmation plus EMSA and domain mapping; multiple orthogonal methods in one study\",\n      \"pmids\": [\"15388789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nrf3 is subject to rapid proteasomal degradation (stabilized by MG-132) and is N-glycosylated, representing the first identification of a post-translational modification of Nrf3; Nrf3 associates with the endoplasmic reticulum.\",\n      \"method\": \"Cycloheximide chase, proteasome inhibitor (MG-132) treatment, N-glycosylation analysis, cellular fractionation/ER association assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical assays (CHX chase, glycosylation, ER fractionation) in single lab with multiple methods\",\n      \"pmids\": [\"17976382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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 Asn glycosylation; the c region (residues 24–39) contains a signal peptidase cleavage site generating the ~90-kDa mature glycoprotein from a ~96-kDa precursor. The ~90- and ~80-kDa isoforms localize to the nuclear envelope and the ~70-kDa (non-glycated) isoform to the nucleoplasm. ER stressors tunicamycin and brefeldin A activate Nrf3, and NHB1 is required for this response.\",\n      \"method\": \"Deletion and point mutants expressed in cells, subcellular fractionation, western blot, glycosylation analysis (glycosidase treatment), ER stress induction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic mutagenesis of signal peptide domains combined with biochemical fractionation, glycosylation assays, and functional ER-stress response; multiple orthogonal methods in one detailed study\",\n      \"pmids\": [\"19047052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nrf3 is required for smooth muscle cell (SMC) differentiation from embryonic stem cells. Nrf3 overexpression dose-dependently enhances SMC differentiation and upregulates the SMC-specific transcription factor myocardin (but not SRF). Nrf3 directly binds to promoters of SMC differentiation genes (ChIP). Nrf3 overexpression enhances NADPH oxidase-dependent ROS production and inhibits antioxidant signaling, and Nrf3 is involved in ER stressor-induced SMC differentiation.\",\n      \"method\": \"Knockdown and overexpression in ESC differentiation model, qRT-PCR/western blot for markers, chromatin immunoprecipitation (ChIP), NADPH oxidase/ROS assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function combined with ChIP and mechanistic ROS pathway dissection; multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"20093628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nrf3 directly binds to the promoter regions of the Pla2g7 (platelet-activating factor acetylhydrolase) gene and regulates its expression; Pla2g7 activity mediates SRF binding to SMC differentiation gene promoters and is required for SMC differentiation, placing Nrf3 upstream of Pla2g7 in a pathway controlling vascular smooth muscle differentiation.\",\n      \"method\": \"ChIP assay, promoter reporter assay, knockdown/overexpression of Pla2g7 and Nrf3 in ESC differentiation model, enzymatic activity assay, ROS measurements\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown/OE, single lab\",\n      \"pmids\": [\"22247257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NFE2L3 is ubiquitinated and degraded via the SCF-FBW7 E3 ubiquitin ligase complex. GSK3 phosphorylates NFE2L3 and this phosphorylation is required for FBW7-dependent ubiquitination and degradation. Dimerization of FBW7 is required for NFE2L3 degradation. FBW7 abrogates NFE2L3-mediated repression of the NQO1 ARE.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, kinase assay (GSK3 phosphorylation), FBW7 mutant overexpression, NQO1-ARE reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct ubiquitination assay, kinase assay, co-IP, and functional reporter in one study with multiple orthogonal methods\",\n      \"pmids\": [\"26306035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Under basal conditions NRF3 is rapidly degraded in the cytoplasm by the ER-associated degradation (ERAD) ubiquitin ligase HRD1 and VCP (valosin-containing protein). Nuclear NRF3 is separately degraded by β-TRCP, an adaptor for the SCF ubiquitin ligase. Nuclear translocation of NRF3 from the ER requires the aspartic protease DDI2 but does not require inhibition of