{"gene":"NKRF","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2004,"finding":"NKRF (NRF) localizes predominantly to nucleoli via a large central domain, with only small fractions in nucleoplasm and cytoplasm. An N-terminal nuclear localization sequence drives nuclear accumulation of all N-terminal fragments, while C-terminal fragments also localize to the nucleus without canonical NLS motifs. FRAP analysis showed nucleolar localization correlates inversely with protein mobility. NKRF binds double-stranded RNA (dsRNA), a property mapping to multiple fragments overlapping the nucleolar affinity domain, and treatment with actinomycin D releases NKRF from nucleoli, suggesting RNA binding mediates nucleolar retention.","method":"GFP tagging, confocal microscopy, FRAP, subcellular fractionation, deletion mapping, dsRNA binding assay, actinomycin D treatment","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, FRAP, deletion mapping, RNA binding assay) in a single focused study on NKRF","pmids":["15226370"],"is_preprint":false},{"year":2004,"finding":"NKRF (NRF) constitutively silences the IFN-β, IL-8, and iNOS genes by binding to cis-acting negative regulatory elements (NRE) in their promoters; mRNA ablation experiments demonstrated that NRF mediates constitutive but not post-stimulated (cytokine/pathogen-induced) silencing of these genes.","method":"mRNA ablation (antisense/siRNA knockdown), promoter binding assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with gene expression readout, single lab, referenced in the localization paper (PMID 15226370)","pmids":["15226370"],"is_preprint":false},{"year":2007,"finding":"NKRF (NRF) directly interacts with NF-κB p65 in cells, as demonstrated by tandem affinity purification. A synthetic peptide corresponding to NRF amino acids 223–238 disrupts endogenous NRF/p65 binding, and nucleofection of this peptide into IL-1-stimulated or Helicobacter pylori-infected epithelial cells significantly decreases endogenous IL-8 gene transcription, establishing that the NRF/NF-κB p65 interaction is required for IL-8 gene activation.","method":"Tandem affinity purification (TAP), synthetic peptide inhibitor, nucleofection into human cervical and gastric epithelial cells, IL-8 mRNA quantification","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — TAP identifies the interaction, peptide disruption in live cells confirms functional relevance, two cell/stimulus contexts tested","pmids":["18025206"],"is_preprint":false},{"year":2007,"finding":"The NKRF (NRF) mRNA 5'-UTR contains an internal ribosome entry segment (IRES) that drives cap-independent translation. A minimal 150-nt region proximal to the start codon is sufficient for IRES activity, within which a 14-nt RNA element (nt 640–653) is essential. The RNA-binding protein JKTBP1 binds the IRES module upstream of this element (nt 579–639); JKTBP1 overexpression enhances NRF IRES activity, and siRNA knockdown of JKTBP1 reduces both NRF IRES activity and endogenous NRF protein levels.","method":"Enzymatic RNA structure analysis, point mutation analysis, dicistronic reporter assay, ESI/MS/MS protein identification, EMSA, siRNA knockdown","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro RNA structure probing, mutagenesis, mass spectrometry identification of binding protein, EMSA, and functional siRNA knockdown; multiple orthogonal methods","pmids":["17592041"],"is_preprint":false},{"year":2013,"finding":"NKRF activation is induced by high-tidal-volume mechanical ventilation in mouse lungs. iPSC or iPSC-conditioned medium administration attenuates ventilator-induced lung injury, and this protection is mimicked by NKRF siRNA knockdown, indicating that NKRF pathway activation contributes to ventilation-induced neutrophil infiltration, MIP-2 production, and oxidative stress.","method":"Mouse ventilator-induced lung injury model, iPSC/conditioned medium administration, NKRF siRNA knockdown, lung injury indices (permeability, neutrophil counts, MDA, MIP-2)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with siRNA knockdown and pharmacological controls, single lab","pmids":["23840526"],"is_preprint":false},{"year":2019,"finding":"miR-301a directly targets NKRF in JEV-infected microglial cells. miR-301a overexpression reduces NKRF protein, enhancing NF-κB nuclear translocation and amplifying inflammatory cytokine production; NKRF overexpression in miR-301a-inhibited cells restores NF-κB nuclear accumulation to basal levels. In vivo neutralization of miR-301a in mouse brain restores NKRF expression and reduces inflammatory response, microglial activation, and neuronal apoptosis.","method":"miRNA overexpression/inhibition, NKRF overexpression, NF-κB nuclear translocation assay, in vivo miR-301a neutralization in mouse brain","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function in vitro and in vivo, NKRF rescue experiment confirms pathway placement, replicated across conditions","pmids":["31527198"],"is_preprint":false},{"year":2020,"finding":"HuR (RNA-binding protein) stabilizes NKRF mRNA by binding to its AU-rich elements. HuR overexpression increases NKRF levels; NKRF overexpression in HuR-deficient nucleus pulposus cells suppresses NF-κB-driven inflammation and extracellular matrix degradation; NKRF (but not HuR) overexpression ameliorates intervertebral disc degeneration in rats in vivo.","method":"HuR overexpression/knockdown, mRNA stability assay, NKRF overexpression, NF-κB pathway activity readouts (inflammation/ECM markers), rat IVDD model","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mRNA stability mechanism established, rescue