{"gene":"KLF11","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1998,"finding":"KLF11 (TIEG2) is a nuclear protein that specifically binds to Sp1-like (GC-rich) DNA sequences in vitro and represses promoters containing Sp1-like binding sites; overexpression inhibits cell proliferation in CHO cells.","method":"Nuclear fractionation, in vitro DNA-binding assay, luciferase reporter assay, [3H]thymidine/MTS proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (DNA binding, reporter assay, proliferation assay) in a foundational characterization paper, independently replicated in subsequent work","pmids":["9748269"],"is_preprint":false},{"year":1999,"finding":"KLF11 (FKLF) acts as a transcriptional activator of the gamma- and epsilon-globin gene promoters via the CACCC box in erythroid cells; transfection of KLF11 cDNA into K562 cells enhanced endogenous epsilon- and gamma-globin gene expression.","method":"Luciferase reporter assay with CACCC box deletion constructs, transfection into K562 erythroid cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with deletion mapping plus endogenous gene expression, single lab","pmids":["10207080"],"is_preprint":false},{"year":2002,"finding":"The Mad1-like Sin3-interacting domain (SID) of KLF11 (TIEG2) binds mSin3A to mediate transcriptional repression; this interaction is disrupted by EGF-Ras-MEK1-ERK2 signaling via phosphorylation of four serine/threonine sites adjacent to the SID, thereby inhibiting KLF11's repression activity.","method":"Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase assay, reporter assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation, mutagenesis of phospho-sites, Co-IP confirming disrupted SID-mSin3A interaction; replicated in subsequent work","pmids":["12006497"],"is_preprint":false},{"year":2003,"finding":"KLF11 represses transcription of SOD2 and Catalase1 promoters via its Mad1-like SID-mSin3A interaction; this repression renders cells more sensitive to oxidative stress, an effect rescuable by adenoviral SOD2/Catalase1 re-expression. KLF11 also inhibits neoplastic transformation and cell growth in vitro and in vivo.","method":"Chromatin immunoprecipitation (ChIP), adenoviral rescue experiment, transgenic mouse model, cell growth/transformation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirming direct promoter occupancy, in vivo transgenic model, mechanistic rescue experiment, multiple orthogonal methods","pmids":["12970187"],"is_preprint":false},{"year":2004,"finding":"KLF11 represses Smad7 transcription by recruiting mSin3A via GC-rich sites on the Smad7 promoter, thereby potentiating TGF-β signaling. In pancreatic cancer cells with oncogenic Ras, ERK phosphorylates KLF11 and disrupts KLF11-mSin3A interaction; an ERK-insensitive KLF11 mutant restores mSin3A binding and Smad7 repression.","method":"Reporter assay, real-time PCR, co-immunoprecipitation, in vitro ERK phosphorylation, site-directed mutagenesis","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-IP, in vitro kinase assay, mutagenesis restoring function, multiple orthogonal methods in single rigorous study","pmids":["15300592"],"is_preprint":false},{"year":2004,"finding":"KLF11 binds to an Sp1 site flanking the SRE in the caveolin-1 promoter and acts as a dominant repressor. Cholesterol depletion displaces KLF11 from this site (via down-regulation of KLF11 expression and competition by Sp1), enabling SREBP/Sp1-mediated activation of caveolin-1 transcription.","method":"RNA interference, chromatin immunoprecipitation, EMSA, luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — four orthogonal methods (RNAi, ChIP, EMSA, reporter) in single study demonstrating mechanism","pmids":["15531587"],"is_preprint":false},{"year":2004,"finding":"KLF11 (TIEG2) acts as a transcriptional activator of MAO B gene expression via Sp1 sites, and as a repressor at the CACCC element; gel-shift and ChIP confirmed direct binding to both elements in the MAO B core promoter.","method":"Cotransfection reporter assays, gel-shift (EMSA), chromatin immunoprecipitation, RT-PCR, western blot, MAO B catalytic activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, EMSA, promoter deletion, mRNA, protein, enzymatic activity), single lab","pmids":["15024015"],"is_preprint":false},{"year":2005,"finding":"KLF11 binds the insulin promoter at GC-rich sites and activates its transcriptional activity in pancreatic beta cells, as a glucose-inducible regulator. The Gln62Arg variant impairs mSin3A-binding activity of KLF11 and reduces insulin promoter activation.","method":"Random oligonucleotide binding assay, EMSA, luciferase reporter assay, chromatin immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — four orthogonal assays establishing DNA binding, promoter occupancy, and transcriptional activation in beta cells","pmids":["15774581"],"is_preprint":false},{"year":2006,"finding":"KLF11 cooperates with Smad3 to repress c-myc transcription via the TGF-β inhibitory element (TIE) in the c-myc promoter; ERK hyperactivation in pancreatic cancer cells with oncogenic Ras disrupts KLF11-Smad3 complex formation and KLF11-Smad3 binding to the TIE, preventing c-myc repression and growth inhibition.","method":"Co-immunoprecipitation, GST pulldown, reporter assay, DNA binding assay, RNA interference, U0126 ERK inhibitor treatment","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP and GST pulldown define direct KLF11-Smad3 interaction; mechanistic rescue by ERK inhibition; multiple orthogonal methods","pmids":["17114344"],"is_preprint":false},{"year":2007,"finding":"KLF11 (TIEG2) induces caspase-3-dependent apoptosis in oligodendroglial OLI-neu cells and decreases Bcl-XL levels by repressing the Bcl-XL promoter; the N-terminal repression domains (including the SID) are required for pro-apoptotic activity.","method":"Overexpression in OLI-neu cells, caspase-3 activation assay, western blot (Bcl-XL), reporter assay with Bcl-XL promoter","journal":"Journal of neural transmission","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus protein-level validation in defined cell system, single lab","pmids":["17308981"],"is_preprint":false},{"year":2007,"finding":"The amino-terminus of KLF11 (Tieg3) is essential for transcriptional repression; the SID within this domain is required for repressive activity. The zinc finger DNA-binding domain (DBD) alone can activate transcription and contains two closely located putative bipartite nuclear localization signals (NLS) within the second and third zinc fingers that are necessary and sufficient for nuclear localization.","method":"GAL4-based luciferase assays, EGFP-fusion protein localization (live imaging), NLS deletion/mutation mapping","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain mapping with reporter assay and direct imaging of localization, single lab","pmids":["17252542"],"is_preprint":false},{"year":2008,"finding":"KLF11 (Tieg3) enhances TGF-β signaling in oligodendroglial cells by transcriptionally repressing Smad7, disrupting the negative feedback loop; loss of the N-terminal repression domains (including SID) abolishes both the pro-apoptotic function and Smad7 repression.","method":"Overexpression/deletion mutants in OLI-neu cells, reporter assay on Smad7 promoter, apoptosis/caspase-3 assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with domain-deletion mutants, functional apoptosis readout, single lab","pmids":["18189266"],"is_preprint":false},{"year":2009,"finding":"KLF11 activates Pdx-1 transcription in pancreatic beta cells through two evolutionarily conserved GC-rich elements (GC1 and GC2) in the Pdx-1 Area II control region; KLF11 associates with Area II by ChIP and interacts with the coactivator p300 via its zinc finger domain in vivo to mediate this activation.","method":"Random oligonucleotide binding analysis, ChIP, luciferase reporter assay with GC1/GC2 mutations, co-immunoprecipitation (in vivo interaction with p300)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, in vivo Co-IP, reporter assays with specific element mutations, multiple orthogonal methods in single study","pmids":["19843526"],"is_preprint":false},{"year":2010,"finding":"KLF11 directly binds the UCP1 promoter via GC-box elements and activates UCP1 transcription; KLF11 is required for UCP1 expression during brown adipocyte differentiation of muBM3.1 mesenchymal stem cells.","method":"Reporter assay with UCP1 promoter, ChIP/DNA binding assay, brown adipocyte differentiation model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay and functional knockdown, single lab","pmids":["20709022"],"is_preprint":false},{"year":2010,"finding":"KLF11 integrates progesterone receptor (PR) signaling to inhibit uterine leiomyoma cell proliferation. PR knockdown increases KLF11 expression; KLF11 knockdown abolishes the antiproliferative effect of RU486. KLF11 basal promoter and a distal PR-binding region (20.5 kb upstream) containing Sp1 sites (not classical PREs) recruit Sp1, RNA Pol II, PR, SRC-1 and SRC-2.","method":"ChIP-cloning to identify PR-binding site, luciferase reporter assay, siRNA knockdown of PR and KLF11, proliferation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-based discovery, siRNA functional rescue, reporter assay; multiple orthogonal approaches","pmids":["20124487"],"is_preprint":false},{"year":2012,"finding":"Glucocorticoids (dexamethasone) induce KLF11 mRNA and protein in neurons; KLF11 then translocates from cytoplasm to nucleus and activates the MAO A promoter via Sp/KLF-binding sites, increasing MAO A mRNA and enzymatic activity. KLF11 knockout mice show reduced brain cortex MAO A expression; chronic social defeat stress activates the KLF11 pathway in rat brain with increased MAO A.","method":"siRNA knockdown, KLF11 overexpression, KLF11 knockout mice, nuclear/cytoplasmic fractionation, MAO A promoter reporter, MAO A catalytic activity assay, in vivo stress model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods including KO mouse, subcellular fractionation, enzymatic activity; replicated in vivo","pmids":["22628545"],"is_preprint":false},{"year":2012,"finding":"KLF11 overexpression in mouse livers activates the PPARα signaling pathway to improve fatty liver by promoting fatty acid oxidation; KLF11 knockdown decreases fatty acid oxidation and raises hepatic TG levels. PPARα knockdown abolishes KLF11's effects on fatty acid oxidation genes and hepatic TG.","method":"Adenoviral overexpression/shRNA in db/db and DIO mice, histology, biochemical TG assay, epistasis by co-injection with Ad-shPPARα","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function in multiple mouse