HRD1-VCP-mediated degradation. NRF3 induces expression of UHMK1 (U2AF homology motif kinase 1) to promote cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, DDI2 knockdown, subcellular fractionation, gene expression profiling, cell proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical methods (co-IP, ubiquitination, fractionation, knockdown) in a single comprehensive study\",\n      \"pmids\": [\"28970512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NRF3 specifically enhances assembly of the 20S proteasome by directly inducing transcription of POMP (proteasome maturation protein chaperone), leading to ubiquitin-independent proteolysis of the tumor suppressors p53 and Rb, thereby promoting cancer cell proliferation, tumorigenesis, and metastasis.\",\n      \"method\": \"ChIP assay (NRF3 binding to POMP promoter), siRNA knockdown, protein stability assay with 20S proteasome inhibitor (bortezomib) vs. E1 inhibitor (TAK-243), western blot for p53/Rb, cell viability assays, xenograft tumor models\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct ChIP, pharmacological dissection of ubiquitin-independent vs. ubiquitin-dependent proteolysis, in vitro and in vivo tumor models; multiple orthogonal methods\",\n      \"pmids\": [\"32123008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The RELA subunit of NF-κB directly regulates NFE2L3 expression in colon cancer cells. NFE2L3 knockdown increases levels of DUX4, which functions as a direct CDK1 inhibitor, thereby decreasing colon cancer cell proliferation in vitro and tumor growth in vivo.\",\n      \"method\": \"ChIP assay, siRNA/shRNA knockdown, luciferase reporter assay, cell proliferation assays, xenograft mouse model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional KD with defined phenotypic readout and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"31693889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The β-catenin/TCF4 complex directly binds a conserved WRE (TCF/LEF consensus element) in the NRF3 gene promoter and induces NRF3 expression in colon cancer cells. NRF3 activation in turn promotes cell proliferation and GLUT1 expression.\",\n      \"method\": \"ChIP assay (β-catenin/TCF4 binding to NRF3 WRE), reporter assay, NRF3 expression in Apc-deficient mouse intestine and organoids, qRT-PCR, western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP on the NRF3 promoter, reporter assay, validated in vivo in Apc-KO model; multiple orthogonal methods\",\n      \"pmids\": [\"31288376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NFE2L3 and NFE2L1 complementarily maintain basal proteasome activity in cancer cells. NFE2L3 represses NFE2L1 translation by inducing CPEB3, which binds the 3' UTR of NFE2L1 mRNA and reduces polysome formation on it. Double knockdown of NFE2L1 and NFE2L3 impairs basal proteasome activity and reduces expression of seven proteasome-related genes (PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, POMP).\",\n      \"method\": \"Double siRNA knockdown, polysome profiling, RIP (RNA immunoprecipitation for CPEB3 binding to NFE2L1 3' UTR), proteasome activity assays, western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — polysome profiling, RIP, and functional proteasome assays in one study; multiple orthogonal methods\",\n      \"pmids\": [\"32366381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nrf3-deficient keratinocytes exhibit stronger cell-cell and cell-matrix adhesion with higher cell-surface integrin levels, enhanced focal adhesion kinase (FAK) activation, more and larger focal adhesions, and higher motility, and are protected from UV- and oxidative stress-induced apoptosis in vitro and in vivo, demonstrating that Nrf3 promotes apoptosis by suppressing integrin-mediated cell adhesion signaling.\",\n      \"method\": \"Nrf3 KO mouse model, primary keratinocyte culture, UV/oxidative stress treatment, integrin surface expression (flow cytometry), FAK phosphorylation (western blot), focal adhesion staining, live-cell motility assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with multiple mechanistic readouts (integrin levels, FAK, focal adhesions, motility) and in vivo confirmation\",\n      \"pmids\": [\"29487353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NFE2L3 directly binds the regulatory sequences of IL33 and RAB27A loci in human colorectal carcinoma cells (validated by ChIP), and its loss reduces IL33 transcript levels and modulates mast cell numbers and immune checkpoint marker expression in the tumor microenvironment.