{"gene":"KLB","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2012,"finding":"KLB (β-Klotho) is an indispensable co-receptor mediating the binding of FGF19 and FGF21 to FGFRs; FGF21 binds FGFR1-KLB complex with much higher affinity than FGFR4-KLB, while FGF19 binds both FGFR1-KLB and FGFR4-KLB with comparable affinity. FGF1 binding to FGFRs does not require KLB and is to a distinct site from FGF19/FGF21.","method":"Direct quantitative binding kinetics assays, downstream signal transduction assays, and early response gene expression measurements in mice","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (binding kinetics, signaling assays, in vivo tissue responses, KLB/FGFR1 ablation), consistent results across assay types","pmids":["22442730"],"is_preprint":false},{"year":2012,"finding":"KLB and FGFR1c form a 1:1 heterocomplex at the plasma membrane independent of the galectin lattice; addition of FGF21 induces FGFR1c dimerization without changing KLB aggregate size, resulting in a 1:2 KLB-FGFR1c signaling complex. KLB associates with the galectin lattice, and disruption of this lattice (via lactose) increases KLB mobility and enhances FGF21-induced signaling.","method":"Fluorescence recovery after photobleaching (FRAP), number and brightness analysis, co-immunoprecipitation with galectin-3, live-cell imaging of fluorescent protein-tagged KLB and FGFR1c","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal live-cell biophysical methods plus co-IP, single lab but rigorous quantitative approaches","pmids":["22523080"],"is_preprint":false},{"year":2016,"finding":"Brain-specific KLB knockout mice show increased alcohol preference, and FGF21 inhibits alcohol drinking by acting on the brain via the KLB co-receptor, establishing a liver-brain FGF21/KLB endocrine axis regulating alcohol consumption.","method":"Brain-specific KLB knockout mice with alcohol preference behavioral testing; FGF21 administration experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with defined behavioral phenotype, replicated with exogenous FGF21 administration","pmids":["27911795"],"is_preprint":false},{"year":2017,"finding":"KLB is required for FGF21 signaling to GnRH neurons; loss-of-function KLB mutations in CHH patients impair FGF21/KLB/FGFR1 signaling, and in mice lacking Klb, GnRH neurons cannot release GnRH in response to FGF21, causing delayed puberty and subfertility. Peripheral FGF21 reaches GnRH neurons via circumventricular organs.","method":"Genetic screening of CHH patients; Klb knockout mouse model; GnRH neuron functional assays; FGF21 administration with brain delivery tracking","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined neuroendocrine phenotype plus human genetics plus FGF21 functional rescue experiments","pmids":["28754744"],"is_preprint":false},{"year":2018,"finding":"Short C-terminal peptides of FGF19 and FGF21 are sufficient to bind KLB and act as antagonists of FGF19/21 receptor signaling. Both FGFs maintain highly conserved structural determinants for KLB binding. A single C-terminal amino acid in FGF19 modulates relative activity through FGFR1 vs. FGFR4. An FGF21 chimera with an optimized C-terminal sequence acts as a super-agonist of KLB-mediated signaling.","method":"In vitro functional assays with C-terminal peptide fragments; alanine-scanning mutagenesis; in vivo metabolic outcomes in obese mice","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with mutagenesis scanning plus in vivo validation, single lab with multiple orthogonal methods","pmids":["29789271"],"is_preprint":false},{"year":2018,"finding":"Tyrosine-207 of FGF21 is the crucial amino acid responsible for loss of FGFR1-KLB binding affinity upon iodination; mutation of Y207 to phenylalanine preserves FGFR1-KLB affinity. An intramolecular disulfide bond between cysteine-102 and cysteine-121 exists in FGF21 but is not responsible for the loss of binding.","method":"Site-directed mutagenesis, molecular modeling, iodination experiments, FGFR1-KLB binding affinity assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — site-directed mutagenesis with binding assays, single lab, single study","pmids":["30317562"],"is_preprint":false},{"year":2021,"finding":"Neuronal KLB is required for part of glucagon receptor (GCGR) agonism-mediated weight loss; mice with neuronal Klb deficiency or central KLB pharmacological inhibition show partial resistance to GCGR-agonist-induced weight loss, but central KLB is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides.","method":"Neuronal Klb conditional knockout mice; central pharmacological KLB antagonism (compound 1153); chronic GCGR agonism (IUB288) with body weight and metabolic measurements","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two complementary approaches (genetic KO and pharmacological antagonism) with defined metabolic phenotypes in the same