experiment with NKRF OE, in vivo validation in rat model, single lab with multiple orthogonal approaches","pmids":["33330514"],"is_preprint":false},{"year":2021,"finding":"miR-192 directly targets NKRF in lung cancer cells. miR-192 overexpression suppresses NKRF, increases NF-κB nuclear protein and transcriptional activation, and upregulates anti-apoptotic targets (cIAP1, cIAP2, Bcl-xl, XIAP), conferring cisplatin resistance. Inhibition of NF-κB by curcumin reverses the pro-survival and cisplatin-resistance effects of miR-192 upregulation.","method":"miR-192 overexpression/inhibition, luciferase reporter (3'UTR), NF-κB nuclear translocation, western blot for downstream targets, cisplatin resistance assay, NF-κB pathway inhibition rescue","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms direct targeting, functional NF-κB pathway readout, single lab","pmids":["34953057"],"is_preprint":false},{"year":2020,"finding":"miR-301a-3p targets NKRF in gastric cancer cells (confirmed by luciferase reporter assay). Overexpression of miR-301a-3p decreases NKRF expression, activates NF-κB signaling, and promotes GC cell proliferation and invasion; these effects are mediated through NKRF downregulation.","method":"miR-301a-3p overexpression, luciferase reporter assay (NKRF 3'UTR), RT-qPCR/western blot, NF-κB pathway readout, proliferation/invasion assays","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR targeting confirmed by luciferase assay, NF-κB pathway functional readout; single lab","pmids":["32468020"],"is_preprint":false},{"year":2023,"finding":"NKRF in cardiac fibroblasts (CFs) inhibits HuR transcription by binding to the classical negative regulatory element (NRE) in the HuR promoter via an NF-κB-dependent mechanism. This reduces HuR-mediated stabilization of Mmp2 and Mmp9 mRNAs. CF-specific NKRF knockout (NKRF-CKO) mice show worsened cardiac function, increased infarct size, and elevated MMP2/MMP9 post-myocardial infarction compared with littermates, demonstrating that NKRF protects against pathological cardiac remodeling by suppressing CF migration and invasion.","method":"CF-specific NKRF knockout mouse model (NKRF-CKO), promoter binding assay, NRE mutagenesis, in vitro CF migration/invasion assays, in vivo post-MI cardiac function (echocardiography, infarct size)","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional knockout mouse with defined cellular and molecular mechanism (promoter binding, mRNA stability), multiple in vivo and in vitro endpoints; single lab but rigorous design","pmids":["37667861"],"is_preprint":false},{"year":2017,"finding":"LvNKRF (the NKRF ortholog from Litopenaeus vannamei shrimp) localizes to the nucleus and interacts with both Dorsal and Relish (the two shrimp NF-κB family members). Unlike mammalian NKRF which inhibits NF-κB, LvNKRF enhances NF-κB activity; LvNKRF expression is upregulated by WSSV infection and silencing of LvNKRF reduces shrimp mortality and viral replication from WSSV, suggesting LvNKRF facilitates viral exploitation of the host NF-κB pathway.","method":"Gene identification, nuclear localization assay, protein-protein interaction assay, RNAi silencing, WSSV infection model, viral copy number quantification","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction and localization confirmed, functional RNAi knockdown in vivo; invertebrate ortholog with opposite function to mammalian NKRF","pmids":["28564581"],"is_preprint":false}],"current_model":"NKRF (NF-κB repressing factor) is a nucleolar/nuclear protein that constitutively represses transcription of NF-κB-target genes (including IFN-β, IL-8, and iNOS) by binding negative regulatory elements (NRE) in their promoters; it physically interacts with NF-κB p65 (amino acids 223–238 of NKRF mediate this interaction), and disruption of this interaction de-represses IL-8 transcription; NKRF mRNA is translated via a cap-independent IRES mechanism facilitated by RNA-binding protein JKTBP1; NKRF is itself post-transcriptionally regulated by HuR (which stabilizes NKRF mRNA via AU-rich elements) and negatively regulated by miR-301a and miR-192 (which suppress NKRF to activate NF-κB); in cardiac fibroblasts, NKRF suppresses HuR transcription through NRE binding, thereby limiting MMP2/MMP9 mRNA stability and CF invasion, protecting against post-MI cardiac remodeling."},"narrative":{"mechanistic_narrative":"NKRF (NF-κB repressing factor) is a predominantly nucleolar protein that acts as a constitutive transcriptional repressor of NF-κB target genes, restraining basal inflammatory gene expression [PMID:15226370]. It silences the IFN-β, IL-8, and iNOS genes by binding cis-acting negative regulatory elements (NRE) in their promoters, mediating constitutive but not stimulus-induced repression [PMID:15226370]. Paradoxically, NKRF also physically engages NF-κB p65 — an interaction mapped to NKRF residues 223–238 — and disruption of this contact reduces, rather than increases, IL-8 transcription in IL-1-stimulated and Helicobacter pylori-infected epithelial cells, indicating that NKRF/p65 association is required for IL-8 gene activation in those contexts [PMID:18025206]. NKRF localizes to nucleoli through a large central domain whose retention depends on double-stranded RNA binding, as actinomycin D treatment releases it from the nucleolus [PMID:15226370]. Its own expression is controlled at multiple post-transcriptional levels: NKRF mRNA is translated via a 5'-UTR IRES whose activity depends on the RNA-binding protein JKTBP1 [PMID:17592041], the mRNA is stabilized by HuR through AU-rich elements [PMID:33330514], and it is repressed by