{"gene":"NR1H4","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"RIP14 (NR1H4/FXR) binds DNA as a heterodimer with RXR and can be activated by all-trans-retinoic acid and the synthetic retinoid TTNPB; mutagenesis of the ligand-dependent activation function (AF-2) demonstrated that TTNPB activates the RIP14 component of the RIP14-RXR heterodimer, while 9-cis-RA and LG1069 activate RXR. No direct binding of tRA or TTNPB to RIP14 was detected by multiple approaches, suggesting RIP14 responds to an as-yet-unidentified retinoid metabolite.","method":"Transactivation reporter assays, AF-2 domain mutagenesis, DNA-binding assays, ligand-binding assays (negative result for direct binding)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct mutagenesis of activation function combined with reporter assays and multiple binding approaches in a single rigorous study","pmids":["9223286"],"is_preprint":false},{"year":2000,"finding":"FXR functions as a bile acid receptor: chenodeoxycholic acid (CDCA), a primary bile acid, binds directly to and activates FXR. Activated FXR mediates feedback suppression of CYP7A1 (the rate-limiting enzyme in bile acid biosynthesis) and activates intestinal bile acid binding protein (IBABP) involved in enterohepatic circulation of bile acids.","method":"Ligand-binding assays, transactivation reporter assays, target gene expression analysis","journal":"Trends in cardiovascular medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct ligand binding and transcriptional activation demonstrated; finding replicated across multiple independent labs as reflected throughout corpus","pmids":["11150726"],"is_preprint":false},{"year":2005,"finding":"FXR-activating bile acid ligands repress rabbit ASBT (apical sodium-dependent bile acid transporter) expression via the regulatory cascade FXR→SHP→FTF (alpha-fetoprotein transcription factor). A cis-acting FTF binding site in the ASBT promoter is required for this repression; SHP inhibits FTF-dependent transactivation of the ASBT promoter. Non-FXR-activating bile acids (UDCA, ursocholic acid) do not repress ASBT.","method":"In vivo feeding experiments in rabbits, ASBT promoter cloning, luciferase reporter assays in Caco-2 cells, site-directed deletion of FTF binding element","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo plus in vitro promoter studies with deletion mutants demonstrating the FXR-SHP-FTF cascade","pmids":["15591588"],"is_preprint":false},{"year":2007,"finding":"The FXRalpha (NR1H4) ligand binding domain (LBD) acquired bile acid ligand specificity by deletion of a sequence present in the ancestral FXRbeta LBD. Deletion of the extra amino acids in skate FXRbeta and replacement with corresponding hFXRalpha sequence conferred responsiveness to ursodeoxycholic acid, GW4064, and fexaramine. All-trans retinoic acid was capable of transactivating both hFXRalpha and sFxr.","method":"Phylogenetic analysis, luciferase reporter assays, LBD domain deletion/replacement mutagenesis","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function mutagenesis of LBD combined with reporter assays in a single study defining the molecular basis of ligand specificity acquisition","pmids":["17567710"],"is_preprint":false},{"year":2009,"finding":"FXR activation by the bile acid CDCA promotes endothelial cell motility and in vitro tube formation via a FXR→MMP-9→FAK(Y397 phosphorylation)→paxillin signaling axis. FAK phosphorylation at Y397 (but not Y576/577 or Y925) is required for CDCA-induced paxillin activation and downstream MMP-9 upregulation. FXR or MMP-9 siRNA knockdown abolished the motility increase.","method":"Time-lapse video microscopy, siRNA knockdown, site-specific phosphodeficient FAK mutant, immunoblotting","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — phosphodeficient mutant combined with siRNA knockdown and functional migration/tube formation readouts in a single study","pmids":["19150878"],"is_preprint":false},{"year":2010,"finding":"Multiple post-translational modifications regulate FXR transcriptional activity: SUMOylation and phosphorylation have been reported to distinguish between FXR-mediated transactivation and transrepression, with dysregulation of these modifications contributing to metabolic disease states.","method":"Review of PTM studies (biochemical analysis of SUMOylation and phosphorylation of FXR reported in the literature surveyed)","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review paper summarizing others' findings without original experimental data described in the abstract","pmids":["21130162"],"is_preprint":false},{"year":2012,"finding":"FXR directly binds an IR9 DNA motif within the SOCS3 promoter region, inducing SOCS3 transcription. FXR-mediated SOCS3 induction inhibits STAT3 phosphorylation and HCC cell growth; siRNA knockdown of SOCS3 abrogated the anti-tumor effects of FXR activation. In vivo, GW4064 treatment decelerated HCC xenograft growth with up-regulated SOCS3 and p21 and inhibited STAT3 phosphorylation.","method":"Reporter assay, EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown, xenograft mouse model","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct DNA binding demonstrated by EMSA and ChIP, functional rescue by siRNA, and in vivo xenograft validation in a single study","pmids":["26416445"],"is_preprint":false},{"year":2014,"finding":"FXR is expressed in renal tubules throughout the kidney. FXR directly binds and activates a response element in the AQP2 gene promoter, increasing AQP2 transcription in collecting duct cells. FXR knockout mice exhibit impaired urine concentrating ability and polyuria with reduced renal AQP2 expression; FXR agonist treatment increased urine osmolality and upregulated AQP2.","method":"FXR knockout mice phenotyping, FXR agonist/ligand treatment, AQP2 promoter luciferase reporter assay with FXR response element identification, primary inner medullary collecting duct cell culture","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding demonstrated, genetic KO phenotype confirmed, and in vitro mechanistic studies converge on same conclusion","pmids":["24464484"],"is_preprint":false},{"year":2015,"finding":"FXR activation by GW4064 in mice rapidly increases hepatic Srebp-2 mRNA, precursor SREBP-2 protein, and miR-33, yet does not increase nuclear SREBP-2 (nSREBP-2) or SREBP-2 target genes. FXR agonists induce INSIG-2A, which likely prevents processing of pSREBP-2 to nSREBP-2. FXR-dependent induction of both Srebp-2 and miR-33 requires transcription of the Srebp-2 gene (absent in Scap-/- mice). A ChIP-seq-identified FXR response element was found within intron 10 of Srebp-2.","method":"ChIP-seq (FXR response element identification), FXR agonist treatment in mice, Scap-/- epistasis, qPCR, immunoblotting","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP-seq identification of FXR response element combined with genetic epistasis (Scap-/-) and in vivo agonist studies","pmids":["25593129"],"is_preprint":false},{"year":2015,"finding":"O-GlcNAcylation modifies FXR in response to glucose, and FXR directly interacts with ChREBP, acting as a repressor on the carbohydrate response element (ChoRE) of glycolytic genes. O-GlcNAcylation of FXR can modify its mutual affinity with ChREBP and their transcriptional activity.","method":"Co-immunoprecipitation, O-GlcNAcylation assays, reporter assays, interaction studies","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct interaction and post-translational modification described; review format but reports original experimental findings on FXR-ChREBP interaction and FXR O-GlcNAcylation","pmids":["25628602"],"is_preprint":false},{"year":2018,"finding":"FXR activation represses cilia formation (ciliogenesis) by suppressing autophagy. Pharmacological activation of NR1H4/FXR in cells reduced cilia length/frequency, while knockdown of NR1H4 enhanced ciliogenesis by inducing autophagy. In vivo, NR1H4 agonist exacerbated starvation-induced kidney damage in ppara-/- mice by impairing the autophagy-ciliogenesis axis.","method":"Pharmacological activation and genetic knockdown of