\",\n      \"method\": \"ChIP assay, Nfe2l3-/- mouse model with colitis-cancer protocol, toluidine blue staining for mast cells, RNA-seq/CIBERSORT, CD3/FOXP3 immunostaining\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP in human cells plus KO mouse model; single lab but multiple methods\",\n      \"pmids\": [\"35091681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NRF3 activates mTORC1 in cancer cells in an arginine-dependent manner by inducing expression of SLC38A9 and RagC for lysosomal mTORC1 recruitment, as well as RAB5-mediated macropinocytosis and SLC7A1-mediated arginine transport for arginine loading into lysosomes. Inhibition of the NRF3-mTORC1 axis impairs mitochondrial function and leads to cancer cell apoptosis.\",\n      \"method\": \"siRNA knockdown, mTORC1 activity assays, amino acid stimulation experiments, ChIP (NRF3 binding to target gene promoters), metabolomics, cell viability assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional mTORC1 pathway assays; single lab\",\n      \"pmids\": [\"36818298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NFE2L3 promotes HCC cell proliferation by acting as a transcription factor that directly induces expression of proteasome subunit genes and ISG15, enhancing proteasome-dependent degradation of ISGylated p53; ISGylation of p53 reduces p53 stability and facilitates HCC cell growth.\",\n      \"method\": \"ChIP assay, knockdown/overexpression, proteasome activity assay, western blot for ISGylated p53, cell proliferation assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional assays for ISGylation/p53 degradation; single lab\",\n      \"pmids\": [\"37350063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nrf3 coordinates the melanogenesis cascade by upregulating the core melanogenic gene circuit (Mitf, Tyr, Tyrp1, Pmel, Oca2) and inducing Cln3 for melanin precursor uptake via macropinocytosis, as well as Ulk2 and Gabarapl2 for autophagosome-mediated melanosome formation and autolysosomal melanosome degradation. The HIV-1 protease inhibitor nelfinavir suppresses this Nrf3-mediated melanin production.\",\n      \"method\": \"siRNA knockdown, ChIP assay (Nrf3 binding to target promoters), macropinocytosis assay, autophagy/autolysosome assays, melanin production quantification, pharmacological inhibitor (nelfinavir)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP combined with multiple functional assays (macropinocytosis, autophagy, melanin); single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36640303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NRF3 suppresses squamous carcinogenesis and its tumor-suppressive effect involves interaction with HSPA5 (GRP78/BiP), a key regulator of the unfolded protein response. NRF3 deficiency increases HSPA5 levels, which promotes cancer cell survival and migration; pharmacological or knockdown inhibition of HSPA5 rescues the malignant phenotypes of NRF3-deficient SCC cells.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (NRF3 interactome), NRF3-KO mouse skin carcinogenesis model, 3D invasion assay, xenograft, HSPA5 knockdown/inhibitor rescue experiments\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS for interaction plus KO model and rescue experiments; single lab\",\n      \"pmids\": [\"37807968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nrf3 promotes cardiomyocyte apoptosis and impairs cardiac function after myocardial infarction by increasing mitochondrial ROS production through suppression of Pitx2 expression. Mechanistically, Nrf3 binds to the Pitx2 promoter and recruits hnRNPK and DNMT1 to increase DNA methylation and thereby inhibit Pitx2 transcription.\",\n      \"method\": \"Global and CM-specific Nrf3 KO mice (MI/I-R injury models), ChIP-seq (Nrf3 at Pitx2 promoter), IP-mass spectrometry (Nrf3 interactors: hnRNPK, DNMT1), mitochondrial ROS measurement, AAV-mediated CM-specific overexpression/knockdown, MitoParaquat rescue experiment, cardiac function analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-seq, IP-MS, multiple KO models (global and cell-specific), rescue experiments with AAV and MitoParaquat; highly orthogonal evidence in one study\",\n      \"pmids\": [\"40099370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nrf3 promotes VSMC proliferation, migration, and inflammatory response leading to neointimal hyperplasia after vascular injury. Mechanistically, ER stress activates Nrf3 expression via ATF4. Nrf3 transcriptionally upregulates Trim5, which in turn enhances autophagy in VSMCs to drive dysfunction and injury-induced neointimal hyperplasia.