miR-301a/miR-301a-3p and miR-192, which downregulate NKRF to license NF-κB nuclear translocation and inflammatory or pro-survival signaling [PMID:31527198, PMID:34953057, PMID:32468020]. Through this repressive output, NKRF restrains pathological NF-κB-driven processes in vivo, including ventilator-induced lung injury [PMID:23840526], intervertebral disc degeneration [PMID:33330514], JEV-associated neuroinflammation [PMID:31527198], and post-myocardial-infarction cardiac remodeling, where cardiac-fibroblast NKRF suppresses HuR transcription via NRE binding to limit MMP2/MMP9-driven invasion [PMID:37667861].","teleology":[{"year":2004,"claim":"Established where NKRF resides and how it is retained there, linking its localization to RNA binding rather than canonical protein-targeting alone.","evidence":"GFP tagging, confocal microscopy, FRAP, deletion mapping, and dsRNA-binding/actinomycin D assays","pmids":["15226370"],"confidence":"High","gaps":["The functional consequence of nucleolar sequestration for transcriptional repression is not defined","The dsRNA ligand(s) retained in the nucleolus are not identified"]},{"year":2004,"claim":"Defined NKRF's core function as a constitutive repressor acting through promoter NRE elements, distinguishing basal silencing from inducible expression.","evidence":"mRNA ablation knockdown with promoter-binding readouts on IFN-β, IL-8, and iNOS","pmids":["15226370"],"confidence":"Medium","gaps":["The corepressor machinery NKRF recruits at NREs is not identified","Why repression is constitutive but lost upon stimulation is unexplained"]},{"year":2007,"claim":"Mapped a direct NKRF/NF-κB p65 interaction interface and showed, unexpectedly, that this contact is required for IL-8 activation, complicating the simple repressor model.","evidence":"Tandem affinity purification plus a 223–238 peptide inhibitor nucleofected into IL-1-stimulated and H. pylori-infected epithelial cells","pmids":["18025206"],"confidence":"High","gaps":["The reconciliation between NRE-mediated repression and p65-dependent activation at the same locus is unresolved","Structural basis of the 223–238 contact with p65 is unknown"]},{"year":2007,"claim":"Showed NKRF protein output is set translationally through an IRES, identifying JKTBP1 as a trans-acting factor controlling NKRF abundance.","evidence":"RNA structure probing, mutagenesis, dicistronic reporters, mass spectrometry, EMSA, and JKTBP1 siRNA knockdown","pmids":["17592041"],"confidence":"High","gaps":["Conditions that favor cap-independent over cap-dependent NKRF translation are not defined","Whether IRES usage changes during inflammation is untested"]},{"year":2013,"claim":"Placed NKRF pathway activation as a contributor to mechanical-stress lung injury in vivo.","evidence":"Mouse ventilator-induced lung injury model with NKRF siRNA and iPSC/conditioned-medium rescue","pmids":["23840526"],"confidence":"Medium","gaps":["The molecular events downstream of NKRF activation in this model are not dissected","Whether NKRF acts here as repressor or via p65 association is unclear"]},{"year":2019,"claim":"Established NKRF as a direct miRNA target whose loss de-represses NF-κB, with reciprocal rescue confirming pathway placement in neuroinflammation.","evidence":"miR-301a gain/loss-of-function with NKRF rescue in microglia and in vivo miR-301a neutralization in mouse brain","pmids":["31527198"],"confidence":"High","gaps":["Direct 3'UTR binding site not mapped in this study","Upstream signals controlling miR-301a are not defined"]},{"year":2020,"claim":"Identified HuR-dependent mRNA stabilization as a positive post-transcriptional control of NKRF, with disease relevance in disc degeneration.","evidence":"HuR overexpression/knockdown, mRNA stability assays, NKRF rescue, and a rat IVDD model","pmids":["33330514"],"confidence":"High","gaps":["The interplay between HuR stabilization and miRNA repression of NKRF is not integrated","AU-rich element location within NKRF mRNA not precisely mapped here"]},{"year":2020,"claim":"Extended the miRNA→NKRF→NF-κB axis to cancer, showing direct 3'UTR targeting drives proliferation and invasion.","evidence":"miR-301a-3p overexpression with luciferase 3'UTR reporter and proliferation/invasion assays in gastric cancer cells","pmids":["32468020"],"confidence":"Medium","gaps":["Single-lab functional readout without in vivo confirmation","Endogenous miR-301a-3p levels in patient tissue not correlated with NKRF"]},{"year":2021,"claim":"Showed a second miRNA (miR-192) suppresses NKRF to drive NF-κB-dependent anti-apoptotic gene expression and chemoresistance.","evidence":"miR-192 manipulation, 3'UTR luciferase reporter, and cisplatin-resistance assays with NF-κB inhibitor rescue in lung cancer cells","pmids":["34953057"],"confidence":"Medium","gaps":["No in vivo validation of the miR-192/NKRF axis","Whether multiple miRNAs co-regulate NKRF in the same tumor is untested"]},{"year":2023,"claim":"Defined a concrete physiological repressor circuit: NKRF binds the HuR promoter NRE to limit MMP2/MMP9 and protect against cardiac remodeling, using a conditional knockout.","evidence":"Cardiac-fibroblast-specific NKRF knockout mice, promoter NRE mutagenesis, migration/invasion assays, and post-MI echocardiography","pmids":["37667861"],"confidence":"High","gaps":["The NF-κB-dependent component of NKRF binding at the HuR promoter is not mechanistically separated from direct NRE binding","Generality of the NKRF→HuR repression to other cell types is unknown"]},{"year":2017,"claim":"Showed the invertebrate NKRF ortholog interacts with NF-κB family members but enhances rather than inhibits NF-κB, revealing