study","pmids":["33411693"],"is_preprint":false},{"year":2021,"finding":"KLB knockdown in muscle progenitor cells (MPCs) promotes myogenesis and mTOR activation, whereas FGF21 treatment inhibits myogenesis in a dose-dependent manner, establishing KLB as a mediator of impaired muscle development in IUGR through inhibition of mTOR signaling. These effects are conserved in both porcine and human fetal MPCs.","method":"KLB siRNA knockdown in fetal muscle progenitor cells; FGF21 treatment; fusion index measurement; myogenic transcript quantification; mTOR activity assays; in vitro human and pig fetal MPC cultures","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype plus FGF21 functional experiments, replicated across two species (pig and human), single lab","pmids":["35081669"],"is_preprint":false},{"year":2023,"finding":"KLB is an upstream regulator of β-catenin signaling in hepatocellular carcinoma; KLB knockdown promotes HCC cell metastasis via β-catenin-driven EMT. HDAC3 acts as a deacetylase for KLB, and HDAC3 inhibitor-induced acetylation leads to KLB inactivation, blocking FGF21-KLB signaling and triggering EMT.","method":"KLB knockdown in Huh7 cells; migration/invasion assays; co-immunoprecipitation for acetylation; gene set variation analysis; in vitro and in vivo metastasis assays; HDAC3 inhibitor treatment","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — KD with defined phenotype, co-IP for PTM identification, in vitro and in vivo validation, single lab","pmids":["37350415"],"is_preprint":false},{"year":2024,"finding":"In liver, KLB knockdown reduces the beneficial effects of ketogenic diet on hepatic steatosis, insulin resistance, and lipid metabolism, demonstrating that liver FGF21-KLB-FGFR1 signaling is required for KD-induced amelioration of fatty liver.","method":"Adeno-associated virus-mediated liver-specific KLB knockdown mice; ketogenic diet feeding; multi-omics; phenotypic assessment of hepatic steatosis and insulin resistance","journal":"Nutrition & diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — liver-specific KD with defined metabolic phenotype and multi-omics, single lab","pmids":["38609395"],"is_preprint":false},{"year":2025,"finding":"KLB overexpression in hepatocytes (HepG2 cells) reduces intracellular lipid accumulation in free fatty acid-loaded cells by modulating lipid metabolism gene expression, and counteracts LPS-induced inflammatory gene activation and NF-κB (p65) phosphorylation, establishing a cell-autonomous anti-lipogenic and anti-inflammatory role for KLB in hepatocytes.","method":"KLB overexpression in HepG2 cells; free fatty acid loading; lipid accumulation assays; gene expression analysis; LPS stimulation with NF-κB phosphorylation measurement","journal":"JHEP reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — OE with defined cellular phenotypes (lipid and inflammatory), multiple readouts, single lab","pmids":["41810430"],"is_preprint":false},{"year":2026,"finding":"KLB knockdown in HCC cells enhances expression of TFRC (a ferroptosis driver gene) and blocks the ferroptosis-inhibitory effect of FGF19, indicating that FGF19 inhibits ferroptosis in HCC cells through FGFR4-KLB co-receptor signaling.","method":"KLB knockdown; western blotting; reactive oxygen species (ROS) assay; TFRC expression measurement","journal":"Arab journal of gastroenterology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD with limited readouts (western blot, ROS assay), single lab, single study","pmids":["41654439"],"is_preprint":false},{"year":2024,"finding":"FGF21 autocrinally drives lipolysis in cancer-associated adipocytes through upregulation of adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling; FGF21 deletion in adipose tissue impedes lipolysis, demonstrating that KLB is required for FGF21-mediated ATGL induction in adipocytes.","method":"FGF21 adipose-specific deletion; ATGL inhibition; FGFR1/KLB signaling pathway analysis; p38 pathway assessment; lipolysis assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, pathway placement inferred from KO and inhibition, mechanistic detail limited in abstract","pmids":[],"is_preprint":true},{"year":2025,"finding":"A discrete population of glutamatergic, Klb-expressing neurons in the nucleus of the solitary tract (NTS) mediates FGF21 action during dietary protein restriction; these neurons are directly activated by FGF21, and their selective ablation prevents metabolic adaptations (food intake, food choice, energy expenditure) to protein restriction, while chemogenetic activation is sufficient to drive these responses.","method":"Novel Klb-Flp mouse line; intersectional genetics; neuronal ablation; chemogenetic activation (DREADD); metabolic phenotyping during protein restriction","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint with cell-type-specific ablation and chemogenetic activation showing bidirectional control, multiple metabolic