\",\n      \"method\": \"Nrf3-/- and VSMC-specific Nrf3-KO mice (wire injury model), porcine carotid stenting model, ChIP assay (Nrf3 binding to Trim5 promoter), transcriptomics, rescue by Nrf3/Trim5 re-expression, Nrf3 inhibitor perivascular delivery\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO models, ChIP, transcriptomics, rescue experiments, and large-animal model validation; multiple orthogonal methods across labs/models\",\n      \"pmids\": [\"40377016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-mediated N6-methyladenosine (m6A) modification stabilizes NFE2L3 mRNA, increasing NFE2L3 protein levels, which in turn activates the WNT signaling pathway to maintain cancer stem cell (OV6+) stemness in lung adenocarcinoma.\",\n      \"method\": \"m6A-RIP, RNA stability assays, METTL3 knockdown/overexpression, western blot, reporter assays, xenograft models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP and RNA stability assays support mechanism; single lab\",\n      \"pmids\": [\"40249818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10-mediated ac4C acetylation of NFE2L3 mRNA promotes its stability. NFE2L3 then acts as a transcription factor that directly induces LASP1 expression (shown by ChIP-seq), activating the AKT/GSK3β/β-catenin signaling axis in clear cell renal cell carcinoma.\",\n      \"method\": \"acRIP-seq, RIP, RNA stability assay, dual luciferase reporter, ChIP-seq (NFE2L3 at LASP1 locus), NAT10 knockdown/overexpression, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acRIP-seq, ChIP-seq, and RNA stability assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40169553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ChIP-exo sequencing defined 22 genes transcriptionally regulated specifically by NRF3 in U2OS cells, distinct from the larger NRF1 and NRF2 target sets, with all three NRFs binding ARE motifs but with different flanking sequence preferences (NRF2 prefers GC-rich flanks; NRF1 prefers AT-rich flanks).\",\n      \"method\": \"ChIP-exo sequencing combined with RNA-seq in U2OS cells expressing each NRF member\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — high-resolution ChIP-exo plus RNA-seq; single study defining genome-wide binding and transcriptional targets\",\n      \"pmids\": [\"31628195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NFE2L3 promotes mevalonate/cholesterol biosynthesis by inducing SREBP2 and HMGCR gene expression, reduces intracellular levels of neural fatty acids by inducing GGPS1, and promotes macropinocytosis for cholesterol uptake by inducing RAB5 gene expression.\",\n      \"method\": \"ChIP assay, gene expression analysis (qRT-PCR/western blot), macropinocytosis assay, lipid metabolomics (referenced from prior studies summarized in the review)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review summarizing prior data; individual experimental details not fully described in this abstract\",\n      \"pmids\": [\"34884489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NFE2L3 directly binds the promoter region of IL-6 and transcriptionally regulates IL-6 expression, thereby promoting radioresistance in esophageal squamous cell carcinoma cells via IL-6/STAT3 signaling.\",\n      \"method\": \"Dual luciferase reporter gene assay, RNA-seq, qRT-PCR, western blot, clonogenic survival assay, xenograft radiosensitivity model\",\n      \"journal\": \"Computer methods and programs in biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assay for direct promoter binding combined with in vivo xenograft validation; single lab\",\n      \"pmids\": [\"36108571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nrf3 directly binds the p110α (PIK3CA) promoter and activates PI3K/AKT/mTOR signaling to promote proliferation and migration of triple-negative breast cancer cells.