context- or species-dependent directionality.","evidence":"LvNKRF identification, interaction assays with Dorsal and Relish, and RNAi during WSSV infection in shrimp","pmids":["28564581"],"confidence":"Medium","gaps":["Whether the opposite functional sign reflects a species difference or assay context is unresolved","Direct relevance to mammalian NKRF mechanism is limited"]},{"year":null,"claim":"It remains unresolved how NKRF switches between repressing NF-κB targets via NRE binding and being required for p65-dependent activation, and what corepressor/coactivator machinery and nucleolar RNA functions underlie these opposing outputs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the NKRF–NRE or NKRF–p65 complexes","The corepressor complex recruited at NREs is unidentified","Functional role of nucleolar dsRNA-dependent retention in transcriptional control is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,9]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5]}],"complexes":[],"partners":["RELA","JKTBP1","ELAVL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15226","full_name":"NF-kappa-B-repressing factor","aliases":["Protein ITBA4"],"length_aa":690,"mass_kda":77.7,"function":"Enhances the ATPase activity of DHX15 by acting like a brace that tethers mobile sections of DHX15 together, stabilizing a functional conformation with high RNA affinity of DHX15 (PubMed:12381793). Involved in the constitutive silencing of the interferon beta promoter, independently of the virus-induced signals, and in the inhibition of the basal and cytokine-induced iNOS promoter activity (PubMed:12381793). Also involved in the regulation of IL-8 transcription (PubMed:12381793). May also act as a DNA-binding transcription regulator: interacts with a specific negative regulatory element (NRE) 5'-AATTCCTCTGA-3' to mediate transcriptional repression of certain NK-kappa-B responsive genes (PubMed:10562553)","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/O15226/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NKRF"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTCF","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX5","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"METAP2","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NKRF","total_profiled":1310},"omim":[{"mim_id":"300440","title":"NFKB-REPRESSING FACTOR; NKRF","url":"https://www.omim.org/entry/300440"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NKRF"},"hgnc":{"alias_symbol":["XTBD3","ITBA4","NRF"],"prev_symbol":[]},"alphafold":{"accession":"O15226","domains":[{"cath_id":"3.30.160.20","chopping":"163-329","consensus_level":"high","plddt":81.0344,"start":163,"end":329},{"cath_id":"3.30.160.20","chopping":"336-411","consensus_level":"high","plddt":88.7954,"start":336,"end":411},{"cath_id":"3.30.160.20","chopping":"442-515","consensus_level":"high","plddt":91.2488,"start":442,"end":515},{"cath_id":"3.30.1370.50","chopping":"517-542_600-690","consensus_level":"medium","plddt":83.4935,"start":517,"end":690}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15226","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15226-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15226-F1-predicted_aligned_error_v6.png","plddt_mean":69.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NKRF","jax_strain_url":"https://www.jax.org/strain/search?query=NKRF"},"sequence":{"accession":"O15226","fasta_url":"https://rest.uniprot.org/uniprotkb/O15226.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15226/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15226"}},"corpus_meta":[{"pmid":"22560223","id":"PMC_22560223","title":"TOR 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Emerging role of PPAR-γ/Nrf-2/NF-κB signaling pathway.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36812672","citation_count":17,"is_preprint":false},{"pmid":"21622902","id":"PMC_21622902","title":"Nrf-2 regulates cyclosporine-stimulated HO-1 expression in gingiva.","date":"2011","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/21622902","citation_count":17,"is_preprint":false},{"pmid":"30560518","id":"PMC_30560518","title":"δ-Opioid Receptor-Nrf-2-Mediated Inhibition of Inflammatory Cytokines in Neonatal Hypoxic-Ischemic Encephalopathy.","date":"2018","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/30560518","citation_count":17,"is_preprint":false},{"pmid":"37667861","id":"PMC_37667861","title":"NKRF in Cardiac Fibroblasts Protects against Cardiac Remodeling Post-Myocardial Infarction via Human Antigen R.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37667861","citation_count":16,"is_preprint":false},{"pmid":"35569770","id":"PMC_35569770","title":"Effects of NRF-1 and PGC-1α cooperation on HIF-1α and rat cardiomyocyte apoptosis under hypoxia.","date":"2022","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/35569770","citation_count":16,"is_preprint":false},{"pmid":"29346597","id":"PMC_29346597","title":"Exenatide Increases IL-1RA Concentration and Induces Nrf-2‒Keap-1‒Regulated Antioxidant Enzymes: Relevance to β-Cell Function.","date":"2018","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29346597","citation_count":16,"is_preprint":false},{"pmid":"32468020","id":"PMC_32468020","title":"Upregulation of miRNA‑301a‑3p promotes tumor progression in gastric cancer by suppressing NKRF and activating NF‑κB signaling.","date":"2020","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32468020","citation_count":16,"is_preprint":false},{"pmid":"33838628","id":"PMC_33838628","title":"Upregulation of NOX-2 and Nrf-2 Promotes 5-Fluorouracil Resistance of Human Colon