{"gene":"NR4A3","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2007,"finding":"Abrogation of both NR4A3 (Nor-1) and NR4A1 (Nur77) in mice leads to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells and myeloid progenitors, decreased expression of AP-1 transcription factors JunB and c-Jun, and defective extrinsic apoptotic (Fas-L and TRAIL) signaling, identifying NR4A3 as a critical tumor suppressor of myeloid leukemogenesis.","method":"Genetic knockout (double Nr4a1/Nr4a3 knockout mice), flow cytometry, gene expression analysis, functional apoptosis assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined cellular phenotype, multiple orthogonal readouts (HSC expansion, AP-1 expression, apoptotic signaling), replicated in human AML patient samples","pmids":["17515897"],"is_preprint":false},{"year":2018,"finding":"NR4A1 and NR4A3 restrict HSC proliferation through two direct mechanisms: (1) binding to a hematopoietic-specific Cebpa enhancer to activate C/EBPα transcription and drive an antiproliferative network; (2) occupying regulatory regions of NF-κB-regulated inflammatory cytokines to antagonize NF-κB signaling activation.","method":"Conditional knockout mouse (CDKO), molecular profiling, chromatin immunoprecipitation (ChIP), enhancer binding assays, NF-κB pathway analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined phenotype, direct chromatin binding demonstrated by ChIP, multiple orthogonal mechanistic readouts in single study","pmids":["29343483"],"is_preprint":false},{"year":2019,"finding":"Enhancer hijacking via recurrent t(4;9)(q13;q31) chromosomal rearrangement translocates active enhancer regions from the SCPP gene cluster to the region upstream of NR4A3, causing NR4A3 overexpression in acinic cell carcinoma (AciCC). NR4A3 overexpression in mouse salivary gland cells increases expression of known NR4A3 target genes and stimulates cell proliferation.","method":"Genomic sequencing, chromatin analysis, RNA-seq, transcription factor binding motif analysis, NR4A3 overexpression in mouse salivary gland cells, cell proliferation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genomic rearrangement characterized, functional overexpression with target gene and proliferation readouts, multiple orthogonal methods in single study","pmids":["30664630"],"is_preprint":false},{"year":2009,"finding":"The EWSR1/NR4A3 fusion protein in extraskeletal myxoid chondrosarcoma (EMC) activates transcription of PPARG through a DNA response element in the PPARG promoter. An endogenous NR4A3 isoform lacking the C-terminal domain is highly expressed in EWSR1/NR4A3-positive tumors and may negatively regulate the fusion protein's activity on the PPARG promoter.","method":"Expression microarray, western blot, immunohistochemistry, bioinformatic identification of NR4A3 response element, band-shift (EMSA) experiments, transient transfection/reporter assays, co-transfection experiments","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — EMSA demonstrating direct DNA binding, reporter gene transactivation assays, mutagenesis-class functional analysis, single lab with multiple orthogonal methods","pmids":["18855877"],"is_preprint":false},{"year":2014,"finding":"NR4A3 is downstream of the homeodomain transcription factor Nkx6.1 in pancreatic β-cells and is both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Nr4a3 (with Nr4a1) increases expression of E2F1 and cyclin E1, and induces components of the anaphase-promoting complex (including UBE2C), resulting in degradation of the cell cycle inhibitor p21.","method":"Islet overexpression, siRNA knockdown, knockout mice, gene expression analysis, cell cycle analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function experiments, genetic KO mouse, pathway dissection with multiple downstream molecular readouts","pmids":["24706823"],"is_preprint":false},{"year":2016,"finding":"Deletion of Nr4a1 and Nr4a3 in pancreatic β-cells impedes mitochondrial respiration and reduces glucose-stimulated insulin secretion, associated with decreased expression of mitochondrial dehydrogenase subunits Idh3g and Sdhb and reduced ATP production, without reducing mitochondrial content.","method":"β-cell-specific knockout, mitochondrial respiration assays (Seahorse), glucose-stimulated insulin secretion assays, gene expression analysis","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean cell-type-specific KO, multiple orthogonal functional readouts (respiration, ATP, GSIS), molecular mechanism identified","pmids":["27221116"],"is_preprint":false},{"year":2018,"finding":"NR4A3 is a direct transcriptional target of p53: p53 directly binds the NR4A3 promoter and induces its transcription. NR4A3 overexpression promotes apoptosis by augmenting expression of pro-apoptotic genes PUMA and Bax. NR4A3 also physically interacts with anti-apoptotic Bcl-2 protein, sequestering it from inhibiting apoptosis.","method":"ChIP assay (p53 binding to NR4A3 promoter), reporter assays, NR4A3 overexpression and knockdown in cancer cells, apoptosis assays, co-immunoprecipitation (NR4A3-Bcl-2 interaction)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP demonstrating direct promoter binding, co-IP for protein interaction, gain/loss-of-function with defined apoptotic readouts, single lab with multiple orthogonal methods","pmids":["30455429"],"is_preprint":false},{"year":2016,"finding":"NR4A3 is essential for migration of CD103+ dendritic cells to lymph nodes through regulation of CCR7 surface expression. Nr4a3-deficient CD103+ DCs show markedly reduced CCR7, mediated by reduced FOXO1 protein levels through an AKT-dependent mechanism. NR4A3 also maintains homeostatic mitochondrial function in CD103+ DCs.","method":"Nr4a3 knockout mice, mixed-chimera studies (cell-intrinsic defect), flow cytometry, in vivo DC migration assays, FOXO1/AKT signaling analysis, in vivo TLR7 agonist and bacterial infection models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, cell-intrinsic defect confirmed by chimera studies, molecular pathway (NR4A3→FOXO1→CCR7 via AKT) established with multiple readouts","pmids":["27820700"],"is_preprint":false},{"year":2019,"finding":"NR4A3 is required for the proper differentiation of monocyte-derived dendritic cells (MoDCs) but not other DC types. Nr4a3-/- mice show severely impaired generation of DC-SIGN+ MoDCs in response to LPS, resulting in inability to mount optimal CD8+ T cell responses to gram-negative bacteria. Transcriptomic analysis shows NR4A3 skews monocyte differentiation toward MoDCs at the expense of macrophages.","method":"Nr4a3 knockout mice, flow cytometry, LPS stimulation, RNA-seq/transcriptomic analysis, in vivo bacterial infection models, CD8+ T cell response assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO, defined cell differentiation phenotype, transcriptomic mechanism, in vivo functional consequence","pmids":["31285338"],"is_preprint":false},{"year":2020,"finding":"NR4A3 programs early CD8+ T cell differentiation fate: NR4A3-deficient murine CD8+ T cells preferentially differentiate into memory precursor and central memory cells while also producing more cytokines. This is mediated through early influence on the memory transcriptional program and chromatin accessibility at bZIP transcription factor motifs, impacting Fos/Jun target gene transcription.","method":"NR4A3-deficient mouse model, adoptive transfer experiments, single-cell transcriptomics, ATAC-seq (chromatin accessibility), cytokine production assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined differentiation phenotype, mechanistic epigenomic data (ATAC-seq), multiple orthogonal methods in single study","pmids":["32913051"],"is_preprint":false},{"year":2020,"finding":"NR4A3 and BLIMP1 (PRDM1) reciprocally regulate CAR T cell stemness and exhaustion. Dual knockout of PRDM1 and NR4A3 skews CAR T cell phenotypes from TIM-3+CD8+ toward TCF1+CD8+, countering exhaustion and improving antitumor responses in solid tumors — an effect not achieved by single knockouts alone. In PRDM1-deficient cells, NR4A3 is part of an NFAT-driven compensatory exhaustion program.","method":"PRDM1 and NR4A3 single and double knockout in CAR T cells, scRNA-seq, epigenetic profiling, in vivo mouse tumor models, clinical trial CAR T cell samples","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO (single and double), in vivo tumor models, mechanistic epistasis with clinical validation, multiple orthogonal methods","pmids":["36350986"],"is_preprint":false},{"year":2020,"finding":"Nr4a1 and Nr4a3 reporter mice show differential sensitivity to TCR signal strength and duration. Nr4a2 and Nr4a3 expression is regulated downstream of calcineurin and requires NFAT1 (which directly binds Nr4a2 and Nr4a3 loci), while Nr4a1 shows redundancy for NFAT1. Nr4a3-Tocky requires cognate peptide:MHC interactions for expression, whereas Nr4a1-GFP responds to tonic signals during T cell development.","method":"Nr4a1-GFP and Nr4a3-Timer (Tocky) reporter mice, calcineurin inhibitor treatment, NFAT1 binding assays, TCR signaling pathway inhibitors (Src family kinase inhibitors), flow cytometry","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual reporter mouse models, NFAT1 binding demonstrated, pharmacological pathway dissection with multiple orthogonal methods","pmids":["33147449"],"is_preprint":false},{"year":2017,"finding":"NR4A2 and NR4A3 are upregulated downstream of PKA activation in neutrophils (induced by adenosine, prostaglandin E2, and direct PKA agonists) and positively regulate neutrophil survival. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces absolute neutrophil number without affecting migration.","method":"Human neutrophil gene arrays, PKA agonists, siRNA knockdown, antisense morpholino knockdown in zebrafish, apoptosis/survival assays, flow cytometry","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PKA-dependent induction demonstrated, zebrafish in vivo knockdown, but mechanistic dissection of NR4A3 vs NR4A2 contributions is not fully resolved","pmids":["28637666"],"is_preprint":false},{"year":2017,"finding":"NR4A3 knockdown in bone marrow-derived dendritic cells suppresses TLR-mediated upregulation of CD80, CD86, IL-10, IL-6, and IL-12, and reduces T cell proliferation and IL-2 production. Mechanistically, NR4A3 regulates DC activation via controlling expression of IKKβ, IRF4, and IRF8 — where IKKβ mediates IL-10/IL-6 induction and IRF4/IRF8 mediate IL-12 induction.","method":"siRNA knockdown in bone marrow-derived DCs, LPS/CpG/poly(I:C) stimulation, qRT-PCR, western blot, T cell co-culture assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with multiple downstream readouts, epistasis via individual IKKβ/IRF4/IRF8 siRNA knockdowns, single lab","pmids":["28893954"],"is_preprint":false},{"year":2017,"finding":"NR4A3 (NOR-1) directly regulates vitronectin (VTN) in human vascular smooth muscle cells (VSMCs): NOR-1 binds the NBRE(-202/-195) site in the VTN promoter (identified by deletion/site-directed mutagenesis, EMSA, and ChIP). NOR-1-induced VTN secretion promotes VSMC migration.","method":"Lentiviral NOR-1 overexpression and siRNA silencing, deletion and site-directed mutagenesis, EMSA, ChIP, VTN blocking antibody experiments, cell migration assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct DNA binding demonstrated by EMSA and ChIP, promoter mutagenesis mapping the functional element, functional migration assay with antibody rescue, single lab with multiple orthogonal methods","pmids":["28666984"],"is_preprint":false},{"year":2019,"finding":"Nor1/Nr4a3 negatively regulates β-cell mass: Nor1 knockout mice display increased β-cell mass and improved glucose tolerance. Nor1 expression is increased by pro-inflammatory cytokines and elevated glucose in β-cells. Nor1 overexpression causes apoptosis in INS and human islet cells, while siRNA knockdown prevents cytokine-induced β-cell death. Nor1 expression is elevated in islets of type 2 diabetic individuals.","method":"Nr4a3 knockout mice, histological analysis, gain/loss-of-function (overexpression and siRNA) in INS cells and human islets, apoptosis assays, glucose tolerance tests","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse, gain and loss-of-function in multiple cell types including human islets, multiple orthogonal functional readouts","pmids":["30696767"],"is_preprint":false},{"year":2020,"finding":"Nor1/Nr4a3 is predominantly cytoplasmic in pancreatic β-cells and undergoes mitochondrial translocation upon activation by pro-inflammatory cytokines. Mitochondrial localization of Nor1 reduces glucose oxidation, lowers ATP production rates, inhibits glucose-stimulated insulin secretion, and provokes mitochondrial fragmentation via mitophagy.","method":"Subcellular fractionation, fluorescence microscopy, Nor1 overexpression in INS832/13 cells and human β-cells, mitochondrial function assays, western blot for mitophagy markers","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by imaging and fractionation with functional consequence, overexpression model, single lab","pmids":["31936632"],"is_preprint":false},{"year":2016,"finding":"Muscle contraction (exercise) induces rapid demethylation at the Nr4a3 promoter preceded by hydroxymethylation: electrical pulse stimulation of C2C12 myotubes causes demethylation at 60 min and re-methylation at 120 min, with hydroxymethylation elevated immediately after stimulation. Nr4a3 was identified as the most exercise-responsive gene in acute exercise in humans.","method":"Acute human exercise study, electrical pulse stimulation (EPS) of C2C12 myotubes, targeted bisulfite sequencing, gene expression analysis","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bisulfite sequencing directly measuring epigenetic modification at Nr4a3 promoter in response to defined stimulus, both human and cell culture models, single lab","pmids":["28066330"],"is_preprint":false},{"year":2014,"finding":"NR4A3 overexpression in pancreatic MIN6 β-cells reduces insulin gene (Ins1, Ins2) transcription and insulin protein secretion. This effect requires both the AF1 activation domain and the DNA-binding domain of NR4A3. NR4A3 reduces insulin gene expression by downregulating transcriptional regulators Pdx1 and NeuroD1.","method":"Adenoviral overexpression of NR4A3 and deletion mutants in MIN6 cells, qPCR, insulin secretion assays, ER stress induction","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mutagenesis establishing AF1 and DBD requirement, functional insulin secretion readout, single lab","pmids":["24638142"],"is_preprint":false},{"year":2018,"finding":"NR4A3 knockdown in human BeWo trophoblast cells increases FSK-induced cell fusion and expression of CGB and syncytin2, whereas STAT5B knockdown decreases these. cAMP-PKA signaling upregulates both STAT5B and NR4A3, but NR4A3 acts as a negative regulator of syncytialization by decreasing syncytin2 expression, opposing STAT5B's positive effect.","method":"siRNA knockdown of STAT5B and NR4A3 in BeWo cells, microarray analysis, FSK stimulation, cell fusion assays, syncytialization marker expression","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with defined cellular phenotype, pathway placement via opposing regulatory roles, single lab","pmids":["29377304"],"is_preprint":false},{"year":2019,"finding":"NR4A3 acts pro-inflammatory in osteoarthritis chondrocytes: NR4A3 overexpression enhances IL-1β-induced expression of matrix-degrading enzymes (MMP-3, MMP-9, iNOS, COX-2) and NF-κB activation, while NR4A3 knockdown reduces these effects. NR4A3 overexpression also enhances starvation-induced chondrocyte apoptosis.","method":"Lentiviral NR4A3 overexpression, siRNA knockdown in chondrocytes, IL-1β stimulation, western blot, qRT-PCR, NF-κB pathway analysis, apoptosis assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal gain/loss-of-function with molecular pathway (NF-κB) identified, single lab, single cell type","pmids":["31701670"],"is_preprint":false},{"year":2014,"finding":"Nuclear receptor Nr4a3 regulates mast cell cytokine/chemokine secretion following high-affinity IgE receptor activation and negatively affects mast cell tryptase transcript and protein levels, as well as the mast cell's responsiveness to allergen.","method":"Nr4a3 knockout-based functional studies in mast cells, IgE receptor activation assays, cytokine/chemokine measurement, tryptase expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined mast cell functional phenotypes, single lab","pmids":["24586680"],"is_preprint":false},{"year":2016,"finding":"Intragenic DNA hypermethylation at CpG sites in exon 3 of NR4A3 (but not the promoter region) silences NR4A3 expression in AML. A DNA methyltransferase inhibitor restores NR4A3 expression following reduction in methylation at intragenic CpG sites. Exon 3 contains histone marks (H3K4me1, H2A.Z) in non-malignant cells that are absent in leukemia cells with CpG hypermethylation.","method":"Bisulfite sequencing of AML cell lines and primary AML cells, DNA methyltransferase inhibitor treatment, ChIP-seq/in silico histone mark analysis","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bisulfite sequencing directly measuring intragenic methylation, pharmacological restoration of expression, correlation with histone marks, single lab","pmids":["27697661"],"is_preprint":false},{"year":2017,"finding":"NR4A3 overexpression or pharmacological activation in aggressive lymphoma cell lines induces apoptosis, abrogates tumor growth in NSG xenograft mouse models, and drives apoptosis by inducing pro-apoptotic genes BAK, PUMA, BIK, BIM, BID, and TRAIL (similar to NR4A1).","method":"Stable NR4A3 transduction of lymphoma cell lines, NSG xenograft mouse model, pharmacological NR4A3 activation, transcript analysis, apoptosis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft model, defined pro-apoptotic gene targets identified, single lab","pmids":["28249906"],"is_preprint":false},{"year":2020,"finding":"Oncogenic NR4A3 interacts physically with the MYB DNA-binding domain via its ligand-binding domain in acinic cell carcinoma. Co-expression of NR4A3 and MYB cooperatively regulates a distinct gene set and is more potent at inducing transformation (anchorage-independent growth, invasiveness) than either alone.","method":"RNA-seq of AciCC samples, protein-protein interaction assay (LBD-DBD binding), transformation assays, anchorage-independent growth, invasion assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct physical interaction demonstrated, cooperative functional effects, single lab","pmids":["32867110"],"is_preprint":false},{"year":2020,"finding":"miR-106b-5p negatively regulates NR4A3 expression (validated by dual-luciferase reporter assay), and NR4A3 regulates Treg differentiation via Foxp3. Reduced NR4A3 (by miR-106b-5p) leads to decreased Foxp3 and TGF-β expression, contributing to Treg/Th17 imbalance in immune thrombocytopenic purpura.","method":"qRT-PCR, western blot, dual-luciferase reporter assay for miR-106b-5p/NR4A3 interaction, siRNA knockdown of NR4A3, in vivo miR-106b-5p silencing in ITP mouse model","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter validation of miRNA-target relationship, pathway placement via sh-NR4A3 experiments, in vivo model, single lab","pmids":["32323598"],"is_preprint":false},{"year":2022,"finding":"MSC-derived extracellular vesicles deliver miR-146a, which directly targets Nr4a3 (validated by dual-luciferase assay): miR-146a mimic decreases Nr4a3 expression while inhibition promotes it. Upregulation of miR-146a by MSC-EVs decreases Nr4a3 expression and reduces LPS-induced pro-inflammatory cytokines in microglia (BV2 cells), contributing to retinal protection.","method":"Dual-luciferase assay, miR-146a mimic/inhibitor transfection, qPCR, western blot, co-culture of photoreceptors with microglia, in vivo rd10 mouse model","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter validation of miR-146a/NR4A3 targeting, in vivo functional context, single lab","pmids":["35922863"],"is_preprint":false},{"year":2024,"finding":"NR4A3 promotes vascular calcification via histone lactylation: NR4A3 directly binds promoter regions of glycolysis genes ALDOA and PFKL to drive their transcriptional initiation, enhancing glycolytic rate and lactate production. Increased lactate promotes histone lactylation, which in turn activates PHOSPHO1 transcription to drive calcium deposition. NR4A3 deficiency inhibits this cascade and reduces vascular calcification.","method":"NR4A3 knockout mice, vascular calcification models, RNA-seq, CUT&TAG (chromatin binding analysis), metabolic assays, NR4A3 overexpression, Phospho1 pharmacological inhibition and overexpression, in vivo and in vitro calcium deposition assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CUT&TAG establishing direct promoter binding, genetic KO and overexpression, pharmacological rescue experiments, in vivo models, multiple orthogonal methods","pmids":["38629274"],"is_preprint":false},{"year":2020,"finding":"FTO (fat mass and obesity-associated demethylase) regulates NR4A3 mRNA m6A methylation: FTO knockdown increases methylation of NR4A3 mRNA, while FTO (but not catalytically mutated FTO) overexpression reduces NR4A3 mRNA methylation. DHA suppresses AngII-induced VSMC proliferation/inflammation by inhibiting the FTO/NR4A3 axis.","method":"m6A-RNA immunoprecipitation (MeRIP) assay, FTO knockdown/overexpression, AngII stimulation of VSMCs, cell proliferation assays (CCK-8, BrdU), western