models with genetic epistasis (PPARα rescue), multiple metabolic readouts","pmids":["23183531"],"is_preprint":false},{"year":2013,"finding":"KLF11 interacts with PPARγ and acts as a novel PPARγ co-regulator; KLF11 is also a direct transcriptional target of PPARγ. KLF11 deficiency abolishes pioglitazone-mediated cerebrovascular protection and PPARγ transcriptional suppression of pro-apoptotic miR-15a in endothelial cells.","method":"Genome-wide co-activation screen, co-immunoprecipitation, KLF11 knockout mouse, oxygen-glucose deprivation cell model, MCAO stroke model","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP confirming physical interaction, KO mouse in vivo stroke model, loss-of-function rescue experiments; multiple orthogonal methods","pmids":["23408111"],"is_preprint":false},{"year":2013,"finding":"KLF11 binds specific GC-rich promoter elements of collagen, MMP, and TGF-β family genes in endometrial stromal cells and represses their transcription; KLF11 deficiency in mice leads to large fibrotic endometriotic lesions resembling advanced human disease.","method":"ChIP of endometrial stromal cell promoters, Klf11 knockout mouse endometriosis model, comparison with Klf9 knockout","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP of specific promoters, KO mouse with specific phenotype, specificity validated by parallel Klf9 KO control","pmids":["23555910"],"is_preprint":false},{"year":2013,"finding":"KLF11 epigenetically represses glycodelin-A expression in endometrial cells by binding two regulatory elements in the glycodelin promoter and recruiting the SIN3/HDAC corepressor complex, resulting in transcriptional repression.","method":"ChIP, reporter assay, mRNA and protein expression analysis, SIN3/HDAC corepressor recruitment assay","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional reporter assay plus corepressor recruitment, single lab","pmids":["24060634"],"is_preprint":false},{"year":2014,"finding":"KLF11 is required for rosiglitazone-induced browning of human adipocytes; it is directly induced by PPARγ and cooperates with PPARγ in a feed-forward manner to activate the brite-selective gene program and increase mitochondrial oxidative capacity. KLF11 is associated with PPARγ superenhancers selective for brite adipocytes.","method":"siRNA knockdown of KLF11 in human adipocytes, ChIP-seq for PPARγ superenhancers, mitochondrial oxidative capacity measurement, gene expression profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, functional knockdown, mitochondrial functional assay; multiple orthogonal methods in human primary cells","pmids":["25504365"],"is_preprint":false},{"year":2014,"finding":"KLF11 binds CYP3A4 promoter GC elements and recruits SIN3A/HDAC corepressor, causing selective histone deacetylation of the CYP3A4 promoter and repressing CYP3A4 mRNA, protein, and enzymatic activity in endometrial cells. A KLF11 mutation abrogating cofactor recruitment reverses this repression.","method":"ChIP (KLF11 at CYP3A4 promoter), SIN3A/HDAC corepressor co-localization, reporter assay, mRNA/protein/enzyme activity assays, HDAC inhibitor pharmacological reversal, SID-mutation rescue","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, mutagenesis, pharmacological reversal, multiple functional readouts, single lab with orthogonal methods","pmids":["25076120"],"is_preprint":false},{"year":2014,"finding":"KLF11 suppresses hepatic gluconeogenesis by repressing PEPCK-C and PGC-1α gene expression in primary hepatocytes; adenoviral overexpression of KLF11 in diabetic mouse livers improves hyperglycemia, while KLF11 knockdown impairs glucose tolerance.","method":"Adenoviral overexpression/knockdown in primary mouse hepatocytes and in vivo mouse models, glucose output assay, gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo, single lab","pmids":["24586865"],"is_preprint":false},{"year":2016,"finding":"TGF-β1 causes non-canonical (non-SMAD-mediated) transient up-regulation then sustained repression of KLF11, while KLF11 epigenetically represses CYP3A4 via SIN3A/HDAC. KLF11-deficient mice treated with TGF-β receptor inhibitor show reduced endometriotic progression and Cyp3a expression.","method":"Klf11 knockout mouse endometriosis model, TGFβR1 inhibitor treatment, histone acetyltransferase inhibitor, Cyp3a expression analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse plus pharmacological combination in vivo, single lab","pmids":["27384304"],"is_preprint":false},{"year":2017,"finding":"KLF11 binds to the DRD2 promoter and transcriptionally activates DRD2 in endometrial cells; in Klf11-/- mice with endometriosis, lesions show progressive fibrosis and decreased Drd2 expression consistent with loss of KLF11-mediated activation.","method":"ChIP, promoter reporter assay, Klf11-/- mouse endometriosis model, gene expression analysis","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter with in vivo KO model, single lab","pmids":["28372535"],"is_preprint":false},{"year":2019,"finding":"KLF11 transcriptionally suppresses the tissue factor (F3) gene in vascular smooth muscle cells via direct promoter binding (ChIP), reducing arterial thrombosis. Smooth muscle cell-specific Klf11 KO mice show reduced occlusion time in ferric chloride thrombosis model, not rescued by bone marrow transplant.","method":"Reporter assay, ChIP, siRNA knockdown and adenoviral overexpression in human aortic smooth muscle cells, conditional SMC-specific KO mouse, ferric chloride thrombosis model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirming direct promoter occupancy, tissue-specific KO mouse model, gain- and loss-of-function in primary cells","pmids":["30602303"],"is_preprint":false},{"year":2021,"finding":"In venous endothelial cells under prothrombotic conditions, KLF11 reduces TNF-α-induced tissue factor (TF) gene transcription by inhibiting EGR1 binding to the TF promoter, as demonstrated by reporter assay, ChIP, and co-immunoprecipitation. Klf11 KO mice are more susceptible to stasis-induced DVT.","method":"Reporter gene assay, ChIP, co-immunoprecipitation (KLF11-EGR1), gain- and loss-of-function in ECs, Klf11 KO mouse deep vein thrombosis model","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP defining protein-protein interaction, ChIP, reporter assay, in vivo KO model","pmids":["34428834"],"is_preprint":false},{"year":2021,"finding":"KLF11 and YAP/TEAD bind adjacent DNA sites and directly interact; KLF11 recruits SIN3A/HDAC to suppress YAP/TEAD transcriptional output, while YAP/TEAD promotes KLF11 transcription, forming a negative feedback loop that is broken by epigenetic silencing of KLF11 in sarcoma cancer stem cells.","method":"Genome-wide CRISPR-Cas9 screen, co-immunoprecipitation (KLF11-YAP/TEAD), ChIP, KLF11 overexpression/knockdown, in vitro and in vivo functional assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus Co-IP, ChIP, and in vivo experiments; multiple orthogonal methods","pmids":["33571129"],"is_preprint":false},{"year":2021,"finding":"Endothelial KLF11 deficiency aggravates AAA formation, while EC-selective overexpression inhibits it. KLF11 inhibits EC inflammatory response, suppresses MMP9 expression and activity, and reduces NADPH oxidase 2-mediated ROS in ECs; KLF11-deficient ECs also induce smooth muscle cell dedifferentiation and apoptosis.","method":"EC-specific KLF11 transgenic and knockout mice, elastase- and PCSK9/AngII-induced AAA mouse models, gain- and loss-of-function in cultured ECs","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent in vivo AAA models, EC-specific transgenic and KO, multiple mechanistic readouts","pmids":["33507881"],"is_preprint":false},{"year":2023,"finding":"KLF11 binds the GPX4 promoter region and represses its transcription in lung adenocarcinoma cells, promoting ferroptosis and increasing chemosensitivity; ChIP-seq and ChIP-qPCR confirmed GPX4 as a direct KLF11 target, and GPX4 restoration antagonized KLF11-induced ferroptosis.","method":"ChIP-seq, ChIP-qPCR, dual luciferase assay, RNA-seq, KLF11 overexpression/knockout in vitro and in vivo","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq plus ChIP-qPCR plus luciferase assay, GPX4 rescue experiment, in vivo xenograft","pmids":["37248295"],"is_preprint":false},{"year":2024,"finding":"KLF11 promotes ferroptosis in cardiomyocytes by suppressing FSP1 transcription; KLF11 is induced by sorafenib and its overexpression or FSP1 knockdown both increase ferroptotic cell death. Cardiac-specific AAV9-mediated KLF11 silencing or FSP1 overexpression improved cardiac dysfunction in sorafenib-treated mice.","method":"Transcriptome profiling, KLF11 overexpression/knockdown in cardiomyocytes, AAV9 cardiac-specific delivery in mice, FSP1 rescue experiment, GPX4 epistasis","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV9 cardiac model plus in vitro mechanistic epistasis, single lab","pmids":["38725840"],"is_preprint":false},{"year":2024,"finding":"SKP2 E3 ubiquitin ligase triggers K48-linked ubiquitination and proteasomal degradation of KLF11 in chondrocytes; loss of KLF11 transcriptionally activates JMJD3, which demethylates H3K27me3 to activate NOTCH1, promoting OA progression. KLF11 overexpression in vivo delays OA development.","method":"Co-immunoprecipitation (SKP2-KLF11), ubiquitination assay, ChIP (KLF11 on JMJD3 promoter), H3K27me3 analysis, in vivo rat OA model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/ubiquitination assay plus ChIP, single lab with in vivo corroboration","pmids":["38690715"],"is_preprint":false},{"year":2024,"finding":"CGRP increases phosphorylated HP1γ (p-HP1γ) recruitment to the Klf11 enhancer (confirmed by ChIP), which epigenetically activates KLF11 expression; increased KLF11 in turn activates MAOB, depleting dopamine in the dorsal hippocampus and inducing anxiety-like behaviors.","method":"Chromatin immunoprecipitation (HP1γ at Klf11 enhancer), intracerebroventricular CGRP injection, MAOB pharmacological inhibition and knockdown in mice","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming HP1γ at KLF11 enhancer, in vivo pharmacological and genetic validation, single lab","pmids":["38503899"],"is_preprint":false},{"year":2024,"finding":"KLF11 promotes breast cancer cell proliferation by reducing TP53 mRNA transcription and by interacting with MDM2 protein to inhibit MDM2 ubiquitination/degradation, thereby increasing MDM2 levels and accelerating ubiquitin-mediated p53 proteolysis and reducing CDKN1A/BAX/NOXA1.","method":"Co-immunoprecipitation (KLF11-MDM2), ubiquitination assay, RT-qPCR, western blot, in vivo xenograft","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay establishing protein interaction and mechanistic consequence, single lab","pmids":["38810862"],"is_preprint":false},{"year":2025,"finding":"KLF11 forms a transcriptional complex with PPARα and YAP1 in macrophages; KLF11 suppresses PPARα-YAP1-mediated glycolysis and acts as a transcriptional activator of ABCA1/G1. KLF11 knockout abolishes wogonin's inhibitory effect on glycolysis and atherosclerosis.","method":"KLF11 KO mouse atherosclerosis model, co-immunoprecipitation (KLF11-PPARα-YAP1 complex), reporter assay, gain- and loss-of-function in macrophages","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP defining ternary complex, KO mouse, reporter assay; single lab","pmids":["40397286"],"is_preprint":false},{"year":2026,"finding":"FXR directly binds to a FXRE sequence in the KLF11 promoter (confirmed by luciferase reporter and ChIP) and transcriptionally upregulates KLF11; KLF11 then suppresses the JAK2/STAT3 pathway to reduce renal inflammation and apoptosis in contrast-induced AKI. FXR or KLF11 genetic deletion abolishes FXR agonist (CDCA) renoprotection.","method":"Luciferase reporter assay, ChIP (FXR at KLF11 promoter), KLF11 knockdown and FXR KO models, JAK2/STAT3 pathway analysis","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus genetic KO establishing FXR→KLF11→JAK2/STAT3 epistasis, single lab","pmids":["41855776"],"is_preprint":false},{"year":2026,"finding":"KLF11 promotes MDM2 expression, which inhibits E2F1 ubiquitination and stabilizes E2F1, enhancing RAD51-mediated homologous recombination DNA repair and conferring radioresistance in esophageal cancer cells. Co-immunoprecipitation and immunofluorescence confirmed KLF11-MDM2 protein interaction.","method":"Co-immunoprecipitation, immunofluorescence, neutral comet assay, colony formation/apoptosis assays, in vivo xenograft, RT-qPCR/western blot","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing protein interaction, functional assays in vitro and in vivo, single lab","pmids":["41655531"],"is_preprint":false}],"current_model":"KLF11 is a TGF-β-inducible Sp1/KLF-family zinc finger transcription factor that localizes to the nucleus via NLS sequences in its zinc finger domain, binds GC-rich (Sp1-like) DNA elements, and can act as either a repressor or activator depending on context: as a repressor it recruits the SIN3A/HDAC corepressor complex via its Mad1-like SID domain to silence target genes (Smad7, SOD2, Catalase1, GPX4, FSP1, tissue factor F3, collagen/MMP/TGF-β family genes, CYP3A4), while as an activator it interacts with coactivators such as p300 (via its zinc finger domain) or PPARγ to transactivate targets like the insulin gene, Pdx-1, UCP1, MAO A/B, DRD2, and ABCA1/G1; its repressive activity is regulated by ERK/MAPK phosphorylation of serine/threonine sites adjacent to the SID (disrupting SID-mSin3A interaction), by SKP2-mediated ubiquitination and degradation, and by epigenetic silencing of the KLF11 locus itself, placing KLF11 at the intersection of TGF-β signaling amplification, oxidative stress response, metabolic regulation (insulin/glucose/lipid homeostasis), vascular homeostasis, and ferroptosis control."},"narrative":{"mechanistic_narrative":"KLF11 is an Sp1/KLF-family zinc finger transcription factor that binds GC-rich (Sp1-like) DNA elements and functions as a context-dependent repressor or activator, positioning it at the intersection of TGF-β signaling, oxidative stress, metabolic homeostasis, and ferroptosis control [PMID:9748269, PMID:12970187, PMID:15300592]. Its repressive activity depends on an N-terminal Mad1-like Sin3-interacting domain (SID) that recruits the mSin3A/HDAC corepressor complex to silence targets such as SOD2 and Catalase1, Smad7, CYP3A4, and glycodelin-A [PMID:12006497, PMID:12970187, PMID:24060634, PMID:25076120]; nuclear localization is conferred by bipartite NLS sequences within its zinc finger DNA-binding domain, which alone can activate transcription [PMID:17252542]. This SID-mSin3A interaction is the principal regulated node: EGF–Ras–MEK–ERK phosphorylation of serine/threonine sites flanking the SID disrupts corepressor binding and abolishes repression, a switch exploited in oncogenic-Ras pancreatic cancer to relieve KLF11-mediated repression of Smad7 and, with Smad3, of c-myc [PMID:12006497, PMID:15300592, PMID:17114344]. As an activator KLF11 engages coactivators including p300 and PPARγ to transactivate metabolic and developmental targets, driving insulin and Pdx-1 expression in beta cells, UCP1 and the brite/brown adipocyte program, hepatic PPARα-dependent fatty acid oxidation, and ABCA1/G1 [PMID:15774581, PMID:19843526, PMID:20709022, PMID:23183531, PMID:25504365, PMID:40397286]. KLF11 enforces vascular homeostasis by repressing tissue factor (F3) in smooth muscle and endothelial cells—partly by blocking EGR1 promoter binding—and by limiting EC inflammation and ROS to suppress thrombosis and abdominal aortic aneurysm [PMID:30602303, PMID:34428834, PMID:33507881]. In tumor and tissue-protective contexts it represses GPX4 and FSP1 to promote ferroptosis, suppresses YAP/TEAD output via SIN3A/HDAC recruitment, and modulates p53 through MDM2 interaction [PMID:33571129, PMID:37248295, PMID:38725840, PMID:38810862]. KLF11 protein and locus abundance are themselves controlled by SKP2-mediated K48 ubiquitination and proteasomal degradation and by epigenetic activation/silencing of the KLF11 enhancer [PMID:33571129, PMID:38690715, PMID:38503899].","teleology":[{"year":1998,"claim":"Established KLF11 as a nuclear, sequence-specific transcription factor, defining its core biochemical identity as an Sp1-like GC-box binder that represses transcription and restrains proliferation.","evidence":"Nuclear fractionation, in vitro DNA-binding, luciferase reporter, and proliferation assays in CHO cells","pmids":["9748269"],"confidence":"High","gaps":["Did not identify the corepressor machinery or physiological target genes","Repression mechanism at endogenous loci not yet defined"]},{"year":1999,"claim":"Showed KLF11 can also act as an activator, binding the CACCC box to enhance gamma/epsilon-globin transcription, foreshadowing its dual repressor/activator behavior.","evidence":"CACCC-box deletion reporter assays and endogenous globin expression in K562 erythroid cells","pmids":["10207080"],"confidence":"Medium","gaps":["Coactivator partners not identified","Physiological role in erythropoiesis not tested in vivo"]},{"year":2002,"claim":"Identified the molecular basis of KLF11 repression and its regulation: the Mad1-like SID recruits mSin3A, and ERK phosphorylation of SID-flanking residues disrupts this interaction, defining a MAPK-controlled repression switch.","evidence":"Co-IP, site-directed mutagenesis, in vitro kinase assay, reporter assay","pmids":["12006497"],"confidence":"High","gaps":["Endogenous genes regulated by this switch not yet known","HDAC recruitment downstream of mSin3A not directly shown here"]},{"year":2003,"claim":"Linked KLF11 repression to oxidative stress and tumor suppression by showing SID-mSin3A-dependent silencing of SOD2 and Catalase1 sensitizes cells to oxidative stress, with rescue confirming causality.","evidence":"ChIP, adenoviral SOD2/Catalase1 rescue, transgenic mouse, growth/transformation assays","pmids":["12970187"],"confidence":"High","gaps":["Whether antioxidant repression underlies all tumor-suppressive effects unresolved","Tissue specificity of these targets not mapped"]},{"year":2004,"claim":"Connected KLF11 to TGF-β signal amplification and oncogenic Ras: KLF11 represses Smad7 to potentiate TGF-β, and ERK disrupts this in Ras-transformed pancreatic cancer.","evidence":"Reporter, qPCR, Co-IP, in vitro ERK phosphorylation, ERK-insensitive mutant rescue","pmids":["15300592"],"confidence":"High","gaps":["In vivo demonstration in pancreatic tumors not provided","Crosstalk with canonical Smad complexes only partly defined"]},{"year":2004,"claim":"Extended the repressor/activator duality to lipid-regulated and neurotransmitter loci, with KLF11 acting as a cholesterol-sensitive caveolin-1 repressor and a dual regulator of MAO B.","evidence":"RNAi, ChIP, EMSA, reporter assays (caveolin-1); reporter, EMSA, ChIP, enzymatic activity (MAO B)","pmids":["15531587","15024015"],"confidence":"High","gaps":["Mechanism determining activator vs repressor outcome at adjacent elements not fully resolved","In vivo relevance of caveolin-1/MAO B regulation untested here"]},{"year":2005,"claim":"Established KLF11 as a glucose-inducible activator of the insulin gene and revealed a disease-relevant variant (Gln62Arg) that impairs mSin3A binding and insulin promoter activation.","evidence":"Oligonucleotide binding, EMSA, reporter assay, ChIP in pancreatic beta cells","pmids":["15774581"],"confidence":"High","gaps":["How a corepressor-binding variant affects an activation function not mechanistically reconciled","Beta-cell coactivators for insulin activation not identified here"]},{"year":2006,"claim":"Defined a direct KLF11-Smad3 interaction that cooperatively represses c-myc via the TGF-β inhibitory element, disrupted by ERK in oncogenic-Ras cells, deepening the growth-suppression mechanism.","evidence":"Co-IP, GST pulldown, reporter, DNA binding, RNAi, U0126 ERK inhibition","pmids":["17114344"],"confidence":"High","gaps":["Structural basis of KLF11-Smad3 complex unknown","Whether other TIE-containing genes are co-regulated not addressed"]},{"year":2007,"claim":"Mapped KLF11 functional domains and nuclear targeting, showing the N-terminal SID is required for repression and apoptosis while the zinc finger DBD carries bipartite NLS sequences and intrinsic activation capacity.","evidence":"GAL4 reporter assays, EGFP-fusion live imaging, NLS mutation mapping; OLI-neu apoptosis/Bcl-XL assays","pmids":["17252542","17308981"],"confidence":"Medium","gaps":["NLS-binding import machinery not identified","Generality of pro-apoptotic role beyond oligodendroglial cells untested"]},{"year":2008,"claim":"Tied KLF11's pro-apoptotic activity to Smad7 repression in glial cells, showing the SID-dependent disruption of TGF-β negative feedback drives apoptosis.","evidence":"Domain-deletion mutants, Smad7 reporter assay, caspase-3 apoptosis assay in OLI-neu cells","pmids":["18189266"],"confidence":"Medium","gaps":["In vivo neural phenotype not established","Single cell-line system"]},{"year":2009,"claim":"Identified p300 as a KLF11 coactivator engaged through the zinc finger domain to activate Pdx-1, providing a molecular basis for KLF11's activator function in beta cells.","evidence":"Oligonucleotide binding, ChIP at Pdx-1 Area II, GC1/GC2 mutation reporters, in