Carcinoma (HCT-116) Cells.","date":"2021","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/33838628","citation_count":16,"is_preprint":false},{"pmid":"35771985","id":"PMC_35771985","title":"Protection Against Drug-Induced Liver Injuries Through Nutraceuticals via Amelioration of Nrf-2 Signaling.","date":"2022","source":"Journal of the American Nutrition Association","url":"https://pubmed.ncbi.nlm.nih.gov/35771985","citation_count":15,"is_preprint":false},{"pmid":"28993637","id":"PMC_28993637","title":"HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28993637","citation_count":15,"is_preprint":false},{"pmid":"31183386","id":"PMC_31183386","title":"Curcumin and α/β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF-κB.","date":"2019","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/31183386","citation_count":15,"is_preprint":false},{"pmid":"38428781","id":"PMC_38428781","title":"Alleviation of albumin glycation-induced diabetic cardiomyopathy by L-Arginine: Insights into Nrf-2 signaling.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38428781","citation_count":15,"is_preprint":false},{"pmid":"39019088","id":"PMC_39019088","title":"Palladium nanocrystals regulates scleral extracellular matrix remodeling in myopic progression by modulating the hypoxia signaling pathway Nrf-2/Ho-1.","date":"2024","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/39019088","citation_count":14,"is_preprint":false},{"pmid":"35316044","id":"PMC_35316044","title":"A Nrf-2 Stimulatory Hydroxylated Cannabidiol Derivative from Hemp (Cannabis sativa).","date":"2022","source":"Journal of natural products","url":"https://pubmed.ncbi.nlm.nih.gov/35316044","citation_count":13,"is_preprint":false},{"pmid":"34237527","id":"PMC_34237527","title":"AOPPs induce HTR-8/SVneo cell apoptosis by downregulating the Nrf-2/ARE/HO-1 anti-oxidative pathway: Potential implications for preeclampsia.","date":"2021","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/34237527","citation_count":13,"is_preprint":false},{"pmid":"38087141","id":"PMC_38087141","title":"Chitosan-insulin nano-formulations as critical modulators of inflammatory cytokines and Nrf-2 pathway to accelerate burn wound healing.","date":"2023","source":"Discover nano","url":"https://pubmed.ncbi.nlm.nih.gov/38087141","citation_count":13,"is_preprint":false},{"pmid":"35598479","id":"PMC_35598479","title":"Coagulansin-A improves spatial memory in 5xFAD Tg mice by targeting Nrf-2/NF-κB and Bcl-2 pathway.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35598479","citation_count":13,"is_preprint":false},{"pmid":"15257658","id":"PMC_15257658","title":"The NRF-1/alpha-PAL transcription factor regulates human E2F6 promoter activity.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15257658","citation_count":13,"is_preprint":false},{"pmid":"37524754","id":"PMC_37524754","title":"β-Endorphin (an endogenous opioid) inhibits inflammation, oxidative stress and apoptosis via Nrf-2 in asthmatic murine model.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37524754","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56451,"output_tokens":3616,"usd":0.111796,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10986,"output_tokens":3690,"usd":0.07359,"stage2_stop_reason":"end_turn"},"total_usd":0.185386,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical NKRF protein (NF-κB repressing factor, also known as NKRF/NRF/XTBD3/ITBA4). This is distinct from:\n- NRF-1/NRF-2 (nuclear respiratory factors, different genes)\n- Nrf2 (NFE2L2, the antioxidant transcription factor)\n- SKN-1/Nrf (C. elegans ortholog of Nrf2)\n- lncRNA NRF (paper 4)\n- NrfBCD in bacteria (paper 62)\n\nPapers clearly about NKRF (the NF-κB repressing factor protein): 28, 29, 35, 63, 70, 74, 80, 81, 85, 88\n\nLet me extract mechanistic discoveries from these:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"NKRF (NRF) localizes predominantly to nucleoli via a large central domain, with only small fractions in nucleoplasm and cytoplasm. An N-terminal nuclear localization sequence drives nuclear accumulation of all N-terminal fragments, while C-terminal fragments also localize to the nucleus without canonical NLS motifs. FRAP analysis showed nucleolar localization correlates inversely with protein mobility. NKRF binds double-stranded RNA (dsRNA), a property mapping to multiple fragments overlapping the nucleolar affinity domain, and treatment with actinomycin D releases NKRF from nucleoli, suggesting RNA binding mediates nucleolar retention.\",\n      \"method\": \"GFP tagging, confocal microscopy, FRAP, subcellular fractionation, deletion mapping, dsRNA binding assay, actinomycin D treatment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, FRAP, deletion mapping, RNA binding assay) in a single focused study on NKRF\",\n      \"pmids\": [\"15226370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NKRF (NRF) constitutively silences the IFN-β, IL-8, and iNOS genes by binding to cis-acting negative regulatory elements (NRE) in their promoters; mRNA ablation experiments demonstrated that NRF mediates constitutive but not post-stimulated (cytokine/pathogen-induced) silencing of these genes.\",\n      \"method\": \"mRNA ablation (antisense/siRNA knockdown), promoter binding assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with gene expression readout, single lab, referenced in the localization paper (PMID 15226370)\",\n      \"pmids\": [\"15226370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NKRF (NRF) directly interacts with NF-κB p65 in cells, as demonstrated by tandem affinity purification. A synthetic peptide corresponding to NRF amino acids 223–238 disrupts endogenous NRF/p65 binding, and nucleofection of this peptide into IL-1-stimulated or Helicobacter pylori-infected epithelial cells significantly decreases endogenous IL-8 gene transcription, establishing that the NRF/NF-κB p65 interaction is required for IL-8 gene activation.