NR1H4 in cell lines, ppara-/- mouse model, autophagy inhibition experiments (pharmacological and genetic), ciliogenesis quantification","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KD and pharmacological activation with defined cellular (ciliogenesis) and in vivo readouts, multiple orthogonal approaches","pmids":["29771182"],"is_preprint":false},{"year":2019,"finding":"FXR activation inhibits the nonreceptor tyrosine kinase Src (suppressing Tyr416 phosphorylation), which promotes YAP Ser127 phosphorylation and cytosolic retention, protecting against renal fibrosis. FXR agonist GW4064 increased interaction of hippo core kinases (MST1, LATS1, SAV1) and cytosolic accumulation of YAP in HK2 cells. FXR knockout mice showed increased expression of fibrosis, inflammatory, and YAP target genes in kidneys.","method":"FXR agonist treatment and FXR knockout mouse model, co-IP of hippo kinase complex, phosphorylation immunoblotting, siRNA (Src inhibitor PP2), unilateral ureteral obstruction model","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with cellular phenotype, pharmacological validation, and co-IP identifying the mechanistic pathway in a single study","pmids":["31298930"],"is_preprint":false},{"year":2020,"finding":"FXR directly induces Rubicon (an inhibitor of autophagosome-lysosome fusion), identified as a direct FXR transcriptional target by FXR ChIP-seq and luciferase promoter studies in human cholestatic liver. FXR agonists (CDCA and OCA) inhibit autophagic flux at the autophagosome-to-lysosome fusion step in an FXR-dependent manner. Genetic inhibition of Rubicon reverses bile acid-induced impairment of autophagic flux.","method":"FXR ChIP-seq, luciferase promoter assays, autophagic flux assays, Rubicon genetic knockdown, FXR agonist/antagonist pharmacology in vitro","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-seq identification of direct FXR-Rubicon binding combined with functional promoter assays, genetic rescue (Rubicon KD), and pharmacological validation with multiple orthogonal methods","pmids":["32001325"],"is_preprint":false},{"year":2020,"finding":"Activated hepatic stellate cells (HSCs) show limited response to FXR agonists due to enhanced FXR SUMOylation in activated HSCs. SUMOylation inhibitors rescue FXR signaling and increase the efficacy of FXR agonist OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1 (a direct FXR target gene) to stabilize lipid droplets and prevent HSC activation.","method":"SUMOylation assays, FXR agonist treatment, luciferase reporter assays, CCl4/BDL/NASH mouse fibrosis models, Perilipin-1 target gene identification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct biochemical demonstration of FXR SUMOylation as mechanism of agonist resistance, multiple orthogonal in vivo models, and direct target gene identification","pmids":["31932588"],"is_preprint":false},{"year":2020,"finding":"FXR functions as a T cell-intrinsic sensor mediating starvation-induced lymphocyte loss. T cell-specific deletion of FXR prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions. FXR deficiency increased contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions.","method":"T cell-specific FXR knockout, infection models with imposed feeding reduction, metabolic flux analysis (glutamine/fatty acid contribution to respiration), lymphocyte counting","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic KO with defined metabolic and cellular phenotypes","pmids":["33318189"],"is_preprint":false},{"year":2022,"finding":"FXR is a direct transcriptional regulator of ACE2 expression in gastrointestinal and respiratory tissues. FXR inhibition (by z-guggulsterone or UDCA) downregulates ACE2 in human lung, cholangiocyte, and intestinal organoids and in mouse/hamster tissues. Reduced FXR signaling decreases susceptibility to SARS-CoV-2 infection in vitro and in vivo.","method":"FXR ChIP (direct transcriptional regulation of ACE2), human organoids, mouse and hamster in vivo models, ex situ perfused human lungs and livers, nasal epithelium expression studies, SARS-CoV-2 infection assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct transcriptional regulation demonstrated by ChIP, validated in multiple orthogonal model systems (organoids, in vivo, ex vivo human organs) with functional infection readout","pmids":["36470304"],"is_preprint":false},{"year":2022,"finding":"FXR is expressed in innate lymphoid cells (ILCs) and acts as an intrinsic regulator of ILC biology. Intestinal FXR activation blocked inflammation-driven increases in ILCs (particularly ILC3s) and suppressed induction of Il17a and Il17f in ILC3s. A population of ILC precursor-like cells was increased with FXR activation, implicating FXR in ILC maturation/differentiation.","method":"Intestine-selective FXR activation, ILC population analysis by flow cytometry, cytokine expression measurement, IBD mouse models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — selective intestinal FXR activation with defined cellular (ILC subset) phenotypic readouts and molecular (Il17a/f) outcomes","pmids":["36508655"],"is_preprint":false},{"year":2022,"finding":"SIRT6 deacetylates FXR, elevating its transcriptional activity. SIRT6-mediated deacetylation of FXR is required for the hepatoprotective effects of SIRT6 against APAP-induced hepatotoxicity; FXR ablation blunted SIRT6-overexpression-mediated protective effects, while pharmacological FXR activation rescued APAP-induced injury in SIRT6 KO mice.","method":"Hepatocyte-specific SIRT6 KO mice, FXR KO mice, SIRT6 overexpression/pharmacological activation, RNA-seq, deacetylation assays, epistasis (FXR ablation in SIRT6 OE context)","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double KO/rescue), direct deacetylation demonstrated, and in vivo validation with multiple genetic models converging on SIRT6→FXR deacetylation","pmids":["35526796"],"is_preprint":false},{"year":2020,"finding":"BRD4 is a co-factor of FXR required for FXR-mediated bile acid gene regulation. Liver-specific downregulation of BRD4 disrupted bile acid homeostasis, and FXR-mediated regulation of BA-related genes (including SHP and CYP7A1) was BRD4-dependent. Mechanistically, OCA-activated FXR increased binding of the corepressor SMRT and decreased NF-κB binding at inflammatory genes in a BRD4-dependent manner.","method":"Liver-specific BRD4 knockdown, ChIP analysis of FXR/SMRT/NF-κB binding, FXR agonist treatment, cholestatic mouse models, gene expression analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific knockdown with defined molecular phenotype, ChIP demonstrating FXR-SMRT-BRD4 co-occupancy at target gene promoters","pmids":["33290278"],"is_preprint":false},{"year":2019,"finding":"FXR regulates intestinal cancer stem cell (Lgr5+) proliferation. Bile acids that antagonize intestinal FXR (T-βMCA and DCA) induce proliferation and DNA damage in Lgr5+ cells, while selective intestinal FXR activation restricts abnormal Lgr5+ cell growth and curtails colorectal cancer progression. FXR coordinates intestinal self-renewal with bile acid levels.","method":"Lgr5-CreERT2 lineage tracing, intestinal organoids, mouse adenoma-to-adenocarcinoma model (APC mutation + high-fat diet), selective intestinal FXR activation/antagonism, DNA damage quantification","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic models with Lgr5+ cell-specific readouts and multiple orthogonal approaches (organoids, in vivo cancer models, FXR KO) in a single high-impact study","pmids":["30794774"],"is_preprint":false},{"year":2018,"finding":"Metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction. GUDCA was identified as an intestinal FXR antagonist; colonization with B. fragilis abolished metformin's metabolic benefits on glucose intolerance. Metformin decreases gut B. fragilis leading to increased GUDCA which inhibits intestinal FXR signaling.","method":"Metagenomic and metabolomic analysis, germ-free mouse colonization, GUDCA FXR antagonism assays, intestinal FXR-specific mouse models","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — metabolomic identification of