readouts","pmids":[],"is_preprint":true}],"current_model":"KLB (β-Klotho) functions as an obligate co-receptor that enables FGF19 and FGF21 to bind and activate FGFR complexes (preferentially FGFR1-KLB for FGF21, and both FGFR1-KLB and FGFR4-KLB for FGF19); at the plasma membrane KLB forms a 1:1 heterocomplex with FGFR1 that transitions to a 1:2 signaling complex upon FGF21 binding; KLB expression in the brain (including NTS glutamatergic neurons) mediates FGF21's central effects on alcohol preference, energy balance, and protein restriction responses; in peripheral tissues KLB mediates FGF21/FGF19 regulation of lipid metabolism in liver and adipose, muscle development via mTOR, GnRH neuron function, and ferroptosis suppression in liver cancer cells, with KLB itself subject to acetylation/deacetylation by HDAC3 that modulates its activity."},"narrative":{"mechanistic_narrative":"KLB (β-Klotho) is an obligate transmembrane co-receptor that confers receptor selectivity for the endocrine fibroblast growth factors FGF19 and FGF21, enabling them to bind and activate FGFR complexes—FGF21 binds the FGFR1-KLB complex with high affinity while FGF19 engages both FGFR1-KLB and FGFR4-KLB, whereas FGF1 signaling is KLB-independent [PMID:22442730]. At the plasma membrane KLB and FGFR1c assemble as a preformed 1:1 heterocomplex that transitions to a 1:2 KLB-FGFR1c signaling complex upon FGF21-induced FGFR1c dimerization, a process modulated by association with the galectin lattice [PMID:22523080]. Ligand engagement of KLB is governed by conserved C-terminal determinants of FGF19/FGF21 that are sufficient for binding and can be engineered into antagonists or super-agonists [PMID:29789271]. Through this co-receptor function KLB transduces FGF21/FGF19 signals across central and peripheral tissues: brain and NTS glutamatergic KLB-expressing neurons mediate FGF21 control of alcohol preference and adaptation to dietary protein restriction [PMID:27911795], hypothalamic KLB is required for FGF21 signaling to GnRH neurons with loss-of-function KLB mutations causing congenital hypogonadotropic hypothorism in patients [PMID:28754744], and liver and adipose KLB mediate FGF21/FGF19 regulation of lipid metabolism, hepatic steatosis, and inflammation [PMID:38609395, PMID:41810430]. KLB also restrains myogenesis through inhibition of mTOR in muscle progenitor cells [PMID:35081669] and acts in hepatocellular carcinoma where it is deacetylated by HDAC3 and regulates β-catenin-driven EMT [PMID:37350415].","teleology":[{"year":2012,"claim":"Established the core molecular function of KLB: it is the indispensable co-receptor that determines which FGFRs FGF19 and FGF21 can bind and activate, resolving how these endocrine FGFs achieve receptor selectivity.","evidence":"Quantitative binding kinetics, signaling assays, and early-response gene measurements in mice with KLB/FGFR1 ablation","pmids":["22442730"],"confidence":"High","gaps":["Did not resolve the stoichiometry or membrane organization of the receptor complex","Did not address tissue-specific downstream physiology"]},{"year":2012,"claim":"Defined the membrane architecture and assembly dynamics of the receptor complex, showing a preformed 1:1 KLB-FGFR1c heterocomplex converts to a 1:2 signaling complex on ligand binding and that the galectin lattice tunes signaling.","evidence":"FRAP, number-and-brightness analysis, galectin-3 co-IP, and live-cell imaging of tagged KLB and FGFR1c","pmids":["22523080"],"confidence":"High","gaps":["Structural basis of the transition not determined","Mechanism by which the galectin lattice restrains KLB mobility unresolved"]},{"year":2016,"claim":"Demonstrated a physiological central role for KLB by showing brain KLB mediates FGF21's suppression of alcohol intake, defining a liver-brain endocrine axis.","evidence":"Brain-specific KLB knockout mice with alcohol preference testing plus exogenous FGF21 administration","pmids":["27911795"],"confidence":"High","gaps":["Specific neuronal populations not identified","Downstream neural circuitry unresolved"]},{"year":2017,"claim":"Linked KLB to human reproductive disease by showing it is required for FGF21 signaling to GnRH neurons and that loss-of-function mutations cause congenital hypogonadotropic hypogonadism.","evidence":"CHH patient genetic screening, Klb knockout mice, GnRH neuron functional assays, and FGF21 brain-delivery tracking","pmids":["28754744"],"confidence":"High","gaps":["Mechanism by which FGF21 triggers GnRH release downstream of KLB not detailed","Route of peripheral FGF21 access fully via circumventricular organs not exhaustively mapped"]},{"year":2018,"claim":"Mapped the ligand-side determinants of KLB binding, showing FGF C-terminal sequences are sufficient and engineerable, enabling rational agonist/antagonist design.","evidence":"C-terminal peptide functional assays, alanine-scanning mutagenesis, and in vivo metabolic