\",\n      \"method\": \"Tandem affinity purification (TAP), synthetic peptide inhibitor, nucleofection into human cervical and gastric epithelial cells, IL-8 mRNA quantification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — TAP identifies the interaction, peptide disruption in live cells confirms functional relevance, two cell/stimulus contexts tested\",\n      \"pmids\": [\"18025206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The NKRF (NRF) mRNA 5'-UTR contains an internal ribosome entry segment (IRES) that drives cap-independent translation. A minimal 150-nt region proximal to the start codon is sufficient for IRES activity, within which a 14-nt RNA element (nt 640–653) is essential. The RNA-binding protein JKTBP1 binds the IRES module upstream of this element (nt 579–639); JKTBP1 overexpression enhances NRF IRES activity, and siRNA knockdown of JKTBP1 reduces both NRF IRES activity and endogenous NRF protein levels.\",\n      \"method\": \"Enzymatic RNA structure analysis, point mutation analysis, dicistronic reporter assay, ESI/MS/MS protein identification, EMSA, siRNA knockdown\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro RNA structure probing, mutagenesis, mass spectrometry identification of binding protein, EMSA, and functional siRNA knockdown; multiple orthogonal methods\",\n      \"pmids\": [\"17592041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NKRF activation is induced by high-tidal-volume mechanical ventilation in mouse lungs. iPSC or iPSC-conditioned medium administration attenuates ventilator-induced lung injury, and this protection is mimicked by NKRF siRNA knockdown, indicating that NKRF pathway activation contributes to ventilation-induced neutrophil infiltration, MIP-2 production, and oxidative stress.\",\n      \"method\": \"Mouse ventilator-induced lung injury model, iPSC/conditioned medium administration, NKRF siRNA knockdown, lung injury indices (permeability, neutrophil counts, MDA, MIP-2)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with siRNA knockdown and pharmacological controls, single lab\",\n      \"pmids\": [\"23840526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-301a directly targets NKRF in JEV-infected microglial cells. miR-301a overexpression reduces NKRF protein, enhancing NF-κB nuclear translocation and amplifying inflammatory cytokine production; NKRF overexpression in miR-301a-inhibited cells restores NF-κB nuclear accumulation to basal levels. In vivo neutralization of miR-301a in mouse brain restores NKRF expression and reduces inflammatory response, microglial activation, and neuronal apoptosis.\",\n      \"method\": \"miRNA overexpression/inhibition, NKRF overexpression, NF-κB nuclear translocation assay, in vivo miR-301a neutralization in mouse brain\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function in vitro and in vivo, NKRF rescue experiment confirms pathway placement, replicated across conditions\",\n      \"pmids\": [\"31527198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HuR (RNA-binding protein) stabilizes NKRF mRNA by binding to its AU-rich elements. HuR overexpression increases NKRF levels; NKRF overexpression in HuR-deficient nucleus pulposus cells suppresses NF-κB-driven inflammation and extracellular matrix degradation; NKRF (but not HuR) overexpression ameliorates intervertebral disc degeneration in rats in vivo.\",\n      \"method\": \"HuR overexpression/knockdown, mRNA stability assay, NKRF overexpression, NF-κB pathway activity readouts (inflammation/ECM markers), rat IVDD model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mRNA stability mechanism established, rescue experiment with NKRF OE, in vivo validation in rat model, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"33330514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-192 directly targets NKRF in lung cancer cells. miR-192 overexpression suppresses NKRF, increases NF-κB nuclear protein and transcriptional activation, and upregulates anti-apoptotic targets (cIAP1, cIAP2, Bcl-xl, XIAP), conferring cisplatin resistance. Inhibition of NF-κB by curcumin reverses the pro-survival and cisplatin-resistance effects of miR-192 upregulation.\",\n      \"method\": \"miR-192 overexpression/inhibition, luciferase reporter (3'UTR), NF-κB nuclear translocation, western blot for downstream targets, cisplatin resistance assay, NF-κB pathway inhibition rescue\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms direct targeting, functional NF-κB pathway readout, single lab\",\n      \"pmids\": [\"34953057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-301a-3p targets NKRF in gastric cancer cells (confirmed by luciferase reporter assay). Overexpression of miR-301a-3p decreases NKRF expression, activates NF-κB signaling, and promotes GC cell proliferation and invasion; these effects are mediated through NKRF downregulation.