GUDCA, functional FXR antagonism assay, and genetic/microbiome rescue experiments converge to define the mechanism","pmids":["30397356"],"is_preprint":false}],"current_model":"NR1H4/FXR is a bile acid-activated nuclear receptor that heterodimerizes with RXR and directly binds DNA response elements to transcriptionally regulate genes controlling bile acid synthesis (CYP7A1), transport (BSEP, ASBT, AQP2), and metabolism; its activity is modulated by post-translational modifications including SUMOylation (which limits anti-fibrotic responses in activated stellate cells), phosphorylation, acetylation (reversed by SIRT6 to enhance activity), and O-GlcNAcylation; it interacts with co-factors including BRD4 and SMRT; it suppresses autophagy by directly inducing Rubicon and regulates ciliogenesis via the autophagy axis; it promotes endothelial motility through a FAK(Y397)–MMP-9 pathway; it suppresses hepatocellular carcinoma by directly inducing SOCS3 to inhibit STAT3; it controls intestinal Lgr5+ cancer stem cell proliferation, ILC3-mediated IL-17 production, and T cell metabolic fitness; it directly regulates ACE2 transcription; and intestinal FXR can be antagonized by GUDCA (mediating metformin's metabolic benefits) or by specific bile acid species to coordinate gut-liver signaling through the FXR–SHP–FGF15/19 axis."},"narrative":{"mechanistic_narrative":"NR1H4/FXR is a bile acid-activated nuclear receptor that binds DNA as a heterodimer with RXR to transcriptionally program enterohepatic bile acid homeostasis and a broad range of metabolic, proliferative, and immune processes [PMID:9223286, PMID:11150726]. The primary bile acid chenodeoxycholic acid binds and activates FXR, which then mediates feedback suppression of CYP7A1 and activates intestinal bile acid transport genes [PMID:11150726]; ligand specificity for bile acids is an evolutionarily acquired property of the receptor's ligand-binding domain [PMID:17567710]. As a direct transcription factor, FXR binds defined response elements to control physiologically diverse targets: it represses ASBT through an FXR→SHP→FTF cascade [PMID:15591588], activates renal AQP2 to support urine concentration [PMID:24464484], induces SOCS3 to inhibit STAT3 and restrain hepatocellular carcinoma [PMID:26416445], induces Rubicon to block autophagosome-lysosome fusion and thereby suppress autophagy and ciliogenesis [PMID:29771182, PMID:32001325], and directly drives ACE2 expression in gastrointestinal and respiratory tissues, controlling susceptibility to SARS-CoV-2 [PMID:36470304]. FXR activity is tuned by post-translational modifications: SUMOylation limits agonist responsiveness in activated hepatic stellate cells [PMID:31932588], SIRT6-mediated deacetylation elevates its transcriptional activity to confer hepatoprotection [PMID:35526796], and O-GlcNAcylation modulates its repressive interaction with ChREBP at glycolytic genes [PMID:25628602]. The co-factor BRD4 is required for FXR-dependent bile acid gene regulation and for recruitment of the corepressor SMRT at inflammatory loci [PMID:33290278]. Beyond the liver, FXR governs intestinal Lgr5+ cancer stem cell proliferation [PMID:30794774], ILC3-mediated IL-17 production [PMID:36508655], and T cell metabolic fitness during starvation [PMID:33318189], and intestinal FXR antagonism by the bile acid GUDCA mediates metformin's metabolic benefits [PMID:30397356].","teleology":[{"year":1997,"claim":"Established that FXR is a DNA-binding nuclear receptor acting as an RXR heterodimer with a ligand-dependent activation function, before its physiological ligand was known.","evidence":"Transactivation reporter assays, AF-2 mutagenesis, and DNA-binding/ligand-binding assays","pmids":["9223286"],"confidence":"High","gaps":["Endogenous activating ligand not identified","Direct retinoid binding could not be detected"]},{"year":2000,"claim":"Identified FXR as the bile acid receptor, defining the feedback logic linking bile acid sensing to suppression of synthesis and control of transport.","evidence":"Ligand-binding and transactivation assays with CDCA, plus CYP7A1 and IBABP target gene analysis","pmids":["11150726"],"confidence":"High","gaps":["Structural basis of bile acid binding not resolved in this work","In vivo physiological scope beyond CYP7A1/IBABP not addressed"]},{"year":2005,"claim":"Worked out the FXR→SHP→FTF repression cascade controlling the bile acid transporter ASBT, showing FXR acts through indirect transcriptional repression as well as direct activation.","evidence":"In vivo rabbit feeding, ASBT promoter luciferase assays in Caco-2 cells, and FTF binding element deletion","pmids":["15591588"],"confidence":"High","gaps":["Generalizability of the SHP-FTF cascade to other transporters not established here"]},{"year":2007,"claim":"Defined the molecular basis for bile acid ligand specificity, showing it was acquired by a deletion in the FXRalpha LBD relative to the ancestral FXRbeta.","evidence":"Phylogenetic analysis and LBD domain swap/deletion mutagenesis with reporter assays","pmids":["17567710"],"confidence":"High","gaps":["Does not resolve atomic-level ligand contacts"]},{"year":2009,"claim":"Extended FXR function beyond transcription of metabolic genes to control of endothelial cell motility through a signaling kinase axis.","evidence":"Time-lapse microscopy, siRNA knockdown, and a phosphodeficient FAK(Y397) mutant linking FXR to MMP-9 and paxillin","pmids":["19150878"],"confidence":"High","gaps":["Whether FAK/MMP-9 regulation is direct transcriptional vs. indirect not fully resolved","In vivo vascular relevance not tested"]},{"year":2010,"claim":"Surveyed post-translational control of FXR, proposing SUMOylation and phosphorylation distinguish transactivation from transrepression.","evidence":"Review of PTM literature without original data described","pmids":["21130162"],"confidence":"Low","gaps":["Review without original experimental data","Specific modified residues and enzymes not defined here"]},{"year":2012,"claim":"Demonstrated FXR is a tumor suppressor in HCC by directly inducing SOCS3 to dampen STAT3 signaling.","evidence":"EMSA and ChIP showing FXR binding to an IR9 motif in the SOCS3 promoter, SOCS3 siRNA rescue, and xenograft model","pmids":["26416445"],"confidence":"High","gaps":["Relevance to spontaneous (non-xenograft) HCC not established","Contribution relative to other FXR anti-tumor targets unclear"]},{"year":2014,"claim":"Established a renal role for FXR in water handling via direct transcriptional activation of AQP2.","evidence":"FXR KO mouse phenotyping, agonist treatment, AQP2 promoter reporter with FXRE identification, and collecting duct cell culture","pmids":["24464484"],"confidence":"High","gaps":["Upstream physiological signals driving renal FXR activity not defined"]},{"year":2015,"claim":"Defined two metabolic regulatory layers: FXR transcribes Srebp-2/miR-33 while blocking SREBP-2 processing via INSIG-2A, and O-GlcNAcylation tunes FXR's repressive partnership with ChREBP at glycolytic genes.","evidence":"ChIP-seq FXRE identification with Scap-/- epistasis (Srebp-2/INSIG-2A); Co-IP, O-GlcNAcylation and reporter assays (ChREBP)","pmids":["25593129","25628602"],"confidence":"Medium","gaps":["O-GlcNAc sites on FXR not mapped","Quantitative impact on systemic lipid/carbohydrate balance not established"]},{"year":2018,"claim":"Connected FXR to autophagy and ciliogenesis, showing FXR activation represses cilia formation by suppressing autophagy.","evidence":"Pharmacological activation and knockdown of FXR in cells, ppara-/- starvation kidney injury model, and autophagy inhibition experiments","pmids":["29771182"],"confidence":"High","gaps":["Direct transcriptional target mediating autophagy suppression not yet identified in this study"]},{"year":2018,"claim":"Identified GUDCA as an intestinal FXR antagonist mediating metformin's metabolic benefits through a gut microbiome–FXR axis.","evidence":"Metagenomics/metabolomics, germ-free B. fragilis colonization, GUDCA FXR antagonism assays, and intestine-specific FXR mouse models","pmids":["30397356"],"confidence":"High","gaps":["Downstream