vivo Co-IP with p300","pmids":["19843526"],"confidence":"High","gaps":["Determinants selecting p300 vs mSin3A recruitment unresolved","In vivo beta-cell requirement not tested here"]},{"year":2010,"claim":"Expanded KLF11's activator role into thermogenic and antiproliferative programs, activating UCP1 during brown adipogenesis and mediating progesterone-receptor-coupled suppression of leiomyoma proliferation.","evidence":"UCP1 reporter/ChIP and brown adipocyte differentiation; ChIP-cloning, siRNA, reporter, proliferation assays (PR/leiomyoma)","pmids":["20709022","20124487"],"confidence":"High","gaps":["Coactivators driving UCP1 activation not defined","PR-KLF11 physical interaction not directly shown"]},{"year":2012,"claim":"Established KLF11 as a stress- and hormone-responsive activator of monoamine oxidases and metabolic genes, linking glucocorticoid-induced nuclear translocation to MAO A and identifying PPARα-dependent control of hepatic fatty acid oxidation.","evidence":"KO mice, nuclear/cytoplasmic fractionation, MAO A reporter/activity, stress model; adenoviral gain/loss and PPARα-knockdown epistasis in liver","pmids":["22628545","23183531"],"confidence":"High","gaps":["Signal triggering cytoplasm-to-nucleus translocation not defined","Direct vs indirect PPARα target engagement not fully separated"]},{"year":2013,"claim":"Defined KLF11 as a direct PPARγ co-regulator and target, and broadened its repressive ECM/fibrosis program, integrating metabolic, cerebrovascular-protective, and endometriotic-fibrotic roles.","evidence":"Co-activation screen, Co-IP, KO mouse stroke model; ChIP of collagen/MMP/TGF-β promoters in KO endometriosis model; glycodelin SIN3/HDAC recruitment","pmids":["23408111","23555910","24060634"],"confidence":"High","gaps":["Reciprocal PPARγ-KLF11 feedback dynamics not fully quantified","Mechanism switching KLF11 between fibrotic-gene repression and metabolic activation unresolved"]},{"year":2014,"claim":"Cemented KLF11's role in glucose/lipid homeostasis and drug metabolism, showing PPARγ feed-forward control of adipocyte browning, repression of hepatic gluconeogenic genes, and SIN3A/HDAC-dependent CYP3A4 silencing.","evidence":"ChIP-seq for PPARγ superenhancers and mitochondrial assays; adenoviral hepatocyte gain/loss; CYP3A4 ChIP, SID-mutation and HDAC-inhibitor reversal","pmids":["25504365","24586865","25076120"],"confidence":"High","gaps":["How a single factor coordinates opposing metabolic programs across tissues not mechanistically unified","Gluconeogenic-gene repression mechanism (direct vs PGC-1α-mediated) only partly defined"]},{"year":2017,"claim":"Detailed the TGF-β–KLF11 regulatory loop and an additional activator target (DRD2) in endometriosis, showing non-canonical TGF-β1 control of KLF11 and its downstream Cyp3a/Drd2 outputs.","evidence":"KO mouse endometriosis models with TGFβR1 inhibitor; ChIP and reporter for DRD2","pmids":["27384304","28372535"],"confidence":"Medium","gaps":["Non-SMAD signaling controlling KLF11 expression not defined","Single-lab endometriosis system"]},{"year":2021,"claim":"Established KLF11 as a vascular protective factor and a YAP/TEAD antagonist, repressing tissue factor in SMCs and ECs (including via EGR1 displacement), suppressing thrombosis and aneurysm, and forming a YAP/TEAD negative-feedback loop broken by epigenetic KLF11 silencing.","evidence":"ChIP, Co-IP (KLF11-EGR1; KLF11-YAP/TEAD), tissue-specific KO mice (thrombosis, DVT, AAA), CRISPR screen in sarcoma","pmids":["30602303","34428834","33571129","33507881"],"confidence":"High","gaps":["How SID-mSin3A recruitment to YAP/TEAD sites is targeted not fully resolved","Relationship between vascular and oncogenic YAP roles not integrated"]},{"year":2023,"claim":"Identified KLF11 as a driver of ferroptosis by directly repressing GPX4 in lung adenocarcinoma, increasing chemosensitivity and adding ferroptosis to its tumor-suppressive repertoire.","evidence":"ChIP-seq, ChIP-qPCR, dual luciferase, RNA-seq, GPX4 rescue, in vitro and in vivo overexpression/knockout","pmids":["37248295"],"confidence":"High","gaps":["Whether GPX4 repression uses the SID/mSin3A axis not shown","Generality across other ferroptosis-sensitive tumors untested here"]},{"year":2024,"claim":"Extended KLF11 ferroptosis control to cardiomyocytes via FSP1 repression and revealed protein-level and locus-level regulation through SKP2-mediated degradation and HP1γ-driven enhancer activation, plus an MDM2-dependent p53 suppression mechanism in cancer.","evidence":"AAV9 cardiac models and FSP1 rescue; Co-IP/ubiquitination for SKP2-KLF11; ChIP of HP1γ at Klf11 enhancer; Co-IP and ubiquitination for KLF11-MDM2-p53","pmids":["38725840","38690715","38503899","38810862"],"confidence":"Medium","gaps":["Signals coupling SKP2 activity to KLF11 turnover in disease contexts unclear","How KLF11 (a repressor) raises MDM2 and lowers TP53 mRNA mechanistically not fully resolved"]},{"year":2025,"claim":"Integrated KLF11 into macrophage immunometabolism and atheroprotection through a KLF11-PPARα-YAP1 complex that suppresses glycolysis and activates cholesterol-efflux transporters ABCA1/G1.","evidence":"KO mouse atherosclerosis model, Co-IP defining ternary complex, reporter assays, macrophage gain/loss of function","pmids":["40397286"],"confidence":"Medium","gaps":["Stoichiometry and DNA-binding architecture of the ternary complex undefined","Single-lab finding"]},{"year":2026,"claim":"Positioned KLF11 as a downstream effector of nuclear-receptor (FXR) signaling in renoprotection and as a determinant of DNA-repair-driven radioresistance, broadening its roles into anti-inflammatory and genome-maintenance contexts.","evidence":"FXR ChIP/reporter and genetic KO with JAK2/STAT3 analysis (kidney); Co-IP/IF for KLF11-MDM2, comet and colony assays, xenograft (esophageal cancer)","pmids":["41855776","41655531"],"confidence":"Medium","gaps":["Direct vs indirect KLF11 control of JAK2/STAT3 not resolved","MDM2-E2F1-RAD51 axis defined in a single tumor system only"]},{"year":null,"claim":"It remains unresolved what governs the genome-wide choice between KLF11's repressor (SID-mSin3A/HDAC) and activator (p300/PPARγ) modes at a given GC-rich locus and across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking phosphorylation state, cofactor availability, and local chromatin to activation vs repression","No structural model of KLF11 in repressor vs activator complexes","Tissue-specific cofactor partners only partially catalogued"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,7,12,25,29]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,5,6,7,25,29]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,19,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[17,20,27,34]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8,17,34]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,7,12,25,29]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[16,20,22,34]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,29,30]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[25,26]}],"complexes":["SIN3A/HDAC corepressor complex"],"partners":["SIN3A","SMAD3","EP300","PPARG","PPARA","YAP1","EGR1","MDM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14901","full_name":"Krueppel-like factor 11","aliases":["Transforming growth factor-beta-inducible early growth response protein 2","TGFB-inducible early growth response protein 2","TIEG-2"],"length_aa":512,"mass_kda":55.1,"function":"Transcription factor (PubMed:10207080, PubMed:9748269). Activates the epsilon- and gamma-globin gene promoters and, to a much lower degree, the beta-globin gene and represses promoters containing SP1-like binding inhibiting cell growth (PubMed:10207080, PubMed:16131492, PubMed:9748269). Represses transcription of SMAD7 which enhances TGF-beta signaling (By similarity). Induces apoptosis (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O14901/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLF11","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/KLF11","total_profiled":1310},"omim":[{"mim_id":"610508","title":"MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 7; MODY7","url":"https://www.omim.org/entry/610508"},{"mim_id":"603301","title":"KLF TRANSCRIPTION FACTOR 11; KLF11","url":"https://www.omim.org/entry/603301"},{"mim_id":"125850","title":"MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1; MODY1","url":"https://www.omim.org/entry/125850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Focal adhesion sites","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KLF11"},"hgnc":{"alias_symbol":["Tieg3","MODY7","FKLF"],"prev_symbol":["TIEG2"]},"alphafold":{"accession":"O14901","domains":[{"cath_id":"3.30.160,3.30.160","chopping":"423-450","consensus_level":"medium","plddt":80.3832,"start":423,"end":450},{"cath_id":"-","chopping":"453-498","consensus_level":"medium","plddt":73.75,"start":453,"end":498}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14901","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14901-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14901-F1-predicted_aligned_error_v6.png","plddt_mean":48.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLF11","jax_strain_url":"https://www.jax.org/strain/search?query=KLF11"},"sequence":{"accession":"O14901","fasta_url":"https://rest.uniprot.org/uniprotkb/O14901.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14901/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14901"}},"corpus_meta":[{"pmid":"15774581","id":"PMC_15774581","title":"Role 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38824688","citation_count":5,"is_preprint":false},{"pmid":"35293659","id":"PMC_35293659","title":"KLF11 promotes the progression of glioma via regulating Holliday junction recognition protein.","date":"2022","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/35293659","citation_count":4,"is_preprint":false},{"pmid":"32524199","id":"PMC_32524199","title":"DNA hypomethylation of the Krüppel-like factor 11 (KLF11) gene promoter: a putative biomarker of depression comorbidity in panic disorder and of non-anxious depression?","date":"2020","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/32524199","citation_count":4,"is_preprint":false},{"pmid":"38810862","id":"PMC_38810862","title":"KLF11 promotes the proliferation of breast cancer cells by inhibiting p53-MDM2 signaling.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/38810862","citation_count":3,"is_preprint":false},{"pmid":"38275797","id":"PMC_38275797","title":"miR-10a-5p Regulates the Proliferation and Differentiation of Porcine Preadipocytes Targeting the KLF11 Gene.","date":"2024","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/38275797","citation_count":2,"is_preprint":false},{"pmid":"38368567","id":"PMC_38368567","title":"Effects of KLF11 on Vascular Smooth Muscle Cells and its Underlying Mechanisms in Intracranial Aneurysm.