\",\n      \"method\": \"miR-301a-3p overexpression, luciferase reporter assay (NKRF 3'UTR), RT-qPCR/western blot, NF-κB pathway readout, proliferation/invasion assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR targeting confirmed by luciferase assay, NF-κB pathway functional readout; single lab\",\n      \"pmids\": [\"32468020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NKRF in cardiac fibroblasts (CFs) inhibits HuR transcription by binding to the classical negative regulatory element (NRE) in the HuR promoter via an NF-κB-dependent mechanism. This reduces HuR-mediated stabilization of Mmp2 and Mmp9 mRNAs. CF-specific NKRF knockout (NKRF-CKO) mice show worsened cardiac function, increased infarct size, and elevated MMP2/MMP9 post-myocardial infarction compared with littermates, demonstrating that NKRF protects against pathological cardiac remodeling by suppressing CF migration and invasion.\",\n      \"method\": \"CF-specific NKRF knockout mouse model (NKRF-CKO), promoter binding assay, NRE mutagenesis, in vitro CF migration/invasion assays, in vivo post-MI cardiac function (echocardiography, infarct size)\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional knockout mouse with defined cellular and molecular mechanism (promoter binding, mRNA stability), multiple in vivo and in vitro endpoints; single lab but rigorous design\",\n      \"pmids\": [\"37667861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LvNKRF (the NKRF ortholog from Litopenaeus vannamei shrimp) localizes to the nucleus and interacts with both Dorsal and Relish (the two shrimp NF-κB family members). Unlike mammalian NKRF which inhibits NF-κB, LvNKRF enhances NF-κB activity; LvNKRF expression is upregulated by WSSV infection and silencing of LvNKRF reduces shrimp mortality and viral replication from WSSV, suggesting LvNKRF facilitates viral exploitation of the host NF-κB pathway.\",\n      \"method\": \"Gene identification, nuclear localization assay, protein-protein interaction assay, RNAi silencing, WSSV infection model, viral copy number quantification\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction and localization confirmed, functional RNAi knockdown in vivo; invertebrate ortholog with opposite function to mammalian NKRF\",\n      \"pmids\": [\"28564581\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NKRF (NF-κB repressing factor) is a nucleolar/nuclear protein that constitutively represses transcription of NF-κB-target genes (including IFN-β, IL-8, and iNOS) by binding negative regulatory elements (NRE) in their promoters; it physically interacts with NF-κB p65 (amino acids 223–238 of NKRF mediate this interaction), and disruption of this interaction de-represses IL-8 transcription; NKRF mRNA is translated via a cap-independent IRES mechanism facilitated by RNA-binding protein JKTBP1; NKRF is itself post-transcriptionally regulated by HuR (which stabilizes NKRF mRNA via AU-rich elements) and negatively regulated by miR-301a and miR-192 (which suppress NKRF to activate NF-κB); in cardiac fibroblasts, NKRF suppresses HuR transcription through NRE binding, thereby limiting MMP2/MMP9 mRNA stability and CF invasion, protecting against post-MI cardiac remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NKRF (NF-κB repressing factor) is a predominantly nucleolar protein that acts as a constitutive transcriptional repressor of NF-κB target genes, restraining basal inflammatory gene expression [#0, #1]. It silences the IFN-β, IL-8, and iNOS genes by binding cis-acting negative regulatory elements (NRE) in their promoters, mediating constitutive but not stimulus-induced repression [#1]. Paradoxically, NKRF also physically engages NF-κB p65 — an interaction mapped to NKRF residues 223–238 — and disruption of this contact reduces, rather than increases, IL-8 transcription in IL-1-stimulated and Helicobacter pylori-infected epithelial cells, indicating that NKRF/p65 association is required for IL-8 gene activation in those contexts [#2]. NKRF localizes to nucleoli through a large central domain whose retention depends on double-stranded RNA binding, as actinomycin D treatment releases it from the nucleolus [#0]. Its own expression is controlled at multiple post-transcriptional levels: NKRF mRNA is translated via a 5'-UTR IRES whose activity depends on the RNA-binding protein JKTBP1 [#3], the mRNA is stabilized by HuR through AU-rich elements [#6], and it is repressed by miR-301a/miR-301a-3p and miR-192, which downregulate NKRF to license NF-κB nuclear translocation and inflammatory or pro-survival signaling [#5, #7, #8]. Through this repressive output, NKRF restrains pathological NF-κB-driven processes in vivo, including ventilator-induced lung injury [#4], intervertebral disc degeneration [#6], JEV-associated neuroinflammation [#5], and post-myocardial-infarction cardiac remodeling, where cardiac-fibroblast NKRF suppresses HuR transcription via NRE binding to limit MMP2/MMP9-driven invasion [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established where NKRF resides and how it is retained there, linking its localization to RNA binding rather than canonical protein-targeting alone.\",\n      \"evidence\": \"GFP tagging, confocal microscopy, FRAP, deletion mapping, and dsRNA-binding/actinomycin D assays\",\n      \"pmids\": [\"15226370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The functional consequence of nucleolar sequestration for transcriptional repression is not defined\", \"The dsRNA ligand(s) retained in the nucleolus are not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined NKRF's core function as a constitutive repressor acting through promoter NRE elements, distinguishing basal silencing from inducible expression.\",\n      \"evidence\": \"mRNA ablation knockdown with promoter-binding readouts on IFN-β, IL-8, and iNOS\",\n      \"pmids\": [\"15226370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The corepressor machinery NKRF recruits at NREs is not identified\", \"Why repression is constitutive but lost upon stimulation is unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped a direct NKRF/NF-κB p65 interaction interface and showed, unexpectedly, that this contact is required for IL-8 activation, complicating the simple repressor model.