intestinal FXR targets driving the metabolic effect not fully mapped","Human translatability not established here"]},{"year":2019,"claim":"Showed FXR coordinates intestinal stem cell self-renewal with bile acid levels, restraining Lgr5+ cancer stem cell proliferation; and identified an FXR→Src→YAP renal anti-fibrotic pathway.","evidence":"Lgr5 lineage tracing, organoids, APC/high-fat cancer models (intestinal CSC); FXR KO, co-IP of Hippo kinases and Src phosphorylation immunoblotting (renal)","pmids":["30794774","31298930"],"confidence":"High","gaps":["Whether Src/YAP regulation is direct transcriptional vs. signaling-level remains unresolved","Stem cell direct target genes not enumerated"]},{"year":2020,"claim":"Defined Rubicon and Perilipin-1 as direct FXR targets and SUMOylation as the mechanism of agonist resistance in activated stellate cells, linking FXR to autophagic flux and antifibrotic lipid droplet stability.","evidence":"FXR ChIP-seq, luciferase promoter assays, autophagic flux and Rubicon knockdown (Rubicon); SUMOylation assays, fibrosis mouse models and Perilipin-1 identification (HSC)","pmids":["32001325","31932588"],"confidence":"High","gaps":["SUMO sites and responsible E3 ligase in activated HSCs not pinpointed","Interplay between autophagy suppression and stellate cell quiescence not integrated"]},{"year":2020,"claim":"Established FXR as a cell-intrinsic immune regulator, sensing starvation in T cells to limit their metabolic fitness, and identified BRD4 as a required FXR co-factor for bile acid gene regulation and SMRT/NF-κB control.","evidence":"T cell-specific FXR KO with metabolic flux analysis (T cells); liver-specific BRD4 knockdown with ChIP of FXR/SMRT/NF-κB (cofactor)","pmids":["33318189","33290278"],"confidence":"High","gaps":["Direct FXR target genes controlling T cell metabolism not defined","Mechanism of BRD4 recruitment to FXR not resolved"]},{"year":2022,"claim":"Expanded FXR's regulatory reach to ACE2 transcription (controlling SARS-CoV-2 susceptibility), ILC3 maturation and IL-17 output, and SIRT6-mediated deacetylation as an activating modification conferring hepatoprotection.","evidence":"FXR ChIP and multi-model ACE2 studies (organoids, in vivo, ex vivo human organs); intestinal FXR activation with ILC profiling; SIRT6/FXR double-KO epistasis and deacetylation assays","pmids":["36470304","36508655","35526796"],"confidence":"High","gaps":["FXR-acetylation residues targeted by SIRT6 not mapped","Mechanism by which FXR shapes ILC differentiation not detailed"]},{"year":null,"claim":"How FXR's transcriptional outputs are integrated across tissues to produce coherent metabolic, immune, and proliferative programs, and the residue-level rules governing PTM-dependent switching, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified map of PTM sites and their functional consequences","Tissue-specific cofactor and corepressor logic incompletely defined","Endogenous ligand-PTM crosstalk governing target selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,6,7,8,12,15]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,6,7,8,12]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[1,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,8,9,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,6,7,12,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,16]}],"complexes":[],"partners":["RXR","SHP","CHREBP","BRD4","SMRT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96RI1","full_name":"Bile acid receptor","aliases":["Farnesoid X-activated receptor","Farnesol receptor HRR-1","Nuclear receptor subfamily 1 group H member 4","Retinoid X receptor-interacting protein 14","RXR-interacting protein 14"],"length_aa":486,"mass_kda":55.9,"function":"Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12554753, PubMed:12660231, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit pro-inflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity) Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA), NR0B2/SHP (inducible by unconjugated CDCA DCA and ACA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; not inducible by taurine- and glycine-amidated CDCA Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, ACA and DCA), NR0B2/SHP (inducible by unconjugated CDCA, ACA and DCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; 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AOMS1","url":"https://www.omim.org/entry/605552"},{"mim_id":"605495","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B3; SLCO1B3","url":"https://www.omim.org/entry/605495"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":36.8},{"tissue":"liver","ntpm":112.7}],"url":"https://www.proteinatlas.org/search/NR1H4"},"hgnc":{"alias_symbol":["FXR","RIP14","HRR1","HRR-1"],"prev_symbol":[]},"alphafold":{"accession":"Q96RI1","domains":[{"cath_id":"3.30.50.10","chopping":"147-212","consensus_level":"high","plddt":88.3227,"start":147,"end":212},{"cath_id":"1.10.565.10","chopping":"262-484","consensus_level":"high","plddt":88.3828,"start":262,"end":484}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RI1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RI1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RI1-F1-predicted_aligned_error_v6.png","plddt_mean":68.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR1H4","jax_strain_url":"https://www.jax.org/strain/search?query=NR1H4"},"sequence":{"accession":"Q96RI1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96RI1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96RI1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RI1"}},"corpus_meta":[{"pmid":"30397356","id":"PMC_30397356","title":"Gut microbiota and intestinal FXR mediate the clinical benefits of metformin.","date":"2018","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30397356","citation_count":808,"is_preprint":false},{"pmid":"16460270","id":"PMC_16460270","title":"LXRS and FXR: the yin and yang of cholesterol and fat metabolism.","date":"2006","source":"Annual review of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16460270","citation_count":492,"is_preprint":false},{"pmid":"25920087","id":"PMC_25920087","title":"New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.","date":"2015","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/25920087","citation_count":410,"is_preprint":false},{"pmid":"30794774","id":"PMC_30794774","title":"FXR Regulates Intestinal Cancer Stem Cell Proliferation.","date":"2019","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30794774","citation_count":379,"is_preprint":false},{"pmid":"26579439","id":"PMC_26579439","title":"Bile acid nuclear receptor FXR and digestive system diseases.","date":"2015","source":"Acta pharmaceutica Sinica. 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Implications for Cholestasis and Obesity-Related Disorders.","date":"2021","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34646233","citation_count":28,"is_preprint":false},{"pmid":"23640969","id":"PMC_23640969","title":"Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans.","date":"2013","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23640969","citation_count":28,"is_preprint":false},{"pmid":"33630750","id":"PMC_33630750","title":"MECHANISMS IN ENDOCRINOLOGY: FXR signalling: a novel target in metabolic diseases.","date":"2021","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/33630750","citation_count":28,"is_preprint":false},{"pmid":"28629595","id":"PMC_28629595","title":"A novel intestinal-restricted FXR agonist.","date":"2017","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/28629595","citation_count":27,"is_preprint":false},{"pmid":"35267068","id":"PMC_35267068","title":"Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway.","date":"2022","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35267068","citation_count":27,"is_preprint":false},{"pmid":"33290278","id":"PMC_33290278","title":"BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination.","date":"2020","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/33290278","citation_count":27,"is_preprint":false},{"pmid":"37058105","id":"PMC_37058105","title":"FXR and NASH: an avenue for tissue-specific regulation.","date":"2023","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/37058105","citation_count":26,"is_preprint":false},{"pmid":"25388533","id":"PMC_25388533","title":"Medicinal chemistry and pharmacological effects of Farnesoid X Receptor (FXR) antagonists.","date":"2014","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25388533","citation_count":26,"is_preprint":false},{"pmid":"25593129","id":"PMC_25593129","title":"The nuclear receptor FXR uncouples the actions of miR-33 from SREBP-2.","date":"2015","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25593129","citation_count":26,"is_preprint":false},{"pmid":"32687365","id":"PMC_32687365","title":"Design and Structural Optimization of Dual FXR/PPARδ Activators.