blot, qRT-PCR","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP directly measuring m6A modification of NR4A3 mRNA, catalytic mutant FTO control establishing writer specificity, single lab","pmids":["35059772"],"is_preprint":false},{"year":2020,"finding":"NR4A3 promotes pulmonary arterial smooth muscle cell (PASMC) proliferation via the cyclin D1 pathway. miR-638 directly targets NR4A3 (validated by luciferase reporter assay), and resveratrol prevents MCT-induced pulmonary vascular remodeling by upregulating miR-638 and thereby reducing NR4A3 expression.","method":"Luciferase reporter assay for miR-638/NR4A3, loss-/gain-of-function (miR-638 mimic/antagomir), NR4A3 overexpression, MCT rat model of pulmonary hypertension, PASMC proliferation assays","journal":"Microvascular research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase validation of miRNA targeting, in vivo rat model, NR4A3/cyclin D1 pathway established, single lab","pmids":["32057731"],"is_preprint":false},{"year":2024,"finding":"NR4A3 protects against diabetes-induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress, acting through preserving transcriptional expression of Sdha. NR4A3 deficiency exacerbates atrial hypertrophy, fibrosis, and susceptibility to atrial fibrillation.","method":"Nr4a3 knockout mice (HFD/STZ model), AAV9-Nr4a3 overexpression in db/db mice, RNA-seq, metabolomics, electrophysiological studies, histological analysis","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and AAV-mediated overexpression with in vivo functional readouts, RNA-seq identifying Sdha as downstream target, single lab","pmids":["39098108"],"is_preprint":false}],"current_model":"NR4A3 (NOR-1) is a ligand-independent orphan nuclear receptor that functions as a transcriptional activator and repressor across diverse cell types: it binds specific DNA response elements (NBREs) to directly regulate target genes (including PPARG, VTN, ALDOA, PFKL, Cebpa, cyclin D1, and Sdha); its expression is rapidly induced by TCR signaling (via NFAT1/calcineurin), PKA activation, p53, Nkx6.1, muscle contraction, and inflammatory cytokines; it acts as a critical tumor suppressor in hematopoietic cells (suppressing AML by maintaining C/EBPα and restraining NF-κB inflammatory signaling), regulates CD8+ T cell and DC differentiation, controls β-cell mitochondrial function and insulin secretion (including through cytoplasmic-to-mitochondrial translocation), promotes vascular calcification through a glycolysis→histone lactylation→PHOSPHO1 cascade, and is activated oncogenically in acinic cell carcinoma through enhancer hijacking at the t(4;9)(q13;q31) translocation."},"narrative":{"mechanistic_narrative":"NR4A3 (NOR-1) is a ligand-independent orphan nuclear receptor that acts as a sequence-specific transcriptional regulator induced rapidly by cell-activation signals, coordinating cell-fate, metabolic, and inflammatory programs across hematopoietic, immune, vascular, and endocrine tissues [PMID:17515897, PMID:33147449, PMID:38629274]. As a transcription factor it binds defined response elements in target promoters and enhancers to activate or repress genes: it directly drives a hematopoietic-specific Cebpa enhancer and antagonizes NF-κB-regulated inflammatory loci to restrain HSC proliferation, and its loss together with NR4A1 produces lethal acute myeloid leukemia, establishing it as a myeloid tumor suppressor [PMID:17515897, PMID:29343483]. In other settings it binds NBRE elements to control vitronectin in vascular smooth muscle and glycolytic genes ALDOA and PFKL, the latter feeding a glycolysis→histone-lactylation→PHOSPHO1 cascade that drives vascular calcification [PMID:28666984, PMID:38629274]. Its expression is gated by upstream pathways including TCR/calcineurin–NFAT1 signaling, p53, the homeodomain factor Nkx6.1, PKA, and muscle contraction, and is further tuned post-transcriptionally by FTO-dependent m6A methylation and by multiple microRNAs [PMID:24706823, PMID:30455429, PMID:33147449, PMID:28066330, PMID:35059772]. In immune cells NR4A3 governs differentiation and effector states: it controls CD103+ and monocyte-derived dendritic cell development and migration via FOXO1/CCR7 and IKKβ/IRF4/IRF8 axes, programs early CD8+ T cell memory-versus-effector fate through chromatin accessibility at bZIP motifs, and contributes to CAR-T exhaustion in an NFAT-driven program [PMID:27820700, PMID:31285338, PMID:32913051, PMID:36350986, PMID:28893954]. In pancreatic β-cells it has dual roles — promoting Nkx6.1-driven proliferation and supporting mitochondrial respiration and insulin secretion, while also acting cytotoxically when cytokine-activated and translocated to mitochondria to impair glucose-stimulated insulin secretion [PMID:24706823, PMID:27221116, PMID:30696767, PMID:31936632]. NR4A3 also engages apoptotic machinery, being a p53 target that induces PUMA/Bax and sequesters Bcl-2, and is oncogenically activated by enhancer hijacking at t(4;9) and by the EWSR1/NR4A3 fusion, where it cooperates physically with MYB to drive transformation [PMID:30664630, PMID:18855877, PMID:30455429, PMID:32867110].","teleology":[{"year":2007,"claim":"Established NR4A3 as a genetically required tumor suppressor in the myeloid lineage, answering whether the orphan receptor has a non-redundant role in hematopoietic homeostasis.","evidence":"Double Nr4a1/Nr4a3 knockout mice developing lethal AML with HSC expansion and defective apoptotic signaling","pmids":["17515897"],"confidence":"High","gaps":["Redundancy with NR4A1 leaves NR4A3-specific transcriptional targets undefined in this study","Direct chromatin targets not yet identified"]},{"year":2018,"claim":"Resolved the molecular basis of NR4A tumor suppression by showing direct chromatin binding to activate Cebpa and antagonize NF-κB inflammatory genes.","evidence":"Conditional double knockout with ChIP and enhancer-binding assays in HSCs","pmids":["29343483"],"confidence":"High","gaps":["Does not separate NR4A1 from NR4A3 contributions at each locus","Whether C/EBPα activation is direct or cooperative left open"]},{"year":2018,"claim":"Placed NR4A3 within the p53 apoptotic axis, identifying both an upstream regulator and a protein-level effector mechanism.","evidence":"ChIP of p53 at the NR4A3 promoter plus co-IP of NR4A3 with Bcl-2 and apoptosis assays in cancer cells","pmids":["30455429"],"confidence":"High","gaps":["Bcl-2 sequestration shown by single co-IP without structural mapping","Cell-type generality of the p53→NR4A3 axis untested"]},{"year":2009,"claim":"Demonstrated that fusion-driven NR4A3 retains transactivation function by directly binding the PPARG promoter in chondrosarcoma.","evidence":"EMSA, reporter assays and identification of an NR4A3 response element for the EWSR1/NR4A3 fusion","pmids":["18855877"],"confidence":"High","gaps":["Role of the C-terminally truncated isoform inferred, not functionally proven in vivo","Genome-wide fusion targets not mapped"]},{"year":2019,"claim":"Showed NR4A3 can be oncogenic through enhancer hijacking, contrasting its tumor-suppressor role in myeloid cells with a proliferative role in salivary gland tissue.","evidence":"Genomic characterization of t(4;9), RNA-seq and NR4A3 overexpression with proliferation readouts in mouse salivary gland cells","pmids":["30664630"],"confidence":"High","gaps":["Why NR4A3 is oncogenic here versus tumor-suppressive in HSCs not mechanistically reconciled","Direct transformation targets in salivary cells not enumerated"]},{"year":2020,"claim":"Identified the protein partner that confers context-specific oncogenicity, showing NR4A3 physically cooperates with MYB to drive transformation.","evidence":"LBD-DBD interaction assay and cooperative transformation/invasion assays in acinic cell carcinoma models","pmids":["32867110"],"confidence":"Medium","gaps":["Interaction shown in single lab without reciprocal in vivo validation","Cooperative gene set not linked to specific phenotypic drivers"]},{"year":2014,"claim":"Defined NR4A3 as the effector of Nkx6.1-driven β-cell proliferation through a cell-cycle activation network.","evidence":"Islet gain/loss-of-function and knockout mice with E2F1, cyclin E1, APC/UBE2C and p21 readouts","pmids":["24706823"],"confidence":"High","gaps":["Direct chromatin targets among cell-cycle genes not mapped","Reconciliation with anti-proliferative roles in HSCs unaddressed"]},{"year":2014,"claim":"Showed NR4A3 represses insulin gene expression in a domain-dependent manner, indicating direct transcriptional control of β-cell identity genes.","evidence":"Adenoviral overexpression with AF1/DBD deletion mutants in MIN6 cells and Pdx1/NeuroD1 readouts","pmids":["24638142"],"confidence":"Medium","gaps":["Overexpression-only model; physiological relevance uncertain","Direct vs indirect repression of Pdx1/NeuroD1 not resolved"]},{"year":2016,"claim":"Established a positive role for NR4A3 in β-cell mitochondrial respiration and insulin secretion, complicating its overall metabolic role.","evidence":"β-cell-specific double knockout with Seahorse respiration, ATP, GSIS and Idh3g/Sdhb expression readouts","pmids":["27221116"],"confidence":"High","gaps":["NR4A1 vs NR4A3 contributions not separated","Mechanism of dehydrogenase regulation (direct/indirect) unknown"]},{"year":2019,"claim":"Revealed an opposing cytotoxic role for NR4A3 in β-cells under inflammatory/glucotoxic conditions, linking it to type 2 diabetes pathology.","evidence":"Nr4a3 knockout mice, gain/loss-of-function in INS cells and human islets, apoptosis assays, diabetic islet expression","pmids":["30696767"],"confidence":"High","gaps":["Reconciliation of pro-proliferative/pro-respiration versus pro-apoptotic roles unresolved","Stimulus-dependent target switch not defined"]},{"year":2020,"claim":"Provided a subcellular mechanism for NR4A3 cytotoxicity by showing cytokine-induced mitochondrial translocation impairs respiration.","evidence":"Subcellular fractionation and imaging with mitochondrial function and mitophagy readouts in β-cells","pmids":["31936632"],"confidence":"Medium","gaps":["Translocation mechanism and mitochondrial binding partners unknown","Overexpression model from a single lab"]},{"year":2016,"claim":"Established NR4A3 as essential for CD103+ DC migration via an AKT-FOXO1-CCR7 axis and mitochondrial maintenance.","evidence":"Knockout and mixed-chimera studies with in vivo migration and FOXO1/AKT signaling analysis","pmids":["27820700"],"confidence":"High","gaps":["Whether FOXO1 regulation is transcriptional or post-translational not fully resolved","Direct NR4A3 targets in DCs not mapped"]},{"year":2017,"claim":"Identified NR4A3 as a transcriptional regulator of DC activation through control of IKKβ, IRF4 and IRF8.","evidence":"siRNA knockdown in