\",\n      \"evidence\": \"Tandem affinity purification plus a 223–238 peptide inhibitor nucleofected into IL-1-stimulated and H. pylori-infected epithelial cells\",\n      \"pmids\": [\"18025206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The reconciliation between NRE-mediated repression and p65-dependent activation at the same locus is unresolved\", \"Structural basis of the 223–238 contact with p65 is unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed NKRF protein output is set translationally through an IRES, identifying JKTBP1 as a trans-acting factor controlling NKRF abundance.\",\n      \"evidence\": \"RNA structure probing, mutagenesis, dicistronic reporters, mass spectrometry, EMSA, and JKTBP1 siRNA knockdown\",\n      \"pmids\": [\"17592041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions that favor cap-independent over cap-dependent NKRF translation are not defined\", \"Whether IRES usage changes during inflammation is untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed NKRF pathway activation as a contributor to mechanical-stress lung injury in vivo.\",\n      \"evidence\": \"Mouse ventilator-induced lung injury model with NKRF siRNA and iPSC/conditioned-medium rescue\",\n      \"pmids\": [\"23840526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular events downstream of NKRF activation in this model are not dissected\", \"Whether NKRF acts here as repressor or via p65 association is unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established NKRF as a direct miRNA target whose loss de-represses NF-κB, with reciprocal rescue confirming pathway placement in neuroinflammation.\",\n      \"evidence\": \"miR-301a gain/loss-of-function with NKRF rescue in microglia and in vivo miR-301a neutralization in mouse brain\",\n      \"pmids\": [\"31527198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct 3'UTR binding site not mapped in this study\", \"Upstream signals controlling miR-301a are not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified HuR-dependent mRNA stabilization as a positive post-transcriptional control of NKRF, with disease relevance in disc degeneration.\",\n      \"evidence\": \"HuR overexpression/knockdown, mRNA stability assays, NKRF rescue, and a rat IVDD model\",\n      \"pmids\": [\"33330514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The interplay between HuR stabilization and miRNA repression of NKRF is not integrated\", \"AU-rich element location within NKRF mRNA not precisely mapped here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the miRNA→NKRF→NF-κB axis to cancer, showing direct 3'UTR targeting drives proliferation and invasion.\",\n      \"evidence\": \"miR-301a-3p overexpression with luciferase 3'UTR reporter and proliferation/invasion assays in gastric cancer cells\",\n      \"pmids\": [\"32468020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional readout without in vivo confirmation\", \"Endogenous miR-301a-3p levels in patient tissue not correlated with NKRF\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed a second miRNA (miR-192) suppresses NKRF to drive NF-κB-dependent anti-apoptotic gene expression and chemoresistance.\",\n      \"evidence\": \"miR-192 manipulation, 3'UTR luciferase reporter, and cisplatin-resistance assays with NF-κB inhibitor rescue in lung cancer cells\",\n      \"pmids\": [\"34953057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation of the miR-192/NKRF axis\", \"Whether multiple miRNAs co-regulate NKRF in the same tumor is untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a concrete physiological repressor circuit: NKRF binds the HuR promoter NRE to limit MMP2/MMP9 and protect against cardiac remodeling, using a conditional knockout.\",\n      \"evidence\": \"Cardiac-fibroblast-specific NKRF knockout mice, promoter NRE mutagenesis, migration/invasion assays, and post-MI echocardiography\",\n      \"pmids\": [\"37667861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The NF-κB-dependent component of NKRF binding at the HuR promoter is not mechanistically separated from direct NRE binding\", \"Generality of the NKRF→HuR repression to other cell types is unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the invertebrate NKRF ortholog interacts with NF-κB family members but enhances rather than inhibits NF-κB, revealing context- or species-dependent directionality.\",\n      \"evidence\": \"LvNKRF identification, interaction assays with Dorsal and Relish, and RNAi during WSSV infection in shrimp\",\n      \"pmids\": [\"28564581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the opposite functional sign reflects a species difference or assay context is unresolved\", \"Direct relevance to mammalian NKRF mechanism is limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how NKRF switches between repressing NF-κB targets via NRE binding and being required for p65-dependent activation, and what corepressor/coactivator machinery and nucleolar RNA functions underlie these opposing outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the NKRF–NRE or NKRF–p65 complexes\", \"The corepressor complex recruited at NREs is unidentified\", \"Functional role of nucleolar dsRNA-dependent retention in transcriptional control is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RELA\", \"JKTBP1\", \"ELAVL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}