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32687365","citation_count":25,"is_preprint":false},{"pmid":"32003602","id":"PMC_32003602","title":"Bile acid treatment and FXR agonism lower postprandial lipemia in mice.","date":"2020","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32003602","citation_count":24,"is_preprint":false},{"pmid":"35526796","id":"PMC_35526796","title":"Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity.","date":"2022","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/35526796","citation_count":24,"is_preprint":false},{"pmid":"22648540","id":"PMC_22648540","title":"Farnesoid X Receptor (FXR) from normal to malignant state.","date":"2012","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/22648540","citation_count":23,"is_preprint":false},{"pmid":"35616366","id":"PMC_35616366","title":"Dihydroartemisinin promoted FXR expression independent of YAP1 in hepatocellular carcinoma.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35616366","citation_count":23,"is_preprint":false},{"pmid":"36768731","id":"PMC_36768731","title":"Role of FXR in Renal Physiology and Kidney Diseases.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36768731","citation_count":22,"is_preprint":false},{"pmid":"34995680","id":"PMC_34995680","title":"Pleiotropic roles of FXR in liver and colorectal cancers.","date":"2022","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34995680","citation_count":22,"is_preprint":false},{"pmid":"28660075","id":"PMC_28660075","title":"The bile acid receptor FXR attenuates acinar cell autophagy in chronic pancreatitis.","date":"2017","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/28660075","citation_count":22,"is_preprint":false},{"pmid":"38763006","id":"PMC_38763006","title":"Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38763006","citation_count":21,"is_preprint":false},{"pmid":"29908754","id":"PMC_29908754","title":"Bile acids and FXR in functional gastrointestinal disorders.","date":"2018","source":"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/29908754","citation_count":21,"is_preprint":false},{"pmid":"16101408","id":"PMC_16101408","title":"FXR, a therapeutic target for bile acid and lipid disorders.","date":"2005","source":"Mini reviews in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16101408","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43610,"output_tokens":6148,"usd":0.111525,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14839,"output_tokens":4769,"usd":0.09671,"stage2_stop_reason":"end_turn"},"total_usd":0.208235,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"RIP14 (NR1H4/FXR) binds DNA as a heterodimer with RXR and can be activated by all-trans-retinoic acid and the synthetic retinoid TTNPB; mutagenesis of the ligand-dependent activation function (AF-2) demonstrated that TTNPB activates the RIP14 component of the RIP14-RXR heterodimer, while 9-cis-RA and LG1069 activate RXR. No direct binding of tRA or TTNPB to RIP14 was detected by multiple approaches, suggesting RIP14 responds to an as-yet-unidentified retinoid metabolite.\",\n      \"method\": \"Transactivation reporter assays, AF-2 domain mutagenesis, DNA-binding assays, ligand-binding assays (negative result for direct binding)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct mutagenesis of activation function combined with reporter assays and multiple binding approaches in a single rigorous study\",\n      \"pmids\": [\"9223286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FXR functions as a bile acid receptor: chenodeoxycholic acid (CDCA), a primary bile acid, binds directly to and activates FXR. Activated FXR mediates feedback suppression of CYP7A1 (the rate-limiting enzyme in bile acid biosynthesis) and activates intestinal bile acid binding protein (IBABP) involved in enterohepatic circulation of bile acids.\",\n      \"method\": \"Ligand-binding assays, transactivation reporter assays, target gene expression analysis\",\n      \"journal\": \"Trends in cardiovascular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct ligand binding and transcriptional activation demonstrated; finding replicated across multiple independent labs as reflected throughout corpus\",\n      \"pmids\": [\"11150726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FXR-activating bile acid ligands repress rabbit ASBT (apical sodium-dependent bile acid transporter) expression via the regulatory cascade FXR→SHP→FTF (alpha-fetoprotein transcription factor). A cis-acting FTF binding site in the ASBT promoter is required for this repression; SHP inhibits FTF-dependent transactivation of the ASBT promoter. Non-FXR-activating bile acids (UDCA, ursocholic acid) do not repress ASBT.\",\n      \"method\": \"In vivo feeding experiments in rabbits, ASBT promoter cloning, luciferase reporter assays in Caco-2 cells, site-directed deletion of FTF binding element\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo plus in vitro promoter studies with deletion mutants demonstrating the FXR-SHP-FTF cascade\",\n      \"pmids\": [\"15591588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The FXRalpha (NR1H4) ligand binding domain (LBD) acquired bile acid ligand specificity by deletion of a sequence present in the ancestral FXRbeta LBD. Deletion of the extra amino acids in skate FXRbeta and replacement with corresponding hFXRalpha sequence conferred responsiveness to ursodeoxycholic acid, GW4064, and fexaramine. All-trans retinoic acid was capable of transactivating both hFXRalpha and sFxr.\",\n      \"method\": \"Phylogenetic analysis, luciferase reporter assays, LBD domain deletion/replacement mutagenesis\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function mutagenesis of LBD combined with reporter assays in a single study defining the molecular basis of ligand specificity acquisition\",\n      \"pmids\": [\"17567710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FXR activation by the bile acid CDCA promotes endothelial cell motility and in vitro tube formation via a FXR→MMP-9→FAK(Y397 phosphorylation)→paxillin signaling axis. FAK phosphorylation at Y397 (but not Y576/577 or Y925) is required for CDCA-induced paxillin activation and downstream MMP-9 upregulation. FXR or MMP-9 siRNA knockdown abolished the motility increase.\",\n      \"method\": \"Time-lapse video microscopy, siRNA knockdown, site-specific phosphodeficient FAK mutant, immunoblotting\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phosphodeficient mutant combined with siRNA knockdown and functional migration/tube formation readouts in a single study\",\n      \"pmids\": [\"19150878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Multiple post-translational modifications regulate FXR transcriptional activity: SUMOylation and phosphorylation have been reported to distinguish between FXR-mediated transactivation and transrepression, with dysregulation of these modifications contributing to metabolic disease states.