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, PI3K inhibitor rescue experiment, overexpression/knockdown studies, xenograft model\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assay for direct p110α promoter binding; single lab\",\n      \"pmids\": [\"37720674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NRF3 inhibited breast cancer cell proliferation and metastasis at least in part by inactivating the AKT signaling pathway, reducing ID3 expression; exogenous ID3 expression reversed NRF3's inhibitory effects on invasion.\",\n      \"method\": \"NRF3 overexpression/silencing, western blot for AKT phosphorylation and ID3, Transwell invasion assay, MTT/colony formation assay\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement based on western blot without direct mechanistic link (e.g., ChIP or reporter) between NRF3 and AKT/ID3\",\n      \"pmids\": [\"31114245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NFE2L3 protein binds the promoter region of BHLHE40 and directly regulates its transcriptional activity in TNBC cells; NFE2L3 regulates BHLHE40 at both transcriptional and translational levels, and BHLHE40 requires NFE2L3 for cell proliferation and migration.\",\n      \"method\": \"Luciferase reporter assay, siRNA/plasmid transfection, qRT-PCR, western blot, cell proliferation and migration assays\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase reporter assay demonstrating NFE2L3 binding to BHLHE40 promoter, plus functional rescue; single lab\",\n      \"pmids\": [\"41613788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2048,\n      \"finding\": \"NFE2L3 protein is mutually regulated with VCP (valosin-containing protein): VCP knockdown dramatically increases NRF3 protein expression, and NRF3 overexpression reciprocally decreases VCP expression. NRF3 protein promotes ROS accumulation and inhibits ERK phosphorylation to suppress TNBC cell metastasis.\",\n      \"method\": \"Co-expression western blot, siRNA knockdown, flow cytometry (ROS), Transwell assay, NAC (ROS scavenger) rescue experiment\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of western blot and knockdown experiments without direct mechanistic link (no co-IP, ChIP, or direct binding assay)\",\n      \"pmids\": [\"39005145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NFE2L3 regulates colitis-related gene expression in vivo: Nfe2l3-/- mice show reduced DSS-induced upregulation of Stat1, Hmox1, and Slc7a11 proteins, and elevated basal pSTAT1 and SLC7A11, consistent with NFE2L3 priming a pro-inflammatory state. ENCODE ChIP data (MAFF and MAFK binding partners) support NFE2L3 binding near these loci.\",\n      \"method\": \"Nfe2l3-/- mouse DSS colitis model, histological analysis, qRT-PCR, western blot, cross-reference with ENCODE ChIP data\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KO mouse with western blot readout; direct NFE2L3 ChIP in the colitis context not performed (ENCODE data used for binding partner inference); single lab\",\n      \"pmids\": [\"40360021\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NFE2L3/NRF3 is an ER-anchored, N-glycosylated CNC-family bZIP transcription factor that is held inactive at the ER under basal conditions through HRD1/VCP-mediated ERAD degradation and GSK3/FBW7-mediated nuclear degradation; upon ER stress or other signals, the aspartic protease DDI2 enables NRF3 nuclear translocation, where it heterodimerizes with small Maf proteins (MafK, MAFG) to bind antioxidant response elements (AREs/MAREs) and regulate target genes—including acting as a direct repressor of NQO1, an inducer of POMP (driving ubiquitin-independent 20S proteasome assembly to degrade p53 and Rb), an inducer of CPEB3 (translationally repressing NFE2L1), an activator of UHMK1 (promoting cell proliferation), an inducer of Pitx2 suppression via hnRNPK/DNMT1 recruitment (promoting mitochondrial ROS and cardiomyocyte apoptosis), and a direct activator of Trim5 (driving VSMC autophagy and neointimal hyperplasia), placing NRF3 as a context-dependent regulator of proteasome homeostasis, redox balance, cell differentiation, and tumor biology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NFE2L3/NRF3 is a CNC-family bZIP transcription factor that heterodimerizes with small Maf proteins (MafK, MAFG) to bind antioxidant/Maf recognition elements (ARE/MARE) and regulate transcription, functioning as