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38368567","citation_count":2,"is_preprint":false},{"pmid":"39193968","id":"PMC_39193968","title":"A Novel KLF11 c.793G>A (p.Glu265Lys) Variant Identified in a Chinese Family with Controversial Association with MODY7.","date":"2024","source":"Clinical 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Proliferation.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41462975","citation_count":0,"is_preprint":false},{"pmid":"41855776","id":"PMC_41855776","title":"FXR-mediated transcriptional regulation of KLF11 mitigates contrast-induced acute kidney injury via suppressing JAK2/STAT3 pathway.","date":"2026","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41855776","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45965,"output_tokens":9237,"usd":0.138225,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19269,"output_tokens":7126,"usd":0.137247,"stage2_stop_reason":"end_turn"},"total_usd":0.275472,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"KLF11 (TIEG2) is a nuclear protein that specifically binds to Sp1-like (GC-rich) DNA sequences in vitro and represses promoters containing Sp1-like binding sites; overexpression inhibits cell proliferation in CHO cells.\",\n      \"method\": \"Nuclear fractionation, in vitro DNA-binding assay, luciferase reporter assay, [3H]thymidine/MTS proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (DNA binding, reporter assay, proliferation assay) in a foundational characterization paper, independently replicated in subsequent work\",\n      \"pmids\": [\"9748269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"KLF11 (FKLF) acts as a transcriptional activator of the gamma- and epsilon-globin gene promoters via the CACCC box in erythroid cells; transfection of KLF11 cDNA into K562 cells enhanced endogenous epsilon- and gamma-globin gene expression.\",\n      \"method\": \"Luciferase reporter assay with CACCC box deletion constructs, transfection into K562 erythroid cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with deletion mapping plus endogenous gene expression, single lab\",\n      \"pmids\": [\"10207080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The Mad1-like Sin3-interacting domain (SID) of KLF11 (TIEG2) binds mSin3A to mediate transcriptional repression; this interaction is disrupted by EGF-Ras-MEK1-ERK2 signaling via phosphorylation of four serine/threonine sites adjacent to the SID, thereby inhibiting KLF11's repression activity.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase assay, reporter assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation, mutagenesis of phospho-sites, Co-IP confirming disrupted SID-mSin3A interaction; replicated in subsequent work\",\n      \"pmids\": [\"12006497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KLF11 represses transcription of SOD2 and Catalase1 promoters via its Mad1-like SID-mSin3A interaction; this repression renders cells more sensitive to oxidative stress, an effect rescuable by adenoviral SOD2/Catalase1 re-expression. KLF11 also inhibits neoplastic transformation and cell growth in vitro and in vivo.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), adenoviral rescue experiment, transgenic mouse model, cell growth/transformation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirming direct promoter occupancy, in vivo transgenic model, mechanistic rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"12970187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KLF11 represses Smad7 transcription by recruiting mSin3A via GC-rich sites on the Smad7 promoter, thereby potentiating TGF-β signaling. In pancreatic cancer cells with oncogenic Ras, ERK phosphorylates KLF11 and disrupts KLF11-mSin3A interaction; an ERK-insensitive KLF11 mutant restores mSin3A binding and Smad7 repression.\",\n      \"method\": \"Reporter assay, real-time PCR, co-immunoprecipitation, in vitro ERK phosphorylation, site-directed mutagenesis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-IP, in vitro kinase assay, mutagenesis restoring function, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"15300592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KLF11 binds to an Sp1 site flanking the SRE in the caveolin-1 promoter and acts as a dominant repressor. Cholesterol depletion displaces KLF11 from this site (via down-regulation of KLF11 expression and competition by Sp1), enabling SREBP/Sp1-mediated activation of caveolin-1 transcription.\",\n      \"method\": \"RNA interference, chromatin immunoprecipitation, EMSA, luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — four orthogonal methods (RNAi, ChIP, EMSA, reporter) in single study demonstrating mechanism\",\n      \"pmids\": [\"15531587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KLF11 (TIEG2) acts as a transcriptional activator of MAO B gene expression via Sp1 sites, and as a repressor at the CACCC element; gel-shift and ChIP confirmed direct binding to both elements in the MAO B core promoter.\",\n      \"method\": \"Cotransfection reporter assays, gel-shift (EMSA), chromatin immunoprecipitation, RT-PCR, western blot, MAO B catalytic activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, EMSA, promoter deletion, mRNA, protein, enzymatic activity), single lab\",\n      \"pmids\": [\"15024015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KLF11 binds the insulin promoter at GC-rich sites and activates its transcriptional activity in pancreatic beta cells, as a glucose-inducible regulator. The Gln62Arg variant impairs mSin3A-binding activity of KLF11 and reduces insulin promoter activation.\",\n      \"method\": \"Random oligonucleotide binding assay, EMSA, luciferase reporter assay, chromatin immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — four orthogonal assays establishing DNA binding, promoter occupancy, and transcriptional activation in beta cells\",\n      \"pmids\": [\"15774581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KLF11 cooperates with Smad3 to repress c-myc transcription via the TGF-β inhibitory element (TIE) in the c-myc promoter; ERK hyperactivation in pancreatic cancer cells with oncogenic Ras disrupts KLF11-Smad3 complex formation and KLF11-Smad3 binding to the TIE, preventing c-myc repression and growth inhibition.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, reporter assay, DNA binding assay, RNA interference, U0126 ERK inhibitor treatment\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP and GST pulldown define direct KLF11-Smad3 interaction; mechanistic rescue by ERK inhibition; multiple orthogonal methods\",\n      \"pmids\": [\"17114344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KLF11 (TIEG2) induces caspase-3-dependent apoptosis in oligodendroglial OLI-neu cells and decreases Bcl-XL levels by repressing the Bcl-XL promoter; the N-terminal repression domains (including the SID) are required for pro-apoptotic activity.\",\n      \"method\": \"Overexpression in OLI-neu cells, caspase-3 activation assay, western blot (Bcl-XL), reporter assay with Bcl-XL promoter\",\n      \"journal\": \"Journal of neural transmission\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus protein-level validation in defined cell system, single lab\",\n      \"pmids\": [\"17308981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The amino-terminus of KLF11 (Tieg3) is essential for transcriptional repression; the SID within this domain is required for repressive activity. The zinc finger DNA-binding domain (DBD) alone can activate transcription and contains two closely located putative bipartite nuclear localization signals (NLS) within the second and third zinc fingers that are necessary and sufficient for nuclear localization.\",\n      \"method\": \"GAL4-based luciferase assays, EGFP-fusion protein localization (live imaging), NLS deletion/mutation mapping\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain mapping with reporter assay and direct imaging of localization, single lab\",\n      \"pmids\": [\"17252542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KLF11 (Tieg3) enhances TGF-β signaling in oligodendroglial cells by transcriptionally repressing Smad7, disrupting the negative feedback loop; loss of the N-terminal repression domains (including SID) abolishes both the pro-apoptotic function and Smad7 repression.\",\n      \"method\": \"Overexpression/deletion mutants in OLI-neu cells, reporter assay on Smad7 promoter, apoptosis/caspase-3 assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with domain-deletion mutants, functional apoptosis readout, single lab\",\n      \"pmids\": [\"18189266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KLF11 activates Pdx-1 transcription in pancreatic beta cells through two evolutionarily conserved GC-rich elements (GC1 and GC2) in the Pdx-1 Area II control region; KLF11 associates with Area II by ChIP and interacts with the coactivator p300 via its zinc finger domain in vivo to mediate this activation.\",\n      \"method\": \"Random oligonucleotide binding analysis, ChIP, luciferase reporter assay with GC1/GC2 mutations, co-immunoprecipitation (in vivo interaction with p300)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, in vivo Co-IP, reporter assays with specific element mutations, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19843526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KLF11 directly binds the UCP1 promoter via GC-box elements and activates UCP1 transcription; KLF11 is required for UCP1 expression during brown adipocyte differentiation of muBM3.1 mesenchymal stem cells.\",\n      \"method\": \"Reporter assay with UCP1 promoter, ChIP/DNA binding assay, brown adipocyte differentiation model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay and functional knockdown, single lab\",\n      \"pmids\": [\"20709022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KLF11 integrates progesterone receptor (PR) signaling to inhibit uterine leiomyoma cell proliferation. PR knockdown increases KLF11 expression; KLF11 knockdown abolishes the antiproliferative effect of RU486. KLF11 basal promoter and a distal PR-binding region (20.5 kb upstream) containing Sp1 sites (not classical PREs) recruit Sp1, RNA Pol II, PR, SRC-1 and SRC-2.