\",\n      \"method\": \"Review of PTM studies (biochemical analysis of SUMOylation and phosphorylation of FXR reported in the literature surveyed)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review paper summarizing others' findings without original experimental data described in the abstract\",\n      \"pmids\": [\"21130162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FXR directly binds an IR9 DNA motif within the SOCS3 promoter region, inducing SOCS3 transcription. FXR-mediated SOCS3 induction inhibits STAT3 phosphorylation and HCC cell growth; siRNA knockdown of SOCS3 abrogated the anti-tumor effects of FXR activation. In vivo, GW4064 treatment decelerated HCC xenograft growth with up-regulated SOCS3 and p21 and inhibited STAT3 phosphorylation.\",\n      \"method\": \"Reporter assay, EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown, xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct DNA binding demonstrated by EMSA and ChIP, functional rescue by siRNA, and in vivo xenograft validation in a single study\",\n      \"pmids\": [\"26416445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FXR is expressed in renal tubules throughout the kidney. FXR directly binds and activates a response element in the AQP2 gene promoter, increasing AQP2 transcription in collecting duct cells. FXR knockout mice exhibit impaired urine concentrating ability and polyuria with reduced renal AQP2 expression; FXR agonist treatment increased urine osmolality and upregulated AQP2.\",\n      \"method\": \"FXR knockout mice phenotyping, FXR agonist/ligand treatment, AQP2 promoter luciferase reporter assay with FXR response element identification, primary inner medullary collecting duct cell culture\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding demonstrated, genetic KO phenotype confirmed, and in vitro mechanistic studies converge on same conclusion\",\n      \"pmids\": [\"24464484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FXR activation by GW4064 in mice rapidly increases hepatic Srebp-2 mRNA, precursor SREBP-2 protein, and miR-33, yet does not increase nuclear SREBP-2 (nSREBP-2) or SREBP-2 target genes. FXR agonists induce INSIG-2A, which likely prevents processing of pSREBP-2 to nSREBP-2. FXR-dependent induction of both Srebp-2 and miR-33 requires transcription of the Srebp-2 gene (absent in Scap-/- mice). A ChIP-seq-identified FXR response element was found within intron 10 of Srebp-2.\",\n      \"method\": \"ChIP-seq (FXR response element identification), FXR agonist treatment in mice, Scap-/- epistasis, qPCR, immunoblotting\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP-seq identification of FXR response element combined with genetic epistasis (Scap-/-) and in vivo agonist studies\",\n      \"pmids\": [\"25593129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"O-GlcNAcylation modifies FXR in response to glucose, and FXR directly interacts with ChREBP, acting as a repressor on the carbohydrate response element (ChoRE) of glycolytic genes. O-GlcNAcylation of FXR can modify its mutual affinity with ChREBP and their transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, O-GlcNAcylation assays, reporter assays, interaction studies\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct interaction and post-translational modification described; review format but reports original experimental findings on FXR-ChREBP interaction and FXR O-GlcNAcylation\",\n      \"pmids\": [\"25628602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FXR activation represses cilia formation (ciliogenesis) by suppressing autophagy. Pharmacological activation of NR1H4/FXR in cells reduced cilia length/frequency, while knockdown of NR1H4 enhanced ciliogenesis by inducing autophagy. In vivo, NR1H4 agonist exacerbated starvation-induced kidney damage in ppara-/- mice by impairing the autophagy-ciliogenesis axis.\",\n      \"method\": \"Pharmacological activation and genetic knockdown of NR1H4 in cell lines, ppara-/- mouse model, autophagy inhibition experiments (pharmacological and genetic), ciliogenesis quantification\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD and pharmacological activation with defined cellular (ciliogenesis) and in vivo readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"29771182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FXR activation inhibits the nonreceptor tyrosine kinase Src (suppressing Tyr416 phosphorylation), which promotes YAP Ser127 phosphorylation and cytosolic retention, protecting against renal fibrosis. FXR agonist GW4064 increased interaction of hippo core kinases (MST1, LATS1, SAV1) and cytosolic accumulation of YAP in HK2 cells. FXR knockout mice showed increased expression of fibrosis, inflammatory, and YAP target genes in kidneys.\",\n      \"method\": \"FXR agonist treatment and FXR knockout mouse model, co-IP of hippo kinase complex, phosphorylation immunoblotting, siRNA (Src inhibitor PP2), unilateral ureteral obstruction model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cellular phenotype, pharmacological validation, and co-IP identifying the mechanistic pathway in a single study\",\n      \"pmids\": [\"31298930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FXR directly induces Rubicon (an inhibitor of autophagosome-lysosome fusion), identified as a direct FXR transcriptional target by FXR ChIP-seq and luciferase promoter studies in human cholestatic liver. FXR agonists (CDCA and OCA) inhibit autophagic flux at the autophagosome-to-lysosome fusion step in an FXR-dependent manner. Genetic inhibition of Rubicon reverses bile acid-induced impairment of autophagic flux.\",\n      \"method\": \"FXR ChIP-seq, luciferase promoter assays, autophagic flux assays, Rubicon genetic knockdown, FXR agonist/antagonist pharmacology in vitro\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-seq identification of direct FXR-Rubicon binding combined with functional promoter assays, genetic rescue (Rubicon KD), and pharmacological validation with multiple orthogonal methods\",\n      \"pmids\": [\"32001325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Activated hepatic stellate cells (HSCs) show limited response to FXR agonists due to enhanced FXR SUMOylation in activated HSCs. SUMOylation inhibitors rescue FXR signaling and increase the efficacy of FXR agonist OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1 (a direct FXR target gene) to stabilize lipid droplets and prevent HSC activation.\",\n      \"method\": \"SUMOylation assays, FXR agonist treatment, luciferase reporter assays, CCl4/BDL/NASH mouse fibrosis models, Perilipin-1 target gene identification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct biochemical demonstration of FXR SUMOylation as mechanism of agonist resistance, multiple orthogonal in vivo models, and direct target gene identification\",\n      \"pmids\": [\"31932588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FXR functions as a T cell-intrinsic sensor mediating starvation-induced lymphocyte loss. T cell-specific deletion of FXR prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions. FXR deficiency increased contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions.\",\n      \"method\": \"T cell-specific FXR knockout, infection models with imposed feeding reduction, metabolic flux analysis (glutamine/fatty acid contribution to respiration), lymphocyte counting\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic KO with defined metabolic and cellular phenotypes\",\n      \"pmids\": [\"33318189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FXR is a direct transcriptional regulator of ACE2 expression in gastrointestinal and respiratory tissues. FXR inhibition (by z-guggulsterone or UDCA) downregulates ACE2 in human lung, cholangiocyte, and intestinal organoids and in mouse/hamster tissues. Reduced FXR signaling decreases susceptibility to SARS-CoV-2 infection in vitro and in vivo.\",\n      \"method\": \"FXR ChIP (direct transcriptional regulation of ACE2), human organoids, mouse and hamster in vivo models, ex situ perfused human lungs and livers, nasal epithelium expression studies, SARS-CoV-2 infection assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct transcriptional regulation demonstrated by ChIP, validated in multiple orthogonal model systems (organoids, in vivo, ex vivo human organs) with functional infection readout\",\n      \"pmids\": [\"36470304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FXR is expressed in innate lymphoid cells (ILCs) and acts as an intrinsic regulator of ILC biology. Intestinal FXR activation blocked inflammation-driven increases in ILCs (particularly ILC3s) and suppressed induction of Il17a and Il17f in ILC3s. A population of ILC precursor-like cells was increased with FXR activation, implicating FXR in ILC maturation/differentiation.