outcomes in obese mice; complemented by site-directed mutagenesis identifying FGF21 Y207 as critical for FGFR1-KLB affinity","pmids":["29789271","30317562"],"confidence":"High","gaps":["Co-crystal structure of KLB with the C-terminal peptides not reported","Generalizability of single-residue tuning across both FGFR1 and FGFR4 contexts limited"]},{"year":2021,"claim":"Extended KLB's central function beyond FGF21, showing neuronal KLB contributes to glucagon-receptor-agonist-induced weight loss, and revealed KLB as a mediator of muscle development via mTOR.","evidence":"Neuronal Klb conditional KO and central pharmacological antagonism with GCGR agonism; separately, KLB siRNA knockdown and FGF21 treatment in pig and human fetal muscle progenitor cells","pmids":["33411693","35081669"],"confidence":"Medium","gaps":["How a GCGR agonist engages the central KLB pathway mechanistically unclear","Direct demonstration that endogenous FGF21 drives the muscle phenotype in vivo lacking"]},{"year":2024,"claim":"Established peripheral metabolic and cancer-associated roles, showing liver KLB is required for ketogenic-diet amelioration of fatty liver and that KLB acts cell-autonomously as anti-lipogenic/anti-inflammatory in hepatocytes; also implicated KLB in tumor biology and PTM regulation.","evidence":"Liver-specific AAV KLB knockdown with ketogenic diet and multi-omics; KLB overexpression in HepG2 with FFA loading and LPS/NF-κB readouts; KLB knockdown with HDAC3 acetylation co-IP and metastasis assays in HCC","pmids":["38609395","41810430","37350415"],"confidence":"Medium","gaps":["Whether acetylation/deacetylation directly alters ligand binding versus downstream output not resolved","Connection between KLB co-receptor function and cell-autonomous anti-inflammatory effects unclear"]},{"year":2025,"claim":"Refined the central circuit, identifying a discrete glutamatergic Klb-expressing NTS neuronal population that is necessary and sufficient for FGF21-driven metabolic adaptation to protein restriction.","evidence":"Klb-Flp mouse line, intersectional genetics, neuronal ablation, and chemogenetic activation during dietary protein restriction (preprint)","pmids":[],"confidence":"Medium","gaps":["Downstream projection targets of these NTS neurons not mapped","Preprint, not yet peer-reviewed"]},{"year":null,"claim":"How KLB acetylation status, galectin-lattice association, and tissue-specific receptor partner availability are integrated to control the magnitude and selectivity of FGF19/FGF21 signaling in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the full ligand-KLB-FGFR signaling complex","Causal role of KLB acetylation in physiological signaling not established in vivo","Mechanism connecting co-receptor activity to ferroptosis suppression unconfirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,10]}],"complexes":["KLB-FGFR1c co-receptor complex","KLB-FGFR4 co-receptor complex"],"partners":["FGFR1","FGFR4","FGF21","FGF19","LGALS3","HDAC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86Z14","full_name":"Beta-klotho","aliases":["Klotho beta-like protein"],"length_aa":1044,"mass_kda":119.8,"function":"Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21 (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86Z14/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLB","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KLB","total_profiled":1310},"omim":[{"mim_id":"620879","title":"FIBROBLAST GROWTH FACTOR-BINDING PROTEIN 3; FGFBP3","url":"https://www.omim.org/entry/620879"},{"mim_id":"611135","title":"KLOTHO, BETA; KLB","url":"https://www.omim.org/entry/611135"},{"mim_id":"609436","title":"FIBROBLAST GROWTH FACTOR 21; FGF21","url":"https://www.omim.org/entry/609436"},{"mim_id":"604824","title":"KLOTHO; KL","url":"https://www.omim.org/entry/604824"},{"mim_id":"603891","title":"FIBROBLAST GROWTH FACTOR 19; FGF19","url":"https://www.omim.org/entry/603891"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adipose tissue","ntpm":18.4},{"tissue":"liver","ntpm":16.6}],"url":"https://www.proteinatlas.org/search/KLB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q86Z14","domains":[{"cath_id":"3.20.20.80","chopping":"87-506","consensus_level":"medium","plddt":95.9718,"start":87,"end":506},{"cath_id":"-","chopping":"513-545_572-595_820-828_866-971","consensus_level":"medium","plddt":93.0194,"start":513,"end":971},{"cath_id":"-","chopping":"600-724","consensus_level":"medium","plddt":95.146,"start":600,"end":724},{"cath_id":"-","chopping":"749-818_830-864","consensus_level":"medium","plddt":95.4076,"start":749,"end":864}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86Z14","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86Z14-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86Z14-F1-predicted_aligned_error_v6.png","plddt_mean":89.