bone marrow-derived DCs with TLR stimulation, epistasis knockdowns and T cell co-culture","pmids":["28893954"],"confidence":"Medium","gaps":["Knockdown-only without genetic confirmation","Direct binding to IKKβ/IRF loci not shown"]},{"year":2019,"claim":"Showed NR4A3 directs monocyte differentiation toward MoDCs, controlling anti-bacterial CD8+ T cell responses.","evidence":"Knockout mice, LPS stimulation, RNA-seq and in vivo infection/CD8 response assays","pmids":["31285338"],"confidence":"High","gaps":["Transcriptional targets driving the MoDC-versus-macrophage switch not defined","Mechanism of lineage skewing unknown"]},{"year":2020,"claim":"Demonstrated NR4A3 programs early CD8+ T cell memory-versus-effector fate via chromatin accessibility at bZIP motifs.","evidence":"NR4A3-deficient mice, adoptive transfer, scRNA-seq, ATAC-seq and cytokine assays","pmids":["32913051"],"confidence":"High","gaps":["Direct binding at bZIP motif regions versus indirect chromatin remodeling not separated","Relationship to Fos/Jun cofactors mechanistically open"]},{"year":2020,"claim":"Placed NR4A3 in an NFAT-driven exhaustion program reciprocal to BLIMP1, with translational relevance for CAR-T engineering.","evidence":"Single and double PRDM1/NR4A3 knockout CAR-T cells, scRNA-seq, in vivo tumor models and clinical samples","pmids":["36350986"],"confidence":"High","gaps":["Direct NR4A3 targets in the exhaustion program not enumerated","Epistasis mechanism with PRDM1 incompletely defined"]},{"year":2020,"claim":"Defined the upstream signaling logic of NR4A3 induction, showing strict dependence on calcineurin and NFAT1 with cognate peptide:MHC requirement.","evidence":"Nr4a3-Timer/Tocky reporter mice, calcineurin inhibition, NFAT1 binding assays and TCR pathway inhibitors","pmids":["33147449"],"confidence":"High","gaps":["Direct vs cooperative NFAT1 binding at Nr4a3 not structurally defined","Downstream consequences of differential signal strength not mapped"]},{"year":2017,"claim":"Extended NR4A3 induction to PKA signaling in neutrophils and linked it to survival.","evidence":"Human neutrophil gene arrays, PKA agonists, siRNA and zebrafish morpholino knockdown","pmids":["28637666"],"confidence":"Medium","gaps":["NR4A3 versus NR4A2 contributions unresolved","Pro-survival transcriptional targets not identified"]},{"year":2014,"claim":"Defined a role for Nr4a3 in regulating mast cell mediator secretion and allergen responsiveness.","evidence":"Knockout-based functional studies with IgE receptor activation and tryptase/cytokine readouts","pmids":["24586680"],"confidence":"Medium","gaps":["Direct targets controlling tryptase and cytokine genes not identified","Mechanism of negative regulation unknown"]},{"year":2017,"claim":"Showed NR4A3 demethylation at its promoter is the most exercise-responsive transcriptional event in skeletal muscle.","evidence":"Acute human exercise study and electrical pulse stimulation of C2C12 myotubes with bisulfite sequencing","pmids":["28066330"],"confidence":"Medium","gaps":["Functional consequence of muscle NR4A3 induction not addressed","Demethylase responsible not identified"]},{"year":2017,"claim":"Demonstrated that NR4A3 activation is pro-apoptotic in lymphoma, supporting a tumor-suppressive function with therapeutic potential.","evidence":"Stable transduction and pharmacological activation in lymphoma lines with NSG xenografts and pro-apoptotic gene analysis","pmids":["28249906"],"confidence":"Medium","gaps":["Direct binding at pro-apoptotic gene loci not shown","Single-lab study without genetic loss-of-function"]},{"year":2019,"claim":"Identified a pro-inflammatory, NF-κB-enhancing role for NR4A3 in osteoarthritis chondrocytes, contrasting its NF-κB-antagonizing role in HSCs.","evidence":"Reciprocal overexpression/knockdown in chondrocytes with IL-1β stimulation and NF-κB analysis","pmids":["31701670"],"confidence":"Medium","gaps":["Direction of NF-κB regulation opposite to HSC findings unexplained","Direct targets not defined"]},{"year":2018,"claim":"Placed NR4A3 in trophoblast syncytialization as a cAMP/PKA-induced negative regulator opposing STAT5B.","evidence":"siRNA knockdown of STAT5B and NR4A3 in BeWo cells with fusion and syncytin2 readouts","pmids":["29377304"],"confidence":"Medium","gaps":["Knockdown-only without genetic confirmation","Direct regulation of syncytin2/CGB not demonstrated"]},{"year":2016,"claim":"Identified intragenic CpG hypermethylation, not promoter methylation, as the mechanism silencing NR4A3 in AML.","evidence":"Bisulfite sequencing of AML cells, DNMT inhibitor restoration and histone mark analysis","pmids":["27697661"],"confidence":"Medium","gaps":["Mechanistic link between exon 3 methylation and silencing not fully defined","Causality of histone mark loss versus methylation unresolved"]},{"year":2020,"claim":"Showed FTO-dependent m6A demethylation post-transcriptionally controls NR4A3 in vascular smooth muscle proliferation.","evidence":"MeRIP with FTO knockdown/overexpression and catalytic-mutant control under AngII stimulation","pmids":["35059772"],"confidence":"Medium","gaps":["m6A reader mediating NR4A3 mRNA fate not identified","Effect on transcript stability versus translation not separated"]},{"year":2020,"claim":"Defined microRNA control of NR4A3 across immune and vascular contexts, linking its levels to Treg differentiation and PASMC proliferation.","evidence":"Dual-luciferase validation of miR-106b-5p, miR-638 and miR-146a targeting NR4A3 with in vivo disease models","pmids":["32323598","32057731","35922863"],"confidence":"Medium","gaps":["Direct NR4A3 transcriptional targets (Foxp3, cyclin D1) not shown to be direct","Single-lab miRNA studies without orthogonal confirmation"]},{"year":2024,"claim":"Established a direct chromatin-to-metabolite mechanism by which NR4A3 drives vascular calcification through glycolysis and histone lactylation.","evidence":"Knockout mice, CUT&TAG at ALDOA/PFKL promoters, metabolic assays and PHOSPHO1 pharmacological rescue","pmids":["38629274"],"confidence":"High","gaps":["Mechanism of NR4A3 activation in calcifying cells not defined","Specificity of lactylation-driven PHOSPHO1 induction not fully mapped"]},{"year":2024,"claim":"Showed NR4A3 protects diabetic atria by preserving mitochondrial Sdha-dependent metabolism, extending its metabolic guardian role to cardiac tissue.","evidence":"Knockout and AAV9 overexpression mouse models with RNA-seq, metabolomics and electrophysiology","pmids":["39098108"],"confidence":"Medium","gaps":["Whether Sdha is a direct NR4A3 target not established","Tissue-specific reconciliation with β-cell cytotoxic roles open"]},{"year":null,"claim":"It remains unresolved how NR4A3 switches between tumor-suppressive/pro-apoptotic, oncogenic, NF-κB-antagonizing and NF-κB-promoting, and metabolically protective versus cytotoxic outputs across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model of cofactor- or context-dependent target selection","Genome-wide direct target catalog across cell types lacking","Ligand/activation-state control of nuclear-versus-mitochondrial function undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,14,27]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,14,27]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,6,14,27]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[16]}],"pathway":[],"complexes":[],"partners":["NR4A1","MYB","BCL2","EWSR1","NFAT1","P53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92570","full_name":"Nuclear receptor subfamily 4 group A member 3","aliases":["Mitogen-induced nuclear orphan receptor","Neuron-derived orphan receptor 1","Nuclear hormone receptor NOR-1","Translocated in extraskeletal chondrosarcoma"],"length_aa":626,"mass_kda":68.2,"function":"Transcriptional activator that binds to regulatory elements in promoter regions in a cell- and response element (target)-specific manner. Induces gene expression by binding as monomers to the NR4A1 response element (NBRE) 5'-AAAAGGTCA-3' site and as homodimers to the Nur response element (NurRE) site in the promoter of their regulated target genes (By similarity). Plays a role in the regulation of proliferation, survival and differentiation of many different cell types and also in metabolism and inflammation. Mediates proliferation of vascular smooth muscle, myeloid progenitor cell and type B pancreatic cells; promotes mitogen-induced vascular smooth muscle cell proliferation through transactivation of SKP2 promoter by binding a NBRE site (By similarity). Upon PDGF stimulation, stimulates vascular smooth muscle cell proliferation by regulating CCND1 and CCND2 expression. In islets, induces type B pancreatic cell proliferation through up-regulation of genes that activate cell cycle, as well as genes that cause degradation of the CDKN1A (By similarity). Negatively regulates myeloid progenitor cell proliferation by repressing RUNX1 in a NBRE site-independent manner. During inner ear, plays a role as a key mediator of the proliferative growth phase of semicircular canal development (By similarity). Also mediates survival of neuron and smooth muscle cells; mediates CREB-induced neuronal survival, and during hippocampus development, plays a critical role in pyramidal cell survival and axonal guidance. Is required for S phase entry of the cell cycle and survival of smooth muscle cells by inducing CCND1, resulting in RB1 phosphorylation. Binds to NBRE motif in CCND1 promoter, resulting in the activation of the promoter and CCND1 transcription (By similarity). Also plays a role in inflammation; upon TNF stimulation, mediates monocyte adhesion by inducing the expression of VCAM1 and ICAM1 by binding to the NBRE consensus site (By similarity) (PubMed:20558821). In mast cells activated by Fc-epsilon receptor cross-linking, promotes the synthesis and release of cytokines but impairs events leading to degranulation (By similarity). Also plays a role in metabolism; by modulating feeding behavior; and by playing a role in energy balance by inhibiting the glucocorticoid-induced orexigenic neuropeptides AGRP expression, at least in part by forming a complex with activated NR3C1 on the AGRP- glucocorticoid response element (GRE), and thus weakening the DNA binding activity of NR3C1. Upon catecholamines stimulation, regulates gene expression that controls oxidative metabolism in skeletal muscle (By similarity). Plays a role in glucose transport by regulating translocation of the SLC2A4 glucose transporter to the cell surface (PubMed:24022864). Finally, during gastrulation plays a crucial role in the formation of anterior mesoderm by controlling cell migration. Inhibits adipogenesis (By similarity). Also participates in cardiac hypertrophy by activating PARP1 (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q92570/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR4A3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR4A3","total_profiled":1310},"omim":[{"mim_id":"612237","title":"CHONDROSARCOMA, EXTRASKELETAL MYXOID","url":"https://www.omim.org/entry/612237"},{"mim_id":"604204","title":"SYNTAXIN 17; STX17","url":"https://www.omim.org/entry/604204"},{"mim_id":"603714","title":"SIX HOMEOBOX 3; SIX3","url":"https://www.omim.org/entry/603714"},{"mim_id":"602563","title":"NK6 HOMEOBOX 1; NKX6-1","url":"https://www.omim.org/entry/602563"},{"mim_id":"602498","title":"TRAFFICKING FROM ER TO GOLGI REGULATOR; TFG","url":"https://www.omim.org/entry/602498"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NR4A3"},"hgnc":{"alias_symbol":["CSMF","CHN","NOR1","MINOR"],"prev_symbol":[]},"alphafold":{"accession":"Q92570","domains":[{"cath_id":"3.30.50.10","chopping":"289-364","consensus_level":"medium","plddt":95.0051,"start":289,"end":364},{"cath_id":"1.10.565.10","chopping":"397-622","consensus_level":"high","plddt":90.8854,"start":397,"end":622}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92570","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92570-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92570-F1-predicted_aligned_error_v6.png","plddt_mean":64.