\",\n      \"method\": \"ChIP-cloning to identify PR-binding site, luciferase reporter assay, siRNA knockdown of PR and KLF11, proliferation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-based discovery, siRNA functional rescue, reporter assay; multiple orthogonal approaches\",\n      \"pmids\": [\"20124487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Glucocorticoids (dexamethasone) induce KLF11 mRNA and protein in neurons; KLF11 then translocates from cytoplasm to nucleus and activates the MAO A promoter via Sp/KLF-binding sites, increasing MAO A mRNA and enzymatic activity. KLF11 knockout mice show reduced brain cortex MAO A expression; chronic social defeat stress activates the KLF11 pathway in rat brain with increased MAO A.\",\n      \"method\": \"siRNA knockdown, KLF11 overexpression, KLF11 knockout mice, nuclear/cytoplasmic fractionation, MAO A promoter reporter, MAO A catalytic activity assay, in vivo stress model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods including KO mouse, subcellular fractionation, enzymatic activity; replicated in vivo\",\n      \"pmids\": [\"22628545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KLF11 overexpression in mouse livers activates the PPARα signaling pathway to improve fatty liver by promoting fatty acid oxidation; KLF11 knockdown decreases fatty acid oxidation and raises hepatic TG levels. PPARα knockdown abolishes KLF11's effects on fatty acid oxidation genes and hepatic TG.\",\n      \"method\": \"Adenoviral overexpression/shRNA in db/db and DIO mice, histology, biochemical TG assay, epistasis by co-injection with Ad-shPPARα\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function in multiple mouse models with genetic epistasis (PPARα rescue), multiple metabolic readouts\",\n      \"pmids\": [\"23183531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KLF11 interacts with PPARγ and acts as a novel PPARγ co-regulator; KLF11 is also a direct transcriptional target of PPARγ. KLF11 deficiency abolishes pioglitazone-mediated cerebrovascular protection and PPARγ transcriptional suppression of pro-apoptotic miR-15a in endothelial cells.\",\n      \"method\": \"Genome-wide co-activation screen, co-immunoprecipitation, KLF11 knockout mouse, oxygen-glucose deprivation cell model, MCAO stroke model\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP confirming physical interaction, KO mouse in vivo stroke model, loss-of-function rescue experiments; multiple orthogonal methods\",\n      \"pmids\": [\"23408111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KLF11 binds specific GC-rich promoter elements of collagen, MMP, and TGF-β family genes in endometrial stromal cells and represses their transcription; KLF11 deficiency in mice leads to large fibrotic endometriotic lesions resembling advanced human disease.\",\n      \"method\": \"ChIP of endometrial stromal cell promoters, Klf11 knockout mouse endometriosis model, comparison with Klf9 knockout\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP of specific promoters, KO mouse with specific phenotype, specificity validated by parallel Klf9 KO control\",\n      \"pmids\": [\"23555910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KLF11 epigenetically represses glycodelin-A expression in endometrial cells by binding two regulatory elements in the glycodelin promoter and recruiting the SIN3/HDAC corepressor complex, resulting in transcriptional repression.\",\n      \"method\": \"ChIP, reporter assay, mRNA and protein expression analysis, SIN3/HDAC corepressor recruitment assay\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional reporter assay plus corepressor recruitment, single lab\",\n      \"pmids\": [\"24060634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF11 is required for rosiglitazone-induced browning of human adipocytes; it is directly induced by PPARγ and cooperates with PPARγ in a feed-forward manner to activate the brite-selective gene program and increase mitochondrial oxidative capacity. KLF11 is associated with PPARγ superenhancers selective for brite adipocytes.\",\n      \"method\": \"siRNA knockdown of KLF11 in human adipocytes, ChIP-seq for PPARγ superenhancers, mitochondrial oxidative capacity measurement, gene expression profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, functional knockdown, mitochondrial functional assay; multiple orthogonal methods in human primary cells\",\n      \"pmids\": [\"25504365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF11 binds CYP3A4 promoter GC elements and recruits SIN3A/HDAC corepressor, causing selective histone deacetylation of the CYP3A4 promoter and repressing CYP3A4 mRNA, protein, and enzymatic activity in endometrial cells. A KLF11 mutation abrogating cofactor recruitment reverses this repression.\",\n      \"method\": \"ChIP (KLF11 at CYP3A4 promoter), SIN3A/HDAC corepressor co-localization, reporter assay, mRNA/protein/enzyme activity assays, HDAC inhibitor pharmacological reversal, SID-mutation rescue\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, mutagenesis, pharmacological reversal, multiple functional readouts, single lab with orthogonal methods\",\n      \"pmids\": [\"25076120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF11 suppresses hepatic gluconeogenesis by repressing PEPCK-C and PGC-1α gene expression in primary hepatocytes; adenoviral overexpression of KLF11 in diabetic mouse livers improves hyperglycemia, while KLF11 knockdown impairs glucose tolerance.\",\n      \"method\": \"Adenoviral overexpression/knockdown in primary mouse hepatocytes and in vivo mouse models, glucose output assay, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo, single lab\",\n      \"pmids\": [\"24586865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TGF-β1 causes non-canonical (non-SMAD-mediated) transient up-regulation then sustained repression of KLF11, while KLF11 epigenetically represses CYP3A4 via SIN3A/HDAC. KLF11-deficient mice treated with TGF-β receptor inhibitor show reduced endometriotic progression and Cyp3a expression.\",\n      \"method\": \"Klf11 knockout mouse endometriosis model, TGFβR1 inhibitor treatment, histone acetyltransferase inhibitor, Cyp3a expression analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse plus pharmacological combination in vivo, single lab\",\n      \"pmids\": [\"27384304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLF11 binds to the DRD2 promoter and transcriptionally activates DRD2 in endometrial cells; in Klf11-/- mice with endometriosis, lesions show progressive fibrosis and decreased Drd2 expression consistent with loss of KLF11-mediated activation.\",\n      \"method\": \"ChIP, promoter reporter assay, Klf11-/- mouse endometriosis model, gene expression analysis\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter with in vivo KO model, single lab\",\n      \"pmids\": [\"28372535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KLF11 transcriptionally suppresses the tissue factor (F3) gene in vascular smooth muscle cells via direct promoter binding (ChIP), reducing arterial thrombosis. Smooth muscle cell-specific Klf11 KO mice show reduced occlusion time in ferric chloride thrombosis model, not rescued by bone marrow transplant.\",\n      \"method\": \"Reporter assay, ChIP, siRNA knockdown and adenoviral overexpression in human aortic smooth muscle cells, conditional SMC-specific KO mouse, ferric chloride thrombosis model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirming direct promoter occupancy, tissue-specific KO mouse model, gain- and loss-of-function in primary cells\",\n      \"pmids\": [\"30602303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In venous endothelial cells under prothrombotic conditions, KLF11 reduces TNF-α-induced tissue factor (TF) gene transcription by inhibiting EGR1 binding to the TF promoter, as demonstrated by reporter assay, ChIP, and co-immunoprecipitation. Klf11 KO mice are more susceptible to stasis-induced DVT.\",\n      \"method\": \"Reporter gene assay, ChIP, co-immunoprecipitation (KLF11-EGR1), gain- and loss-of-function in ECs, Klf11 KO mouse deep vein thrombosis model\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP defining protein-protein interaction, ChIP, reporter assay, in vivo KO model\",\n      \"pmids\": [\"34428834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KLF11 and YAP/TEAD bind adjacent DNA sites and directly interact; KLF11 recruits SIN3A/HDAC to suppress YAP/TEAD transcriptional output, while YAP/TEAD promotes KLF11 transcription, forming a negative feedback loop that is broken by epigenetic silencing of KLF11 in sarcoma cancer stem cells.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, co-immunoprecipitation (KLF11-YAP/TEAD), ChIP, KLF11 overexpression/knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus Co-IP, ChIP, and in vivo experiments; multiple orthogonal methods\",\n      \"pmids\": [\"33571129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endothelial KLF11 deficiency aggravates AAA formation, while EC-selective overexpression inhibits it. KLF11 inhibits EC inflammatory response, suppresses MMP9 expression and activity, and reduces NADPH oxidase 2-mediated ROS in ECs; KLF11-deficient ECs also induce smooth muscle cell dedifferentiation and apoptosis.\",\n      \"method\": \"EC-specific KLF11 transgenic and knockout mice, elastase- and PCSK9/AngII-induced AAA mouse models, gain- and loss-of-function in cultured ECs\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent in vivo AAA models, EC-specific transgenic and KO, multiple mechanistic readouts\",\n      \"pmids\": [\"33507881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KLF11 binds the GPX4 promoter region and represses its transcription in lung adenocarcinoma cells, promoting ferroptosis and increasing chemosensitivity; ChIP-seq and ChIP-qPCR confirmed GPX4 as a direct KLF11 target, and GPX4 restoration antagonized KLF11-induced ferroptosis.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, dual luciferase assay, RNA-seq, KLF11 overexpression/knockout in vitro and in vivo\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq plus ChIP-qPCR plus luciferase assay, GPX4 rescue experiment, in vivo xenograft\",\n      \"pmids\": [\"37248295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KLF11 promotes ferroptosis in cardiomyocytes by suppressing FSP1 transcription; KLF11 is induced by sorafenib and its overexpression or FSP1 knockdown both increase ferroptotic cell death. Cardiac-specific AAV9-mediated KLF11 silencing or FSP1 overexpression improved cardiac dysfunction in sorafenib-treated mice.