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLB","jax_strain_url":"https://www.jax.org/strain/search?query=KLB"},"sequence":{"accession":"Q86Z14","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86Z14.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86Z14/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86Z14"}},"corpus_meta":[{"pmid":"27911795","id":"PMC_27911795","title":"KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27911795","citation_count":195,"is_preprint":false},{"pmid":"22442730","id":"PMC_22442730","title":"Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22442730","citation_count":154,"is_preprint":false},{"pmid":"28754744","id":"PMC_28754744","title":"KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.","date":"2017","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28754744","citation_count":71,"is_preprint":false},{"pmid":"22523080","id":"PMC_22523080","title":"Dynamics and Distribution of Klothoβ (KLB) and fibroblast growth factor receptor-1 (FGFR1) in living cells reveal the fibroblast growth factor-21 (FGF21)-induced receptor complex.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22523080","citation_count":43,"is_preprint":false},{"pmid":"29789271","id":"PMC_29789271","title":"Molecular elements in FGF19 and FGF21 defining KLB/FGFR activity and specificity.","date":"2018","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29789271","citation_count":39,"is_preprint":false},{"pmid":"33411693","id":"PMC_33411693","title":"Glucagon receptor signaling regulates weight loss via central KLB receptor complexes.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/33411693","citation_count":31,"is_preprint":false},{"pmid":"33640795","id":"PMC_33640795","title":"The KLB rs17618244 gene variant is associated with fibrosing MAFLD by promoting hepatic stellate cell 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Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/33045954","citation_count":19,"is_preprint":false},{"pmid":"31792121","id":"PMC_31792121","title":"Precision Oncology for Hepatocellular Cancer: Slivering the Liver by FGF19-FGF4-KLB Pathway Inhibition.","date":"2019","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/31792121","citation_count":15,"is_preprint":false},{"pmid":"37350415","id":"PMC_37350415","title":"Aberrant acetylated modification of FGF21‑KLB signaling contributes to hepatocellular carcinoma metastasis through the β‑catenin pathway.","date":"2023","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37350415","citation_count":5,"is_preprint":false},{"pmid":"30317562","id":"PMC_30317562","title":"Identification of a crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30317562","citation_count":5,"is_preprint":false},{"pmid":"41654439","id":"PMC_41654439","title":"FGF19/FGFR4/KLB signaling participate in the ferroptosis regulation of hepatocellular carcinoma.","date":"2026","source":"Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/41654439","citation_count":0,"is_preprint":false},{"pmid":"41810430","id":"PMC_41810430","title":"The KLB rs12152703 variant confers protection against hepatic inflammation in patients with MASLD by boosting Klotho-beta expression.","date":"2025","source":"JHEP reports : innovation in hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/41810430","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.27.684772","title":"Downregulated expression of hepatic β-Klotho is associated with the hypertensive phenotype in SHR","date":"2025-10-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.27.684772","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.17.25340409","title":"Transcriptomic evidence linking adaptive immunity and the IGF-1 pathway in carpal tunnel syndrome","date":"2025-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.17.25340409","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.19.649640","title":"FGF21 signals through KLB-expressing glutamatergic neurons in the hindbrain to mediate the effects of dietary protein restriction","date":"2025-04-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.19.649640","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.18.618991","title":"Cancer-associated adipocytes mediate CD8  <sup>+</sup>  T cell dysfunction via FGF21-driven lipolysis","date":"2024-10-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.18.618991","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.20.25340712","title":"Comprehensive genomic atlas of plasma proteome in the Japanese population: the Nagahama study","date":"2025-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.20.25340712","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14227,"output_tokens":3770,"usd":0.049615,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11376,"output_tokens":3268,"usd":0.06929,"stage2_stop_reason":"end_turn"},"total_usd":0.118905,"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\": 2012,\n      \"finding\": \"KLB (β-Klotho) is an indispensable co-receptor mediating the binding of FGF19 and FGF21 to FGFRs; FGF21 binds FGFR1-KLB complex with much higher affinity than FGFR4-KLB, while FGF19 binds both FGFR1-KLB and FGFR4-KLB with comparable affinity. FGF1 binding to FGFRs does not require KLB and is to a distinct site from FGF19/FGF21.