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR4A3","jax_strain_url":"https://www.jax.org/strain/search?query=NR4A3"},"sequence":{"accession":"Q92570","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92570.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92570/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92570"}},"corpus_meta":[{"pmid":"18640274","id":"PMC_18640274","title":"Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators.","date":"2008","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18640274","citation_count":536,"is_preprint":false},{"pmid":"12831879","id":"PMC_12831879","title":"Recognition of the DNA minor groove by pyrrole-imidazole polyamides.","date":"2003","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/12831879","citation_count":522,"is_preprint":false},{"pmid":"16443421","id":"PMC_16443421","title":"What does minor elevation of C-reactive protein signify?","date":"2006","source":"The American journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16443421","citation_count":282,"is_preprint":false},{"pmid":"17515897","id":"PMC_17515897","title":"Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia.","date":"2007","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17515897","citation_count":275,"is_preprint":false},{"pmid":"23074130","id":"PMC_23074130","title":"The significant other: splicing by the minor spliceosome.","date":"2012","source":"Wiley interdisciplinary reviews. 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NR4A3 overexpression in mouse salivary gland cells increases expression of known NR4A3 target genes and stimulates cell proliferation.\",\n      \"method\": \"Genomic sequencing, chromatin analysis, RNA-seq, transcription factor binding motif analysis, NR4A3 overexpression in mouse salivary gland cells, cell proliferation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genomic rearrangement characterized, functional overexpression with target gene and proliferation readouts, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30664630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The EWSR1/NR4A3 fusion protein in extraskeletal myxoid chondrosarcoma (EMC) activates transcription of PPARG through a DNA response element in the PPARG promoter. An endogenous NR4A3 isoform lacking the C-terminal domain is highly expressed in EWSR1/NR4A3-positive tumors and may negatively regulate the fusion protein's activity on the PPARG promoter.\",\n      \"method\": \"Expression microarray, western blot, immunohistochemistry, bioinformatic identification of NR4A3 response element, band-shift (EMSA) experiments, transient transfection/reporter assays, co-transfection experiments\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EMSA demonstrating direct DNA binding, reporter gene transactivation assays, mutagenesis-class functional analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18855877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NR4A3 is downstream of the homeodomain transcription factor Nkx6.1 in pancreatic β-cells and is both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Nr4a3 (with Nr4a1) increases expression of E2F1 and cyclin E1, and induces components of the anaphase-promoting complex (including UBE2C), resulting in degradation of the cell cycle inhibitor p21.\",\n      \"method\": \"Islet overexpression, siRNA knockdown, knockout mice, gene expression analysis, cell cycle analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function experiments, genetic KO mouse, pathway dissection with multiple downstream molecular readouts\",\n      \"pmids\": [\"24706823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Deletion of Nr4a1 and Nr4a3 in pancreatic β-cells impedes mitochondrial respiration and reduces glucose-stimulated insulin secretion, associated with decreased expression of mitochondrial dehydrogenase subunits Idh3g and Sdhb and reduced ATP production, without reducing mitochondrial content.\",\n      \"method\": \"β-cell-specific knockout, mitochondrial respiration assays (Seahorse), glucose-stimulated insulin secretion assays, gene expression analysis\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean cell-type-specific KO, multiple orthogonal functional readouts (respiration, ATP, GSIS), molecular mechanism identified\",\n      \"pmids\": [\"27221116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A3 is a direct transcriptional target of p53: p53 directly binds the NR4A3 promoter and induces its transcription. NR4A3 overexpression promotes apoptosis by augmenting expression of pro-apoptotic genes PUMA and Bax. NR4A3 also physically interacts with anti-apoptotic Bcl-2 protein, sequestering it from inhibiting apoptosis.\",\n      \"method\": \"ChIP assay (p53 binding to NR4A3 promoter), reporter assays, NR4A3 overexpression and knockdown in cancer cells, apoptosis assays, co-immunoprecipitation (NR4A3-Bcl-2 interaction)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP demonstrating direct promoter binding, co-IP for protein interaction, gain/loss-of-function with defined apoptotic readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30455429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NR4A3 is essential for migration of CD103+ dendritic cells to lymph nodes through regulation of CCR7 surface expression. Nr4a3-deficient CD103+ DCs show markedly reduced CCR7, mediated by reduced FOXO1 protein levels through an AKT-dependent mechanism. NR4A3 also maintains homeostatic mitochondrial function in CD103+ DCs.\",\n      \"method\": \"Nr4a3 knockout mice, mixed-chimera studies (cell-intrinsic defect), flow cytometry, in vivo DC migration assays, FOXO1/AKT signaling analysis, in vivo TLR7 agonist and bacterial infection models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, cell-intrinsic defect confirmed by chimera studies, molecular pathway (NR4A3→FOXO1→CCR7 via AKT) established with multiple readouts\",\n      \"pmids\": [\"27820700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NR4A3 is required for the proper differentiation of monocyte-derived dendritic cells (MoDCs) but not other DC types. Nr4a3-/- mice show severely impaired generation of DC-SIGN+ MoDCs in response to LPS, resulting in inability to mount optimal CD8+ T cell responses to gram-negative bacteria. Transcriptomic analysis shows NR4A3 skews monocyte differentiation toward MoDCs at the expense of macrophages.\",\n      \"method\": \"Nr4a3 knockout mice, flow cytometry, LPS stimulation, RNA-seq/transcriptomic analysis, in vivo bacterial infection models, CD8+ T cell response assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO, defined cell differentiation phenotype, transcriptomic mechanism, in vivo functional consequence\",\n      \"pmids\": [\"31285338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR4A3 programs early CD8+ T cell differentiation fate: NR4A3-deficient murine CD8+ T cells preferentially differentiate into memory precursor and central memory cells while also producing more cytokines. This is mediated through early influence on the memory transcriptional program and chromatin accessibility at bZIP transcription factor motifs, impacting Fos/Jun target gene transcription.\",\n      \"method\": \"NR4A3-deficient mouse model, adoptive transfer experiments, single-cell transcriptomics, ATAC-seq (chromatin accessibility), cytokine production assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined differentiation phenotype, mechanistic epigenomic data (ATAC-seq), multiple orthogonal methods in single study\",\n      \"pmids\": [\"32913051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR4A3 and BLIMP1 (PRDM1) reciprocally regulate CAR T cell stemness and exhaustion. Dual knockout of PRDM1 and NR4A3 skews CAR T cell phenotypes from TIM-3+CD8+ toward TCF1+CD8+, countering exhaustion and improving antitumor responses in solid tumors — an effect not achieved by single knockouts alone. In PRDM1-deficient cells, NR4A3 is part of an NFAT-driven compensatory exhaustion program.\",\n      \"method\": \"PRDM1 and NR4A3 single and double knockout in CAR T cells, scRNA-seq, epigenetic profiling, in vivo mouse tumor models, clinical trial CAR T cell samples\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO (single and double), in vivo tumor models, mechanistic epistasis with clinical validation, multiple orthogonal methods\",\n      \"pmids\": [\"36350986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nr4a1 and Nr4a3 reporter mice show differential sensitivity to TCR signal strength and duration. Nr4a2 and Nr4a3 expression is regulated downstream of calcineurin and requires NFAT1 (which directly binds Nr4a2 and Nr4a3 loci), while Nr4a1 shows redundancy for NFAT1. Nr4a3-Tocky requires cognate peptide:MHC interactions for expression, whereas Nr4a1-GFP responds to tonic signals during T cell development.\",\n      \"method\": \"Nr4a1-GFP and Nr4a3-Timer (Tocky) reporter mice, calcineurin inhibitor treatment, NFAT1 binding assays, TCR signaling pathway inhibitors (Src family kinase inhibitors), flow cytometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual reporter mouse models, NFAT1 binding demonstrated, pharmacological pathway dissection with multiple orthogonal methods\",\n      \"pmids\": [\"33147449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR4A2 and NR4A3 are upregulated downstream of PKA activation in neutrophils (induced by adenosine, prostaglandin E2, and direct PKA agonists) and positively regulate neutrophil survival. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces absolute neutrophil number without affecting migration.\",\n      \"method\": \"Human neutrophil gene arrays, PKA agonists, siRNA knockdown, antisense morpholino knockdown in zebrafish, apoptosis/survival assays, flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PKA-dependent induction demonstrated, zebrafish in vivo knockdown, but mechanistic dissection of NR4A3 vs NR4A2 contributions is not fully resolved\",\n      \"pmids\": [\"28637666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR4A3 knockdown in bone marrow-derived dendritic cells suppresses TLR-mediated upregulation of CD80, CD86, IL-10, IL-6, and IL-12, and reduces T cell proliferation and IL-2 production. Mechanistically, NR4A3 regulates DC activation via controlling expression of IKKβ, IRF4, and IRF8 — where IKKβ mediates IL-10/IL-6 induction and IRF4/IRF8 mediate IL-12 induction.\",\n      \"method\": \"siRNA knockdown in bone marrow-derived DCs, LPS/CpG/poly(I:C) stimulation, qRT-PCR, western blot, T cell co-culture assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with multiple downstream readouts, epistasis via individual IKKβ/IRF4/IRF8 siRNA knockdowns, single lab\",\n      \"pmids\": [\"28893954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR4A3 (NOR-1) directly regulates vitronectin (VTN) in human vascular smooth muscle cells (VSMCs): NOR-1 binds the NBRE(-202/-195) site in the VTN promoter (identified by deletion/site-directed mutagenesis, EMSA, and ChIP). NOR-1-induced VTN secretion promotes VSMC migration.\",\n      \"method\": \"Lentiviral NOR-1 overexpression and siRNA silencing, deletion and site-directed mutagenesis, EMSA, ChIP, VTN blocking antibody experiments, cell migration assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct DNA binding demonstrated by EMSA and ChIP, promoter mutagenesis mapping the functional element, functional migration assay with antibody rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28666984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nor1/Nr4a3 negatively regulates β-cell mass: Nor1 knockout mice display increased β-cell mass and improved glucose tolerance. Nor1 expression is increased by pro-inflammatory cytokines and elevated glucose in β-cells. Nor1 overexpression causes apoptosis in INS and human islet cells, while siRNA knockdown prevents cytokine-induced β-cell death. Nor1 expression is elevated in islets of type 2 diabetic individuals.\",\n      \"method\": \"Nr4a3 knockout mice, histological analysis, gain/loss-of-function (overexpression and siRNA) in INS cells and human islets, apoptosis assays, glucose tolerance tests\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse, gain and loss-of-function in multiple cell types including human islets, multiple orthogonal functional readouts\",\n      \"pmids\": [\"30696767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nor1/Nr4a3 is predominantly cytoplasmic in pancreatic β-cells and undergoes mitochondrial translocation upon activation by pro-inflammatory cytokines. Mitochondrial localization of Nor1 reduces glucose oxidation, lowers ATP production rates, inhibits glucose-stimulated insulin secretion, and provokes mitochondrial fragmentation via mitophagy.\",\n      \"method\": \"Subcellular fractionation, fluorescence microscopy, Nor1 overexpression in INS832/13 cells and human β-cells, mitochondrial function assays, western blot for mitophagy markers\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by imaging and fractionation with functional consequence, overexpression model, single lab\",\n      \"pmids\": [\"31936632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Muscle contraction (exercise) induces rapid demethylation at the Nr4a3 promoter preceded by hydroxymethylation: electrical pulse stimulation of C2C12 myotubes causes demethylation at 60 min and re-methylation at 120 min, with hydroxymethylation elevated immediately after stimulation. Nr4a3 was identified as the most exercise-responsive gene in acute exercise in humans.\",\n      \"method\": \"Acute human exercise study, electrical pulse stimulation (EPS) of C2C12 myotubes, targeted bisulfite sequencing, gene expression analysis\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bisulfite sequencing directly measuring epigenetic modification at Nr4a3 promoter in response to defined stimulus, both human and cell culture models, single lab\",\n      \"pmids\": [\"28066330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NR4A3 overexpression in pancreatic MIN6 β-cells reduces insulin gene (Ins1, Ins2) transcription and insulin protein secretion. This effect requires both the AF1 activation domain and the DNA-binding domain of NR4A3. NR4A3 reduces insulin gene expression by downregulating transcriptional regulators Pdx1 and NeuroD1.\",\n      \"method\": \"Adenoviral overexpression of NR4A3 and deletion mutants in MIN6 cells, qPCR, insulin secretion assays, ER stress induction\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mutagenesis establishing AF1 and DBD requirement, functional insulin secretion readout, single lab\",\n      \"pmids\": [\"24638142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR4A3 knockdown in human BeWo trophoblast cells increases FSK-induced cell fusion and expression of CGB and syncytin2, whereas STAT5B knockdown decreases these. cAMP-PKA signaling upregulates both STAT5B and NR4A3, but NR4A3 acts as a negative regulator of syncytialization by decreasing syncytin2 expression, opposing STAT5B's positive effect.\",\n      \"method\": \"siRNA knockdown of STAT5B and NR4A3 in BeWo cells, microarray analysis, FSK stimulation, cell fusion assays, syncytialization marker expression\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with defined cellular phenotype, pathway placement via opposing regulatory roles, single lab\",\n      \"pmids\": [\"29377304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NR4A3 acts pro-inflammatory in osteoarthritis chondrocytes: NR4A3 overexpression enhances IL-1β-induced expression of matrix-degrading enzymes (MMP-3, MMP-9, iNOS, COX-2) and NF-κB activation, while NR4A3 knockdown reduces these effects. NR4A3 overexpression also enhances starvation-induced chondrocyte apoptosis.\",\n      \"method\": \"Lentiviral NR4A3 overexpression, siRNA knockdown in chondrocytes, IL-1β stimulation, western blot, qRT-PCR, NF-κB pathway analysis, apoptosis assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal gain/loss-of-function with molecular pathway (NF-κB) identified, single lab, single cell type\",\n      \"pmids\": [\"31701670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nuclear receptor Nr4a3 regulates mast cell cytokine/chemokine secretion following high-affinity IgE receptor activation and negatively affects mast cell tryptase transcript and protein levels, as well as the mast cell's responsiveness to allergen.\",\n      \"method\": \"Nr4a3 knockout-based functional studies in mast cells, IgE receptor activation assays, cytokine/chemokine measurement, tryptase expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined mast cell functional phenotypes, single lab\",\n      \"pmids\": [\"24586680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Intragenic DNA hypermethylation at CpG sites in exon 3 of NR4A3 (but not the promoter region) silences NR4A3 expression in AML. A DNA methyltransferase inhibitor restores NR4A3 expression following reduction in methylation at intragenic CpG sites. Exon 3 contains histone marks (H3K4me1, H2A.Z) in non-malignant cells that are absent in leukemia cells with CpG hypermethylation.\",\n      \"method\": \"Bisulfite sequencing of AML cell lines and primary AML cells, DNA methyltransferase inhibitor treatment, ChIP-seq/in silico histone mark analysis\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bisulfite sequencing directly measuring intragenic methylation, pharmacological restoration of expression, correlation with histone marks, single lab\",\n      \"pmids\": [\"27697661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR4A3 overexpression or pharmacological activation in aggressive lymphoma cell lines induces apoptosis, abrogates tumor growth in NSG xenograft mouse models, and drives apoptosis by inducing pro-apoptotic genes BAK, PUMA, BIK, BIM, BID, and TRAIL (similar to NR4A1).\",\n      \"method\": \"Stable NR4A3 transduction of lymphoma cell lines, NSG xenograft mouse model, pharmacological NR4A3 activation, transcript analysis, apoptosis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft model, defined pro-apoptotic gene targets identified, single lab\",\n      \"pmids\": [\"28249906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Oncogenic NR4A3 interacts physically with the MYB DNA-binding domain via its ligand-binding domain in acinic cell carcinoma. Co-expression of NR4A3 and MYB cooperatively regulates a distinct gene set and is more potent at inducing transformation (anchorage-independent growth, invasiveness) than either alone.\",\n      \"method\": \"RNA-seq of AciCC samples, protein-protein interaction assay (LBD-DBD binding), transformation assays, anchorage-independent growth, invasion assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct physical interaction demonstrated, cooperative functional effects, single lab\",\n      \"pmids\": [\"32867110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-106b-5p negatively regulates NR4A3 expression (validated by dual-luciferase reporter assay), and NR4A3 regulates Treg differentiation via Foxp3. Reduced NR4A3 (by miR-106b-5p) leads to decreased Foxp3 and TGF-β expression, contributing to Treg/Th17 imbalance in immune thrombocytopenic purpura.\",\n      \"method\": \"qRT-PCR, western blot, dual-luciferase reporter assay for miR-106b-5p/NR4A3 interaction, siRNA knockdown of NR4A3, in vivo miR-106b-5p silencing in ITP mouse model\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter validation of miRNA-target relationship, pathway placement via sh-NR4A3 experiments, in vivo model, single lab\",\n      \"pmids\": [\"32323598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MSC-derived extracellular vesicles deliver miR-146a, which directly targets Nr4a3 (validated by dual-luciferase assay): miR-146a mimic decreases Nr4a3 expression while inhibition promotes it. Upregulation of miR-146a by MSC-EVs decreases Nr4a3 expression and reduces LPS-induced pro-inflammatory cytokines in microglia (BV2 cells), contributing to retinal protection.