\",\n      \"method\": \"Transcriptome profiling, KLF11 overexpression/knockdown in cardiomyocytes, AAV9 cardiac-specific delivery in mice, FSP1 rescue experiment, GPX4 epistasis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV9 cardiac model plus in vitro mechanistic epistasis, single lab\",\n      \"pmids\": [\"38725840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKP2 E3 ubiquitin ligase triggers K48-linked ubiquitination and proteasomal degradation of KLF11 in chondrocytes; loss of KLF11 transcriptionally activates JMJD3, which demethylates H3K27me3 to activate NOTCH1, promoting OA progression. KLF11 overexpression in vivo delays OA development.\",\n      \"method\": \"Co-immunoprecipitation (SKP2-KLF11), ubiquitination assay, ChIP (KLF11 on JMJD3 promoter), H3K27me3 analysis, in vivo rat OA model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/ubiquitination assay plus ChIP, single lab with in vivo corroboration\",\n      \"pmids\": [\"38690715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CGRP increases phosphorylated HP1γ (p-HP1γ) recruitment to the Klf11 enhancer (confirmed by ChIP), which epigenetically activates KLF11 expression; increased KLF11 in turn activates MAOB, depleting dopamine in the dorsal hippocampus and inducing anxiety-like behaviors.\",\n      \"method\": \"Chromatin immunoprecipitation (HP1γ at Klf11 enhancer), intracerebroventricular CGRP injection, MAOB pharmacological inhibition and knockdown in mice\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming HP1γ at KLF11 enhancer, in vivo pharmacological and genetic validation, single lab\",\n      \"pmids\": [\"38503899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KLF11 promotes breast cancer cell proliferation by reducing TP53 mRNA transcription and by interacting with MDM2 protein to inhibit MDM2 ubiquitination/degradation, thereby increasing MDM2 levels and accelerating ubiquitin-mediated p53 proteolysis and reducing CDKN1A/BAX/NOXA1.\",\n      \"method\": \"Co-immunoprecipitation (KLF11-MDM2), ubiquitination assay, RT-qPCR, western blot, in vivo xenograft\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay establishing protein interaction and mechanistic consequence, single lab\",\n      \"pmids\": [\"38810862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLF11 forms a transcriptional complex with PPARα and YAP1 in macrophages; KLF11 suppresses PPARα-YAP1-mediated glycolysis and acts as a transcriptional activator of ABCA1/G1. KLF11 knockout abolishes wogonin's inhibitory effect on glycolysis and atherosclerosis.\",\n      \"method\": \"KLF11 KO mouse atherosclerosis model, co-immunoprecipitation (KLF11-PPARα-YAP1 complex), reporter assay, gain- and loss-of-function in macrophages\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defining ternary complex, KO mouse, reporter assay; single lab\",\n      \"pmids\": [\"40397286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FXR directly binds to a FXRE sequence in the KLF11 promoter (confirmed by luciferase reporter and ChIP) and transcriptionally upregulates KLF11; KLF11 then suppresses the JAK2/STAT3 pathway to reduce renal inflammation and apoptosis in contrast-induced AKI. FXR or KLF11 genetic deletion abolishes FXR agonist (CDCA) renoprotection.\",\n      \"method\": \"Luciferase reporter assay, ChIP (FXR at KLF11 promoter), KLF11 knockdown and FXR KO models, JAK2/STAT3 pathway analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus genetic KO establishing FXR→KLF11→JAK2/STAT3 epistasis, single lab\",\n      \"pmids\": [\"41855776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KLF11 promotes MDM2 expression, which inhibits E2F1 ubiquitination and stabilizes E2F1, enhancing RAD51-mediated homologous recombination DNA repair and conferring radioresistance in esophageal cancer cells. Co-immunoprecipitation and immunofluorescence confirmed KLF11-MDM2 protein interaction.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, neutral comet assay, colony formation/apoptosis assays, in vivo xenograft, RT-qPCR/western blot\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing protein interaction, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"41655531\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLF11 is a TGF-β-inducible Sp1/KLF-family zinc finger transcription factor that localizes to the nucleus via NLS sequences in its zinc finger domain, binds GC-rich (Sp1-like) DNA elements, and can act as either a repressor or activator depending on context: as a repressor it recruits the SIN3A/HDAC corepressor complex via its Mad1-like SID domain to silence target genes (Smad7, SOD2, Catalase1, GPX4, FSP1, tissue factor F3, collagen/MMP/TGF-β family genes, CYP3A4), while as an activator it interacts with coactivators such as p300 (via its zinc finger domain) or PPARγ to transactivate targets like the insulin gene, Pdx-1, UCP1, MAO A/B, DRD2, and ABCA1/G1; its repressive activity is regulated by ERK/MAPK phosphorylation of serine/threonine sites adjacent to the SID (disrupting SID-mSin3A interaction), by SKP2-mediated ubiquitination and degradation, and by epigenetic silencing of the KLF11 locus itself, placing KLF11 at the intersection of TGF-β signaling amplification, oxidative stress response, metabolic regulation (insulin/glucose/lipid homeostasis), vascular homeostasis, and ferroptosis control.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLF11 is an Sp1/KLF-family zinc finger transcription factor that binds GC-rich (Sp1-like) DNA elements and functions as a context-dependent repressor or activator, positioning it at the intersection of TGF-\\u03b2 signaling, oxidative stress, metabolic homeostasis, and ferroptosis control [#0, #3, #4]. Its repressive activity depends on an N-terminal Mad1-like Sin3-interacting domain (SID) that recruits the mSin3A/HDAC corepressor complex to silence targets such as SOD2 and Catalase1, Smad7, CYP3A4, and glycodelin-A [#2, #3, #19, #21]; nuclear localization is conferred by bipartite NLS sequences within its zinc finger DNA-binding domain, which alone can activate transcription [#10]. This SID-mSin3A interaction is the principal regulated node: EGF\\u2013Ras\\u2013MEK\\u2013ERK phosphorylation of serine/threonine sites flanking the SID disrupts corepressor binding and abolishes repression, a switch exploited in oncogenic-Ras pancreatic cancer to relieve KLF11-mediated repression of Smad7 and, with Smad3, of c-myc [#2, #4, #8]. As an activator KLF11 engages coactivators including p300 and PPAR\\u03b3 to transactivate metabolic and developmental targets, driving insulin and Pdx-1 expression in beta cells, UCP1 and the brite/brown adipocyte program, hepatic PPAR\\u03b1-dependent fatty acid oxidation, and ABCA1/G1 [#7, #12, #13, #16, #20, #34]. KLF11 enforces vascular homeostasis by repressing tissue factor (F3) in smooth muscle and endothelial cells\\u2014partly by blocking EGR1 promoter binding\\u2014and by limiting EC inflammation and ROS to suppress thrombosis and abdominal aortic aneurysm [#25, #26, #28]. In tumor and tissue-protective contexts it represses GPX4 and FSP1 to promote ferroptosis, suppresses YAP/TEAD output via SIN3A/HDAC recruitment, and modulates p53 through MDM2 interaction [#27, #29, #30, #33]. KLF11 protein and locus abundance are themselves controlled by SKP2-mediated K48 ubiquitination and proteasomal degradation and by epigenetic activation/silencing of the KLF11 enhancer [#27, #31, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established KLF11 as a nuclear, sequence-specific transcription factor, defining its core biochemical identity as an Sp1-like GC-box binder that represses transcription and restrains proliferation.\",\n      \"evidence\": \"Nuclear fractionation, in vitro DNA-binding, luciferase reporter, and proliferation assays in CHO cells\",\n      \"pmids\": [\"9748269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the corepressor machinery or physiological target genes\", \"Repression mechanism at endogenous loci not yet defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed KLF11 can also act as an activator, binding the CACCC box to enhance gamma/epsilon-globin transcription, foreshadowing its dual repressor/activator behavior.\",\n      \"evidence\": \"CACCC-box deletion reporter assays and endogenous globin expression in K562 erythroid cells\",\n      \"pmids\": [\"10207080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coactivator partners not identified\", \"Physiological role in erythropoiesis not tested in vivo\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the molecular basis of KLF11 repression and its regulation: the Mad1-like SID recruits mSin3A, and ERK phosphorylation of SID-flanking residues disrupts this interaction, defining a MAPK-controlled repression switch.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis, in vitro kinase assay, reporter assay\",\n      \"pmids\": [\"12006497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous genes regulated by this switch not yet known\", \"HDAC recruitment downstream of mSin3A not directly shown here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked KLF11 repression to oxidative stress and tumor suppression by showing SID-mSin3A-dependent silencing of SOD2 and Catalase1 sensitizes cells to oxidative stress, with rescue confirming causality.\",\n      \"evidence\": \"ChIP, adenoviral SOD2/Catalase1 rescue, transgenic mouse, growth/transformation assays\",\n      \"pmids\": [\"12970187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether antioxidant repression underlies all tumor-suppressive effects unresolved\", \"Tissue specificity of these targets not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected KLF11 to TGF-\\u03b2 signal amplification and oncogenic Ras: KLF11 represses Smad7 to potentiate TGF-\\u03b2, and ERK disrupts this in Ras-transformed pancreatic cancer.\",\n      \"evidence\": \"Reporter, qPCR, Co-IP, in vitro ERK phosphorylation, ERK-insensitive mutant rescue\",\n      \"pmids\": [\"15300592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration in pancreatic tumors not provided\", \"Crosstalk with canonical Smad complexes only partly defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the repressor/activator duality to lipid-regulated and neurotransmitter loci, with KLF11 acting as a cholesterol-sensitive caveolin-1 repressor and a dual regulator of MAO B.