a context-dependent controller of proteasome homeostasis, redox balance, cell differentiation, and tumor biology [#0, #2, #23]. Its activity is set largely by stringent post-translational control: NRF3 is an N-glycosylated protein targeted to the ER through an N-terminal NHB1 tripartite signal peptide, processed to mature ~90/80-kDa isoforms that distribute between the nuclear envelope and nucleoplasm, with ER stressors (tunicamycin, brefeldin A) triggering its activation [#3, #4]. Under basal conditions NRF3 is rapidly degraded—cytoplasmically by the ERAD ligase HRD1 with VCP, and in the nucleus by SCF adaptors (β-TRCP, and FBW7 following GSK3 phosphorylation)—while the aspartic protease DDI2 enables its nuclear translocation [#7, #8]. As a transcription factor NRF3 acts as a direct repressor of NQO1 [#1] and a direct activator of POMP, driving ubiquitin-independent 20S proteasome assembly to degrade the tumor suppressors p53 and Rb [#9]; it further controls a proteasome program in concert with NFE2L1, which it represses translationally by inducing CPEB3 [#12]. Across tissues NRF3 directs distinct programs: it promotes smooth muscle differentiation via myocardin and Pla2g7 [#5, #6], coordinates melanogenesis [#17], drives cardiomyocyte apoptosis after infarction by recruiting hnRNPK and DNMT1 to methylate and silence the Pitx2 promoter [#19], and promotes injury-induced neointimal hyperplasia by transactivating Trim5 downstream of ATF4/ER stress [#20]. In cancer NRF3 is both oncogenic and tumor-suppressive depending on context—promoting proliferation through targets such as UHMK1, PIK3CA, IL33, and mTORC1-pathway genes [#8, #26, #14, #15], yet suppressing squamous carcinogenesis through interaction with HSPA5/GRP78 [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the fundamental molecular identity of NRF3 as a CNC-bZIP factor that requires small Maf heterodimerization to bind DNA and activate transcription.\",\n      \"evidence\": \"In vitro transcription/translation, EMSA, co-IP, and transactivation assays on the chicken beta-globin MARE\",\n      \"pmids\": [\"10037736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes not yet defined\", \"No data on regulation of NRF3 activity or localization\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined NRF3 as functionally bidirectional—a repressor at the NQO1 ARE yet bearing a strong activation domain—answering whether a CNC factor can negatively regulate ARE genes.\",\n      \"evidence\": \"Overexpression/RNAi in HepG2 and JAR cells, EMSA/supershift, domain deletion, MAFG yeast two-hybrid and TNF-alpha induction\",\n      \"pmids\": [\"15385560\", \"15388789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing repressed vs activated targets unresolved\", \"Signals controlling activation domain usage unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved how NRF3 is spatially controlled, showing it is an ER-targeted N-glycoprotein whose NHB1 signal peptide governs processing, isoform distribution, and ER-stress responsiveness.\",\n      \"evidence\": \"Signal-peptide mutagenesis, subcellular fractionation, glycosidase assays, and ER-stress induction (extending CHX-chase/MG-132 findings)\",\n      \"pmids\": [\"19047052\", \"17976382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease/machinery releasing NRF3 from ER not identified at this stage\", \"Functional consequence of each isoform unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a nuclear degradation route, showing GSK3 phosphorylation primes NRF3 for SCF-FBW7 ubiquitination and relieves ARE repression.\",\n      \"evidence\": \"Co-IP, ubiquitination and kinase assays, FBW7 dimerization mutants, NQO1-ARE reporter\",\n      \"pmids\": [\"26306035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimuli regulating GSK3-FBW7 axis on NRF3 not defined\", \"Relationship to ER-associated degradation not yet integrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Unified NRF3 turnover into compartment-specific pathways and identified DDI2 as the protease enabling nuclear translocation, while linking NRF3 to proliferation via UHMK1.