\",\n      \"method\": \"Dual-luciferase assay, miR-146a mimic/inhibitor transfection, qPCR, western blot, co-culture of photoreceptors with microglia, in vivo rd10 mouse model\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter validation of miR-146a/NR4A3 targeting, in vivo functional context, single lab\",\n      \"pmids\": [\"35922863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR4A3 promotes vascular calcification via histone lactylation: NR4A3 directly binds promoter regions of glycolysis genes ALDOA and PFKL to drive their transcriptional initiation, enhancing glycolytic rate and lactate production. Increased lactate promotes histone lactylation, which in turn activates PHOSPHO1 transcription to drive calcium deposition. NR4A3 deficiency inhibits this cascade and reduces vascular calcification.\",\n      \"method\": \"NR4A3 knockout mice, vascular calcification models, RNA-seq, CUT&TAG (chromatin binding analysis), metabolic assays, NR4A3 overexpression, Phospho1 pharmacological inhibition and overexpression, in vivo and in vitro calcium deposition assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CUT&TAG establishing direct promoter binding, genetic KO and overexpression, pharmacological rescue experiments, in vivo models, multiple orthogonal methods\",\n      \"pmids\": [\"38629274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FTO (fat mass and obesity-associated demethylase) regulates NR4A3 mRNA m6A methylation: FTO knockdown increases methylation of NR4A3 mRNA, while FTO (but not catalytically mutated FTO) overexpression reduces NR4A3 mRNA methylation. DHA suppresses AngII-induced VSMC proliferation/inflammation by inhibiting the FTO/NR4A3 axis.\",\n      \"method\": \"m6A-RNA immunoprecipitation (MeRIP) assay, FTO knockdown/overexpression, AngII stimulation of VSMCs, cell proliferation assays (CCK-8, BrdU), western blot, qRT-PCR\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP directly measuring m6A modification of NR4A3 mRNA, catalytic mutant FTO control establishing writer specificity, single lab\",\n      \"pmids\": [\"35059772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR4A3 promotes pulmonary arterial smooth muscle cell (PASMC) proliferation via the cyclin D1 pathway. miR-638 directly targets NR4A3 (validated by luciferase reporter assay), and resveratrol prevents MCT-induced pulmonary vascular remodeling by upregulating miR-638 and thereby reducing NR4A3 expression.\",\n      \"method\": \"Luciferase reporter assay for miR-638/NR4A3, loss-/gain-of-function (miR-638 mimic/antagomir), NR4A3 overexpression, MCT rat model of pulmonary hypertension, PASMC proliferation assays\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase validation of miRNA targeting, in vivo rat model, NR4A3/cyclin D1 pathway established, single lab\",\n      \"pmids\": [\"32057731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR4A3 protects against diabetes-induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress, acting through preserving transcriptional expression of Sdha. NR4A3 deficiency exacerbates atrial hypertrophy, fibrosis, and susceptibility to atrial fibrillation.\",\n      \"method\": \"Nr4a3 knockout mice (HFD/STZ model), AAV9-Nr4a3 overexpression in db/db mice, RNA-seq, metabolomics, electrophysiological studies, histological analysis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and AAV-mediated overexpression with in vivo functional readouts, RNA-seq identifying Sdha as downstream target, single lab\",\n      \"pmids\": [\"39098108\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR4A3 (NOR-1) is a ligand-independent orphan nuclear receptor that functions as a transcriptional activator and repressor across diverse cell types: it binds specific DNA response elements (NBREs) to directly regulate target genes (including PPARG, VTN, ALDOA, PFKL, Cebpa, cyclin D1, and Sdha); its expression is rapidly induced by TCR signaling (via NFAT1/calcineurin), PKA activation, p53, Nkx6.1, muscle contraction, and inflammatory cytokines; it acts as a critical tumor suppressor in hematopoietic cells (suppressing AML by maintaining C/EBPα and restraining NF-κB inflammatory signaling), regulates CD8+ T cell and DC differentiation, controls β-cell mitochondrial function and insulin secretion (including through cytoplasmic-to-mitochondrial translocation), promotes vascular calcification through a glycolysis→histone lactylation→PHOSPHO1 cascade, and is activated oncogenically in acinic cell carcinoma through enhancer hijacking at the t(4;9)(q13;q31) translocation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR4A3 (NOR-1) is a ligand-independent orphan nuclear receptor that acts as a sequence-specific transcriptional regulator induced rapidly by cell-activation signals, coordinating cell-fate, metabolic, and inflammatory programs across hematopoietic, immune, vascular, and endocrine tissues [#0, #11, #27]. As a transcription factor it binds defined response elements in target promoters and enhancers to activate or repress genes: it directly drives a hematopoietic-specific Cebpa enhancer and antagonizes NF-\\u03baB-regulated inflammatory loci to restrain HSC proliferation, and its loss together with NR4A1 produces lethal acute myeloid leukemia, establishing it as a myeloid tumor suppressor [#0, #1]. In other settings it binds NBRE elements to control vitronectin in vascular smooth muscle and glycolytic genes ALDOA and PFKL, the latter feeding a glycolysis\\u2192histone-lactylation\\u2192PHOSPHO1 cascade that drives vascular calcification [#14, #27]. Its expression is gated by upstream pathways including TCR/calcineurin\\u2013NFAT1 signaling, p53, the homeodomain factor Nkx6.1, PKA, and muscle contraction, and is further tuned post-transcriptionally by FTO-dependent m6A methylation and by multiple microRNAs [#4, #6, #11, #17, #28]. In immune cells NR4A3 governs differentiation and effector states: it controls CD103+ and monocyte-derived dendritic cell development and migration via FOXO1/CCR7 and IKK\\u03b2/IRF4/IRF8 axes, programs early CD8+ T cell memory-versus-effector fate through chromatin accessibility at bZIP motifs, and contributes to CAR-T exhaustion in an NFAT-driven program [#7, #8, #9, #10, #13]. In pancreatic \\u03b2-cells it has dual roles \\u2014 promoting Nkx6.1-driven proliferation and supporting mitochondrial respiration and insulin secretion, while also acting cytotoxically when cytokine-activated and translocated to mitochondria to impair glucose-stimulated insulin secretion [#4, #5, #15, #16]. NR4A3 also engages apoptotic machinery, being a p53 target that induces PUMA/Bax and sequesters Bcl-2, and is oncogenically activated by enhancer hijacking at t(4;9) and by the EWSR1/NR4A3 fusion, where it cooperates physically with MYB to drive transformation [#2, #3, #6, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established NR4A3 as a genetically required tumor suppressor in the myeloid lineage, answering whether the orphan receptor has a non-redundant role in hematopoietic homeostasis.\",\n      \"evidence\": \"Double Nr4a1/Nr4a3 knockout mice developing lethal AML with HSC expansion and defective apoptotic signaling\",\n      \"pmids\": [\"17515897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with NR4A1 leaves NR4A3-specific transcriptional targets undefined in this study\", \"Direct chromatin targets not yet identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the molecular basis of NR4A tumor suppression by showing direct chromatin binding to activate Cebpa and antagonize NF-\\u03baB inflammatory genes.\",\n      \"evidence\": \"Conditional double knockout with ChIP and enhancer-binding assays in HSCs\",\n      \"pmids\": [\"29343483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate NR4A1 from NR4A3 contributions at each locus\", \"Whether C/EBP\\u03b1 activation is direct or cooperative left open\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed NR4A3 within the p53 apoptotic axis, identifying both an upstream regulator and a protein-level effector mechanism.\",\n      \"evidence\": \"ChIP of p53 at the NR4A3 promoter plus co-IP of NR4A3 with Bcl-2 and apoptosis assays in cancer cells\",\n      \"pmids\": [\"30455429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bcl-2 sequestration shown by single co-IP without structural mapping\", \"Cell-type generality of the p53\\u2192NR4A3 axis untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that fusion-driven NR4A3 retains transactivation function by directly binding the PPARG promoter in chondrosarcoma.\",\n      \"evidence\": \"EMSA, reporter assays and identification of an NR4A3 response element for the EWSR1/NR4A3 fusion\",\n      \"pmids\": [\"18855877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of the C-terminally truncated isoform inferred, not functionally proven in vivo\", \"Genome-wide fusion targets not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed NR4A3 can be oncogenic through enhancer hijacking, contrasting its tumor-suppressor role in myeloid cells with a proliferative role in salivary gland tissue.\",\n      \"evidence\": \"Genomic characterization of t(4;9), RNA-seq and NR4A3 overexpression with proliferation readouts in mouse salivary gland cells\",\n      \"pmids\": [\"30664630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why NR4A3 is oncogenic here versus tumor-suppressive in HSCs not mechanistically reconciled\", \"Direct transformation targets in salivary cells not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the protein partner that confers context-specific oncogenicity, showing NR4A3 physically cooperates with MYB to drive transformation.\",\n      \"evidence\": \"LBD-DBD interaction assay and cooperative transformation/invasion assays in acinic cell carcinoma models\",\n      \"pmids\": [\"32867110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction shown in single lab without reciprocal in vivo validation\", \"Cooperative gene set not linked to specific phenotypic drivers\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined NR4A3 as the effector of Nkx6.1-driven \\u03b2-cell proliferation through a cell-cycle activation network.\",\n      \"evidence\": \"Islet gain/loss-of-function and knockout mice with E2F1, cyclin E1, APC/UBE2C and p21 readouts\",\n      \"pmids\": [\"24706823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin targets among cell-cycle genes not mapped\", \"Reconciliation with anti-proliferative roles in HSCs unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed NR4A3 represses insulin gene expression in a domain-dependent manner, indicating direct transcriptional control of \\u03b2-cell identity genes.