\",\n      \"evidence\": \"RNAi, ChIP, EMSA, reporter assays (caveolin-1); reporter, EMSA, ChIP, enzymatic activity (MAO B)\",\n      \"pmids\": [\"15531587\", \"15024015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism determining activator vs repressor outcome at adjacent elements not fully resolved\", \"In vivo relevance of caveolin-1/MAO B regulation untested here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established KLF11 as a glucose-inducible activator of the insulin gene and revealed a disease-relevant variant (Gln62Arg) that impairs mSin3A binding and insulin promoter activation.\",\n      \"evidence\": \"Oligonucleotide binding, EMSA, reporter assay, ChIP in pancreatic beta cells\",\n      \"pmids\": [\"15774581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a corepressor-binding variant affects an activation function not mechanistically reconciled\", \"Beta-cell coactivators for insulin activation not identified here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a direct KLF11-Smad3 interaction that cooperatively represses c-myc via the TGF-\\u03b2 inhibitory element, disrupted by ERK in oncogenic-Ras cells, deepening the growth-suppression mechanism.\",\n      \"evidence\": \"Co-IP, GST pulldown, reporter, DNA binding, RNAi, U0126 ERK inhibition\",\n      \"pmids\": [\"17114344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of KLF11-Smad3 complex unknown\", \"Whether other TIE-containing genes are co-regulated not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped KLF11 functional domains and nuclear targeting, showing the N-terminal SID is required for repression and apoptosis while the zinc finger DBD carries bipartite NLS sequences and intrinsic activation capacity.\",\n      \"evidence\": \"GAL4 reporter assays, EGFP-fusion live imaging, NLS mutation mapping; OLI-neu apoptosis/Bcl-XL assays\",\n      \"pmids\": [\"17252542\", \"17308981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NLS-binding import machinery not identified\", \"Generality of pro-apoptotic role beyond oligodendroglial cells untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Tied KLF11's pro-apoptotic activity to Smad7 repression in glial cells, showing the SID-dependent disruption of TGF-\\u03b2 negative feedback drives apoptosis.\",\n      \"evidence\": \"Domain-deletion mutants, Smad7 reporter assay, caspase-3 apoptosis assay in OLI-neu cells\",\n      \"pmids\": [\"18189266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo neural phenotype not established\", \"Single cell-line system\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified p300 as a KLF11 coactivator engaged through the zinc finger domain to activate Pdx-1, providing a molecular basis for KLF11's activator function in beta cells.\",\n      \"evidence\": \"Oligonucleotide binding, ChIP at Pdx-1 Area II, GC1/GC2 mutation reporters, in vivo Co-IP with p300\",\n      \"pmids\": [\"19843526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting p300 vs mSin3A recruitment unresolved\", \"In vivo beta-cell requirement not tested here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Expanded KLF11's activator role into thermogenic and antiproliferative programs, activating UCP1 during brown adipogenesis and mediating progesterone-receptor-coupled suppression of leiomyoma proliferation.\",\n      \"evidence\": \"UCP1 reporter/ChIP and brown adipocyte differentiation; ChIP-cloning, siRNA, reporter, proliferation assays (PR/leiomyoma)\",\n      \"pmids\": [\"20709022\", \"20124487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivators driving UCP1 activation not defined\", \"PR-KLF11 physical interaction not directly shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established KLF11 as a stress- and hormone-responsive activator of monoamine oxidases and metabolic genes, linking glucocorticoid-induced nuclear translocation to MAO A and identifying PPAR\\u03b1-dependent control of hepatic fatty acid oxidation.\",\n      \"evidence\": \"KO mice, nuclear/cytoplasmic fractionation, MAO A reporter/activity, stress model; adenoviral gain/loss and PPAR\\u03b1-knockdown epistasis in liver\",\n      \"pmids\": [\"22628545\", \"23183531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering cytoplasm-to-nucleus translocation not defined\", \"Direct vs indirect PPAR\\u03b1 target engagement not fully separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined KLF11 as a direct PPAR\\u03b3 co-regulator and target, and broadened its repressive ECM/fibrosis program, integrating metabolic, cerebrovascular-protective, and endometriotic-fibrotic roles.\",\n      \"evidence\": \"Co-activation screen, Co-IP, KO mouse stroke model; ChIP of collagen/MMP/TGF-\\u03b2 promoters in KO endometriosis model; glycodelin SIN3/HDAC recruitment\",\n      \"pmids\": [\"23408111\", \"23555910\", \"24060634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reciprocal PPAR\\u03b3-KLF11 feedback dynamics not fully quantified\", \"Mechanism switching KLF11 between fibrotic-gene repression and metabolic activation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Cemented KLF11's role in glucose/lipid homeostasis and drug metabolism, showing PPAR\\u03b3 feed-forward control of adipocyte browning, repression of hepatic gluconeogenic genes, and SIN3A/HDAC-dependent CYP3A4 silencing.\",\n      \"evidence\": \"ChIP-seq for PPAR\\u03b3 superenhancers and mitochondrial assays; adenoviral hepatocyte gain/loss; CYP3A4 ChIP, SID-mutation and HDAC-inhibitor reversal\",\n      \"pmids\": [\"25504365\", \"24586865\", \"25076120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single factor coordinates opposing metabolic programs across tissues not mechanistically unified\", \"Gluconeogenic-gene repression mechanism (direct vs PGC-1\\u03b1-mediated) only partly defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Detailed the TGF-\\u03b2\\u2013KLF11 regulatory loop and an additional activator target (DRD2) in endometriosis, showing non-canonical TGF-\\u03b21 control of KLF11 and its downstream Cyp3a/Drd2 outputs.\",\n      \"evidence\": \"KO mouse endometriosis models with TGF\\u03b2R1 inhibitor; ChIP and reporter for DRD2\",\n      \"pmids\": [\"27384304\", \"28372535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-SMAD signaling controlling KLF11 expression not defined\", \"Single-lab endometriosis system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established KLF11 as a vascular protective factor and a YAP/TEAD antagonist, repressing tissue factor in SMCs and ECs (including via EGR1 displacement), suppressing thrombosis and aneurysm, and forming a YAP/TEAD negative-feedback loop broken by epigenetic KLF11 silencing.\",\n      \"evidence\": \"ChIP, Co-IP (KLF11-EGR1; KLF11-YAP/TEAD), tissue-specific KO mice (thrombosis, DVT, AAA), CRISPR screen in sarcoma\",\n      \"pmids\": [\"30602303\", \"34428834\", \"33571129\", \"33507881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SID-mSin3A recruitment to YAP/TEAD sites is targeted not fully resolved\", \"Relationship between vascular and oncogenic YAP roles not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified KLF11 as a driver of ferroptosis by directly repressing GPX4 in lung adenocarcinoma, increasing chemosensitivity and adding ferroptosis to its tumor-suppressive repertoire.\",\n      \"evidence\": \"ChIP-seq, ChIP-qPCR, dual luciferase, RNA-seq, GPX4 rescue, in vitro and in vivo overexpression/knockout\",\n      \"pmids\": [\"37248295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPX4 repression uses the SID/mSin3A axis not shown\", \"Generality across other ferroptosis-sensitive tumors untested here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended KLF11 ferroptosis control to cardiomyocytes via FSP1 repression and revealed protein-level and locus-level regulation through SKP2-mediated degradation and HP1\\u03b3-driven enhancer activation, plus an MDM2-dependent p53 suppression mechanism in cancer.\",\n      \"evidence\": \"AAV9 cardiac models and FSP1 rescue; Co-IP/ubiquitination for SKP2-KLF11; ChIP of HP1\\u03b3 at Klf11 enhancer; Co-IP and ubiquitination for KLF11-MDM2-p53\",\n      \"pmids\": [\"38725840\", \"38690715\", \"38503899\", \"38810862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals coupling SKP2 activity to KLF11 turnover in disease contexts unclear\", \"How KLF11 (a repressor) raises MDM2 and lowers TP53 mRNA mechanistically not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated KLF11 into macrophage immunometabolism and atheroprotection through a KLF11-PPAR\\u03b1-YAP1 complex that suppresses glycolysis and activates cholesterol-efflux transporters ABCA1/G1.\",\n      \"evidence\": \"KO mouse atherosclerosis model, Co-IP defining ternary complex, reporter assays, macrophage gain/loss of function\",\n      \"pmids\": [\"40397286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and DNA-binding architecture of the ternary complex undefined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Positioned KLF11 as a downstream effector of nuclear-receptor (FXR) signaling in renoprotection and as a determinant of DNA-repair-driven radioresistance, broadening its roles into anti-inflammatory and genome-maintenance contexts.\",\n      \"evidence\": \"FXR ChIP/reporter and genetic KO with JAK2/STAT3 analysis (kidney); Co-IP/IF for KLF11-MDM2, comet and colony assays, xenograft (esophageal cancer)\",\n      \"pmids\": [\"41855776\", \"41655531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect KLF11 control of JAK2/STAT3 not resolved\", \"MDM2-E2F1-RAD51 axis defined in a single tumor system only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what governs the genome-wide choice between KLF11's repressor (SID-mSin3A/HDAC) and activator (p300/PPAR\\u03b3) modes at a given GC-rich locus and across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking phosphorylation state, cofactor availability, and local chromatin to activation vs repression\", \"No structural model of KLF11 in repressor vs activator complexes\", \"Tissue-specific cofactor partners only partially catalogued\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 7, 12, 25, 29]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 5, 6, 7, 25, 29]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 19, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 20, 27, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 17, 34]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 7, 12, 25, 29]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [16, 20, 22, 34]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 29, 30]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [25, 26]}\n    ],\n    \"complexes\": [\"SIN3A/HDAC corepressor complex\"],\n    \"partners\": [\"SIN3A\", \"Smad3\", \"EP300\", \"PPARG\", \"PPARA\", \"YAP1\", \"EGR1\", \"MDM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}