\",\n      \"method\": \"Intestine-selective FXR activation, ILC population analysis by flow cytometry, cytokine expression measurement, IBD mouse models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective intestinal FXR activation with defined cellular (ILC subset) phenotypic readouts and molecular (Il17a/f) outcomes\",\n      \"pmids\": [\"36508655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT6 deacetylates FXR, elevating its transcriptional activity. SIRT6-mediated deacetylation of FXR is required for the hepatoprotective effects of SIRT6 against APAP-induced hepatotoxicity; FXR ablation blunted SIRT6-overexpression-mediated protective effects, while pharmacological FXR activation rescued APAP-induced injury in SIRT6 KO mice.\",\n      \"method\": \"Hepatocyte-specific SIRT6 KO mice, FXR KO mice, SIRT6 overexpression/pharmacological activation, RNA-seq, deacetylation assays, epistasis (FXR ablation in SIRT6 OE context)\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double KO/rescue), direct deacetylation demonstrated, and in vivo validation with multiple genetic models converging on SIRT6→FXR deacetylation\",\n      \"pmids\": [\"35526796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRD4 is a co-factor of FXR required for FXR-mediated bile acid gene regulation. Liver-specific downregulation of BRD4 disrupted bile acid homeostasis, and FXR-mediated regulation of BA-related genes (including SHP and CYP7A1) was BRD4-dependent. Mechanistically, OCA-activated FXR increased binding of the corepressor SMRT and decreased NF-κB binding at inflammatory genes in a BRD4-dependent manner.\",\n      \"method\": \"Liver-specific BRD4 knockdown, ChIP analysis of FXR/SMRT/NF-κB binding, FXR agonist treatment, cholestatic mouse models, gene expression analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific knockdown with defined molecular phenotype, ChIP demonstrating FXR-SMRT-BRD4 co-occupancy at target gene promoters\",\n      \"pmids\": [\"33290278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FXR regulates intestinal cancer stem cell (Lgr5+) proliferation. Bile acids that antagonize intestinal FXR (T-βMCA and DCA) induce proliferation and DNA damage in Lgr5+ cells, while selective intestinal FXR activation restricts abnormal Lgr5+ cell growth and curtails colorectal cancer progression. FXR coordinates intestinal self-renewal with bile acid levels.\",\n      \"method\": \"Lgr5-CreERT2 lineage tracing, intestinal organoids, mouse adenoma-to-adenocarcinoma model (APC mutation + high-fat diet), selective intestinal FXR activation/antagonism, DNA damage quantification\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic models with Lgr5+ cell-specific readouts and multiple orthogonal approaches (organoids, in vivo cancer models, FXR KO) in a single high-impact study\",\n      \"pmids\": [\"30794774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction. GUDCA was identified as an intestinal FXR antagonist; colonization with B. fragilis abolished metformin's metabolic benefits on glucose intolerance. Metformin decreases gut B. fragilis leading to increased GUDCA which inhibits intestinal FXR signaling.\",\n      \"method\": \"Metagenomic and metabolomic analysis, germ-free mouse colonization, GUDCA FXR antagonism assays, intestinal FXR-specific mouse models\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — metabolomic identification of GUDCA, functional FXR antagonism assay, and genetic/microbiome rescue experiments converge to define the mechanism\",\n      \"pmids\": [\"30397356\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR1H4/FXR is a bile acid-activated nuclear receptor that heterodimerizes with RXR and directly binds DNA response elements to transcriptionally regulate genes controlling bile acid synthesis (CYP7A1), transport (BSEP, ASBT, AQP2), and metabolism; its activity is modulated by post-translational modifications including SUMOylation (which limits anti-fibrotic responses in activated stellate cells), phosphorylation, acetylation (reversed by SIRT6 to enhance activity), and O-GlcNAcylation; it interacts with co-factors including BRD4 and SMRT; it suppresses autophagy by directly inducing Rubicon and regulates ciliogenesis via the autophagy axis; it promotes endothelial motility through a FAK(Y397)–MMP-9 pathway; it suppresses hepatocellular carcinoma by directly inducing SOCS3 to inhibit STAT3; it controls intestinal Lgr5+ cancer stem cell proliferation, ILC3-mediated IL-17 production, and T cell metabolic fitness; it directly regulates ACE2 transcription; and intestinal FXR can be antagonized by GUDCA (mediating metformin's metabolic benefits) or by specific bile acid species to coordinate gut-liver signaling through the FXR–SHP–FGF15/19 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR1H4/FXR is a bile acid-activated nuclear receptor that binds DNA as a heterodimer with RXR to transcriptionally program enterohepatic bile acid homeostasis and a broad range of metabolic, proliferative, and immune processes [#0, #1]. The primary bile acid chenodeoxycholic acid binds and activates FXR, which then mediates feedback suppression of CYP7A1 and activates intestinal bile acid transport genes [#1]; ligand specificity for bile acids is an evolutionarily acquired property of the receptor's ligand-binding domain [#3]. As a direct transcription factor, FXR binds defined response elements to control physiologically diverse targets: it represses ASBT through an FXR\\u2192SHP\\u2192FTF cascade [#2], activates renal AQP2 to support urine concentration [#7], induces SOCS3 to inhibit STAT3 and restrain hepatocellular carcinoma [#6], induces Rubicon to block autophagosome-lysosome fusion and thereby suppress autophagy and ciliogenesis [#10, #12], and directly drives ACE2 expression in gastrointestinal and respiratory tissues, controlling susceptibility to SARS-CoV-2 [#15]. FXR activity is tuned by post-translational modifications: SUMOylation limits agonist responsiveness in activated hepatic stellate cells [#13], SIRT6-mediated deacetylation elevates its transcriptional activity to confer hepatoprotection [#17], and O-GlcNAcylation modulates its repressive interaction with ChREBP at glycolytic genes [#9]. The co-factor BRD4 is required for FXR-dependent bile acid gene regulation and for recruitment of the corepressor SMRT at inflammatory loci [#18]. Beyond the liver, FXR governs intestinal Lgr5+ cancer stem cell proliferation [#19], ILC3-mediated IL-17 production [#16], and T cell metabolic fitness during starvation [#14], and intestinal FXR antagonism by the bile acid GUDCA mediates metformin's metabolic benefits [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that FXR is a DNA-binding nuclear receptor acting as an RXR heterodimer with a ligand-dependent activation function, before its physiological ligand was known.\",\n      \"evidence\": \"Transactivation reporter assays, AF-2 mutagenesis, and DNA-binding/ligand-binding assays\",\n      \"pmids\": [\"9223286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous activating ligand not identified\", \"Direct retinoid binding could not be detected\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified FXR as the bile acid receptor, defining the feedback logic linking bile acid sensing to suppression of synthesis and control of transport.\",\n      \"evidence\": \"Ligand-binding and transactivation assays with CDCA, plus CYP7A1 and IBABP target gene analysis\",\n      \"pmids\": [\"11150726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of bile acid binding not resolved in this work\", \"In vivo physiological scope beyond CYP7A1/IBABP not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Worked out the FXR\\u2192SHP\\u2192FTF repression cascade controlling the bile acid transporter ASBT, showing FXR acts through indirect transcriptional repression as well as direct activation.