\",\n      \"evidence\": \"Adenoviral overexpression with AF1/DBD deletion mutants in MIN6 cells and Pdx1/NeuroD1 readouts\",\n      \"pmids\": [\"24638142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-only model; physiological relevance uncertain\", \"Direct vs indirect repression of Pdx1/NeuroD1 not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a positive role for NR4A3 in \\u03b2-cell mitochondrial respiration and insulin secretion, complicating its overall metabolic role.\",\n      \"evidence\": \"\\u03b2-cell-specific double knockout with Seahorse respiration, ATP, GSIS and Idh3g/Sdhb expression readouts\",\n      \"pmids\": [\"27221116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NR4A1 vs NR4A3 contributions not separated\", \"Mechanism of dehydrogenase regulation (direct/indirect) unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed an opposing cytotoxic role for NR4A3 in \\u03b2-cells under inflammatory/glucotoxic conditions, linking it to type 2 diabetes pathology.\",\n      \"evidence\": \"Nr4a3 knockout mice, gain/loss-of-function in INS cells and human islets, apoptosis assays, diabetic islet expression\",\n      \"pmids\": [\"30696767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of pro-proliferative/pro-respiration versus pro-apoptotic roles unresolved\", \"Stimulus-dependent target switch not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided a subcellular mechanism for NR4A3 cytotoxicity by showing cytokine-induced mitochondrial translocation impairs respiration.\",\n      \"evidence\": \"Subcellular fractionation and imaging with mitochondrial function and mitophagy readouts in \\u03b2-cells\",\n      \"pmids\": [\"31936632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Translocation mechanism and mitochondrial binding partners unknown\", \"Overexpression model from a single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established NR4A3 as essential for CD103+ DC migration via an AKT-FOXO1-CCR7 axis and mitochondrial maintenance.\",\n      \"evidence\": \"Knockout and mixed-chimera studies with in vivo migration and FOXO1/AKT signaling analysis\",\n      \"pmids\": [\"27820700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FOXO1 regulation is transcriptional or post-translational not fully resolved\", \"Direct NR4A3 targets in DCs not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified NR4A3 as a transcriptional regulator of DC activation through control of IKK\\u03b2, IRF4 and IRF8.\",\n      \"evidence\": \"siRNA knockdown in bone marrow-derived DCs with TLR stimulation, epistasis knockdowns and T cell co-culture\",\n      \"pmids\": [\"28893954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown-only without genetic confirmation\", \"Direct binding to IKK\\u03b2/IRF loci not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed NR4A3 directs monocyte differentiation toward MoDCs, controlling anti-bacterial CD8+ T cell responses.\",\n      \"evidence\": \"Knockout mice, LPS stimulation, RNA-seq and in vivo infection/CD8 response assays\",\n      \"pmids\": [\"31285338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets driving the MoDC-versus-macrophage switch not defined\", \"Mechanism of lineage skewing unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated NR4A3 programs early CD8+ T cell memory-versus-effector fate via chromatin accessibility at bZIP motifs.\",\n      \"evidence\": \"NR4A3-deficient mice, adoptive transfer, scRNA-seq, ATAC-seq and cytokine assays\",\n      \"pmids\": [\"32913051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding at bZIP motif regions versus indirect chromatin remodeling not separated\", \"Relationship to Fos/Jun cofactors mechanistically open\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed NR4A3 in an NFAT-driven exhaustion program reciprocal to BLIMP1, with translational relevance for CAR-T engineering.\",\n      \"evidence\": \"Single and double PRDM1/NR4A3 knockout CAR-T cells, scRNA-seq, in vivo tumor models and clinical samples\",\n      \"pmids\": [\"36350986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NR4A3 targets in the exhaustion program not enumerated\", \"Epistasis mechanism with PRDM1 incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the upstream signaling logic of NR4A3 induction, showing strict dependence on calcineurin and NFAT1 with cognate peptide:MHC requirement.\",\n      \"evidence\": \"Nr4a3-Timer/Tocky reporter mice, calcineurin inhibition, NFAT1 binding assays and TCR pathway inhibitors\",\n      \"pmids\": [\"33147449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs cooperative NFAT1 binding at Nr4a3 not structurally defined\", \"Downstream consequences of differential signal strength not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended NR4A3 induction to PKA signaling in neutrophils and linked it to survival.\",\n      \"evidence\": \"Human neutrophil gene arrays, PKA agonists, siRNA and zebrafish morpholino knockdown\",\n      \"pmids\": [\"28637666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NR4A3 versus NR4A2 contributions unresolved\", \"Pro-survival transcriptional targets not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a role for Nr4a3 in regulating mast cell mediator secretion and allergen responsiveness.\",\n      \"evidence\": \"Knockout-based functional studies with IgE receptor activation and tryptase/cytokine readouts\",\n      \"pmids\": [\"24586680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct targets controlling tryptase and cytokine genes not identified\", \"Mechanism of negative regulation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed NR4A3 demethylation at its promoter is the most exercise-responsive transcriptional event in skeletal muscle.\",\n      \"evidence\": \"Acute human exercise study and electrical pulse stimulation of C2C12 myotubes with bisulfite sequencing\",\n      \"pmids\": [\"28066330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of muscle NR4A3 induction not addressed\", \"Demethylase responsible not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that NR4A3 activation is pro-apoptotic in lymphoma, supporting a tumor-suppressive function with therapeutic potential.\",\n      \"evidence\": \"Stable transduction and pharmacological activation in lymphoma lines with NSG xenografts and pro-apoptotic gene analysis\",\n      \"pmids\": [\"28249906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding at pro-apoptotic gene loci not shown\", \"Single-lab study without genetic loss-of-function\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a pro-inflammatory, NF-\\u03baB-enhancing role for NR4A3 in osteoarthritis chondrocytes, contrasting its NF-\\u03baB-antagonizing role in HSCs.\",\n      \"evidence\": \"Reciprocal overexpression/knockdown in chondrocytes with IL-1\\u03b2 stimulation and NF-\\u03baB analysis\",\n      \"pmids\": [\"31701670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of NF-\\u03baB regulation opposite to HSC findings unexplained\", \"Direct targets not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed NR4A3 in trophoblast syncytialization as a cAMP/PKA-induced negative regulator opposing STAT5B.\",\n      \"evidence\": \"siRNA knockdown of STAT5B and NR4A3 in BeWo cells with fusion and syncytin2 readouts\",\n      \"pmids\": [\"29377304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown-only without genetic confirmation\", \"Direct regulation of syncytin2/CGB not demonstrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified intragenic CpG hypermethylation, not promoter methylation, as the mechanism silencing NR4A3 in AML.\",\n      \"evidence\": \"Bisulfite sequencing of AML cells, DNMT inhibitor restoration and histone mark analysis\",\n      \"pmids\": [\"27697661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between exon 3 methylation and silencing not fully defined\", \"Causality of histone mark loss versus methylation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed FTO-dependent m6A demethylation post-transcriptionally controls NR4A3 in vascular smooth muscle proliferation.\",\n      \"evidence\": \"MeRIP with FTO knockdown/overexpression and catalytic-mutant control under AngII stimulation\",\n      \"pmids\": [\"35059772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader mediating NR4A3 mRNA fate not identified\", \"Effect on transcript stability versus translation not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined microRNA control of NR4A3 across immune and vascular contexts, linking its levels to Treg differentiation and PASMC proliferation.\",\n      \"evidence\": \"Dual-luciferase validation of miR-106b-5p, miR-638 and miR-146a targeting NR4A3 with in vivo disease models\",\n      \"pmids\": [\"32323598\", \"32057731\", \"35922863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NR4A3 transcriptional targets (Foxp3, cyclin D1) not shown to be direct\", \"Single-lab miRNA studies without orthogonal confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a direct chromatin-to-metabolite mechanism by which NR4A3 drives vascular calcification through glycolysis and histone lactylation.\",\n      \"evidence\": \"Knockout mice, CUT&TAG at ALDOA/PFKL promoters, metabolic assays and PHOSPHO1 pharmacological rescue\",\n      \"pmids\": [\"38629274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of NR4A3 activation in calcifying cells not defined\", \"Specificity of lactylation-driven PHOSPHO1 induction not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed NR4A3 protects diabetic atria by preserving mitochondrial Sdha-dependent metabolism, extending its metabolic guardian role to cardiac tissue.\",\n      \"evidence\": \"Knockout and AAV9 overexpression mouse models with RNA-seq, metabolomics and electrophysiology\",\n      \"pmids\": [\"39098108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Sdha is a direct NR4A3 target not established\", \"Tissue-specific reconciliation with \\u03b2-cell cytotoxic roles open\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how NR4A3 switches between tumor-suppressive/pro-apoptotic, oncogenic, NF-\\u03baB-antagonizing and NF-\\u03baB-promoting, and metabolically protective versus cytotoxic outputs across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model of cofactor- or context-dependent target selection\", \"Genome-wide direct target catalog across cell types lacking\", \"Ligand/activation-state control of nuclear-versus-mitochondrial function undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 14, 27]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 14, 27]},\n      {\"term_id\": \"GO:0140297\", \"supporting_discovery_ids\": [6, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 6, 14, 27]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NR4A1\",\n      \"MYB\",\n      \"BCL2\",\n      \"EWSR1\",\n      \"NFAT1\",\n      \"p53\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}