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, DDI2 knockdown, fractionation, expression profiling, proliferation assays\",\n      \"pmids\": [\"28970512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger activating DDI2-dependent release unknown\", \"Direct vs indirect UHMK1 regulation not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined NRF3's central role in proteasome homeostasis—directly inducing POMP for ubiquitin-independent 20S assembly to degrade p53/Rb, and repressing NFE2L1 translation through CPEB3.\",\n      \"evidence\": \"ChIP, pharmacological dissection (bortezomib vs TAK-243), xenografts, polysome profiling, RIP, double knockdown proteasome assays\",\n      \"pmids\": [\"32123008\", \"32366381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions favoring proteasome induction vs other programs unclear\", \"In vivo p53/Rb degradation contribution not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed NRF3 within oncogenic signaling networks, showing it is induced by NF-kB (RELA) and Wnt/β-catenin-TCF4 and feeds proliferative outputs in colon cancer.\",\n      \"evidence\": \"ChIP, reporter assays, siRNA/shRNA, Apc-deficient organoids/intestine, xenografts (with genome-wide ChIP-exo defining NRF3-specific targets)\",\n      \"pmids\": [\"31693889\", \"31288376\", \"31628195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of upstream NF-kB/Wnt inputs with ER-anchored regulation unclear\", \"Tissue specificity of the 22-gene NRF3 program not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established physiological roles in adhesion and stress-induced apoptosis, with Nrf3 promoting apoptosis by suppressing integrin-mediated adhesion signaling in keratinocytes.\",\n      \"evidence\": \"Nrf3 KO mice, primary keratinocytes, UV/oxidative stress, integrin flow cytometry, FAK western blot, motility assays\",\n      \"pmids\": [\"29487353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets controlling integrins not defined\", \"Link to ARE/Maf dimerization in this context untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated NRF3 can be tumor-suppressive through a non-transcriptional protein interaction, binding HSPA5/GRP78 to restrain squamous carcinogenesis.\",\n      \"evidence\": \"IP-MS interactome, NRF3-KO skin carcinogenesis model, 3D invasion, xenografts, HSPA5 rescue\",\n      \"pmids\": [\"37807968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of the HSPA5 interaction limited\", \"Context determining oncogenic vs suppressive role unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended NRF3 into cardiovascular pathology, showing epigenetic and autophagic mechanisms—hnRNPK/DNMT1-mediated Pitx2 silencing driving cardiomyocyte apoptosis, and ATF4-induced NRF3 transactivating Trim5 to drive neointimal hyperplasia.\",\n      \"evidence\": \"Global and cell-specific KO mice, ChIP-seq, IP-MS, mitochondrial ROS assays, AAV rescue, porcine stenting model, ChIP\",\n      \"pmids\": [\"40099370\", \"40377016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals selecting epigenetic-repressor vs activator mode unknown\", \"Generalizability of hnRNPK/DNMT1 recruitment to other targets untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed that NRF3 abundance is itself set by mRNA modifications (METTL3 m6A, NAT10 ac4C) that stabilize NFE2L3 transcript and feed Wnt/AKT stemness programs in cancer.\",\n      \"evidence\": \"m6A-RIP, acRIP-seq, RNA stability assays, ChIP-seq (LASP1), knockdown/overexpression, xenografts\",\n      \"pmids\": [\"40249818\", \"40169553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological triggers of these RNA modifications unclear\", \"Interplay with protein-level ERAD/FBW7 control not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What molecular switch dictates whether NRF3 acts as a transcriptional activator, an ARE repressor, an epigenetic silencer via hnRNPK/DNMT1, or a tumor suppressor via HSPA5 in a given cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking upstream stimulus to choice of target program\", \"Determinants of oncogenic vs tumor-suppressive output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 9, 19, 23]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 5, 9, 19, 23]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 9, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 19, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAFK\", \"MAFG\", \"FBW7\", \"HRD1\", \"VCP\", \"DDI2\", \"HNRNPK\", \"DNMT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}