\",\n      \"evidence\": \"In vivo rabbit feeding, ASBT promoter luciferase assays in Caco-2 cells, and FTF binding element deletion\",\n      \"pmids\": [\"15591588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of the SHP-FTF cascade to other transporters not established here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the molecular basis for bile acid ligand specificity, showing it was acquired by a deletion in the FXRalpha LBD relative to the ancestral FXRbeta.\",\n      \"evidence\": \"Phylogenetic analysis and LBD domain swap/deletion mutagenesis with reporter assays\",\n      \"pmids\": [\"17567710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve atomic-level ligand contacts\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended FXR function beyond transcription of metabolic genes to control of endothelial cell motility through a signaling kinase axis.\",\n      \"evidence\": \"Time-lapse microscopy, siRNA knockdown, and a phosphodeficient FAK(Y397) mutant linking FXR to MMP-9 and paxillin\",\n      \"pmids\": [\"19150878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FAK/MMP-9 regulation is direct transcriptional vs. indirect not fully resolved\", \"In vivo vascular relevance not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Surveyed post-translational control of FXR, proposing SUMOylation and phosphorylation distinguish transactivation from transrepression.\",\n      \"evidence\": \"Review of PTM literature without original data described\",\n      \"pmids\": [\"21130162\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Review without original experimental data\", \"Specific modified residues and enzymes not defined here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated FXR is a tumor suppressor in HCC by directly inducing SOCS3 to dampen STAT3 signaling.\",\n      \"evidence\": \"EMSA and ChIP showing FXR binding to an IR9 motif in the SOCS3 promoter, SOCS3 siRNA rescue, and xenograft model\",\n      \"pmids\": [\"26416445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to spontaneous (non-xenograft) HCC not established\", \"Contribution relative to other FXR anti-tumor targets unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established a renal role for FXR in water handling via direct transcriptional activation of AQP2.\",\n      \"evidence\": \"FXR KO mouse phenotyping, agonist treatment, AQP2 promoter reporter with FXRE identification, and collecting duct cell culture\",\n      \"pmids\": [\"24464484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream physiological signals driving renal FXR activity not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined two metabolic regulatory layers: FXR transcribes Srebp-2/miR-33 while blocking SREBP-2 processing via INSIG-2A, and O-GlcNAcylation tunes FXR's repressive partnership with ChREBP at glycolytic genes.\",\n      \"evidence\": \"ChIP-seq FXRE identification with Scap-/- epistasis (Srebp-2/INSIG-2A); Co-IP, O-GlcNAcylation and reporter assays (ChREBP)\",\n      \"pmids\": [\"25593129\", \"25628602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"O-GlcNAc sites on FXR not mapped\", \"Quantitative impact on systemic lipid/carbohydrate balance not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected FXR to autophagy and ciliogenesis, showing FXR activation represses cilia formation by suppressing autophagy.\",\n      \"evidence\": \"Pharmacological activation and knockdown of FXR in cells, ppara-/- starvation kidney injury model, and autophagy inhibition experiments\",\n      \"pmids\": [\"29771182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional target mediating autophagy suppression not yet identified in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified GUDCA as an intestinal FXR antagonist mediating metformin's metabolic benefits through a gut microbiome\\u2013FXR axis.\",\n      \"evidence\": \"Metagenomics/metabolomics, germ-free B. fragilis colonization, GUDCA FXR antagonism assays, and intestine-specific FXR mouse models\",\n      \"pmids\": [\"30397356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream intestinal FXR targets driving the metabolic effect not fully mapped\", \"Human translatability not established here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed FXR coordinates intestinal stem cell self-renewal with bile acid levels, restraining Lgr5+ cancer stem cell proliferation; and identified an FXR\\u2192Src\\u2192YAP renal anti-fibrotic pathway.\",\n      \"evidence\": \"Lgr5 lineage tracing, organoids, APC/high-fat cancer models (intestinal CSC); FXR KO, co-IP of Hippo kinases and Src phosphorylation immunoblotting (renal)\",\n      \"pmids\": [\"30794774\", \"31298930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Src/YAP regulation is direct transcriptional vs. signaling-level remains unresolved\", \"Stem cell direct target genes not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined Rubicon and Perilipin-1 as direct FXR targets and SUMOylation as the mechanism of agonist resistance in activated stellate cells, linking FXR to autophagic flux and antifibrotic lipid droplet stability.\",\n      \"evidence\": \"FXR ChIP-seq, luciferase promoter assays, autophagic flux and Rubicon knockdown (Rubicon); SUMOylation assays, fibrosis mouse models and Perilipin-1 identification (HSC)\",\n      \"pmids\": [\"32001325\", \"31932588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO sites and responsible E3 ligase in activated HSCs not pinpointed\", \"Interplay between autophagy suppression and stellate cell quiescence not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established FXR as a cell-intrinsic immune regulator, sensing starvation in T cells to limit their metabolic fitness, and identified BRD4 as a required FXR co-factor for bile acid gene regulation and SMRT/NF-\\u03baB control.\",\n      \"evidence\": \"T cell-specific FXR KO with metabolic flux analysis (T cells); liver-specific BRD4 knockdown with ChIP of FXR/SMRT/NF-\\u03baB (cofactor)\",\n      \"pmids\": [\"33318189\", \"33290278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FXR target genes controlling T cell metabolism not defined\", \"Mechanism of BRD4 recruitment to FXR not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded FXR's regulatory reach to ACE2 transcription (controlling SARS-CoV-2 susceptibility), ILC3 maturation and IL-17 output, and SIRT6-mediated deacetylation as an activating modification conferring hepatoprotection.\",\n      \"evidence\": \"FXR ChIP and multi-model ACE2 studies (organoids, in vivo, ex vivo human organs); intestinal FXR activation with ILC profiling; SIRT6/FXR double-KO epistasis and deacetylation assays\",\n      \"pmids\": [\"36470304\", \"36508655\", \"35526796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FXR-acetylation residues targeted by SIRT6 not mapped\", \"Mechanism by which FXR shapes ILC differentiation not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FXR's transcriptional outputs are integrated across tissues to produce coherent metabolic, immune, and proliferative programs, and the residue-level rules governing PTM-dependent switching, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified map of PTM sites and their functional consequences\", \"Tissue-specific cofactor and corepressor logic incompletely defined\", \"Endogenous ligand-PTM crosstalk governing target selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7, 8, 12, 15]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 6, 7, 8, 12]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [1, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 8, 9, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 6, 7, 12, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RXR\", \"SHP\", \"ChREBP\", \"BRD4\", \"SMRT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}