\",\n      \"method\": \"Direct quantitative binding kinetics assays, downstream signal transduction assays, and early response gene expression measurements in mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (binding kinetics, signaling assays, in vivo tissue responses, KLB/FGFR1 ablation), consistent results across assay types\",\n      \"pmids\": [\"22442730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KLB and FGFR1c form a 1:1 heterocomplex at the plasma membrane independent of the galectin lattice; addition of FGF21 induces FGFR1c dimerization without changing KLB aggregate size, resulting in a 1:2 KLB-FGFR1c signaling complex. KLB associates with the galectin lattice, and disruption of this lattice (via lactose) increases KLB mobility and enhances FGF21-induced signaling.\",\n      \"method\": \"Fluorescence recovery after photobleaching (FRAP), number and brightness analysis, co-immunoprecipitation with galectin-3, live-cell imaging of fluorescent protein-tagged KLB and FGFR1c\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal live-cell biophysical methods plus co-IP, single lab but rigorous quantitative approaches\",\n      \"pmids\": [\"22523080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Brain-specific KLB knockout mice show increased alcohol preference, and FGF21 inhibits alcohol drinking by acting on the brain via the KLB co-receptor, establishing a liver-brain FGF21/KLB endocrine axis regulating alcohol consumption.\",\n      \"method\": \"Brain-specific KLB knockout mice with alcohol preference behavioral testing; FGF21 administration experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with defined behavioral phenotype, replicated with exogenous FGF21 administration\",\n      \"pmids\": [\"27911795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLB is required for FGF21 signaling to GnRH neurons; loss-of-function KLB mutations in CHH patients impair FGF21/KLB/FGFR1 signaling, and in mice lacking Klb, GnRH neurons cannot release GnRH in response to FGF21, causing delayed puberty and subfertility. Peripheral FGF21 reaches GnRH neurons via circumventricular organs.\",\n      \"method\": \"Genetic screening of CHH patients; Klb knockout mouse model; GnRH neuron functional assays; FGF21 administration with brain delivery tracking\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined neuroendocrine phenotype plus human genetics plus FGF21 functional rescue experiments\",\n      \"pmids\": [\"28754744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Short C-terminal peptides of FGF19 and FGF21 are sufficient to bind KLB and act as antagonists of FGF19/21 receptor signaling. Both FGFs maintain highly conserved structural determinants for KLB binding. A single C-terminal amino acid in FGF19 modulates relative activity through FGFR1 vs. FGFR4. An FGF21 chimera with an optimized C-terminal sequence acts as a super-agonist of KLB-mediated signaling.\",\n      \"method\": \"In vitro functional assays with C-terminal peptide fragments; alanine-scanning mutagenesis; in vivo metabolic outcomes in obese mice\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with mutagenesis scanning plus in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29789271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tyrosine-207 of FGF21 is the crucial amino acid responsible for loss of FGFR1-KLB binding affinity upon iodination; mutation of Y207 to phenylalanine preserves FGFR1-KLB affinity. An intramolecular disulfide bond between cysteine-102 and cysteine-121 exists in FGF21 but is not responsible for the loss of binding.\",\n      \"method\": \"Site-directed mutagenesis, molecular modeling, iodination experiments, FGFR1-KLB binding affinity assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — site-directed mutagenesis with binding assays, single lab, single study\",\n      \"pmids\": [\"30317562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Neuronal KLB is required for part of glucagon receptor (GCGR) agonism-mediated weight loss; mice with neuronal Klb deficiency or central KLB pharmacological inhibition show partial resistance to GCGR-agonist-induced weight loss, but central KLB is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides.\",\n      \"method\": \"Neuronal Klb conditional knockout mice; central pharmacological KLB antagonism (compound 1153); chronic GCGR agonism (IUB288) with body weight and metabolic measurements\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary approaches (genetic KO and pharmacological antagonism) with defined metabolic phenotypes in the same study\",\n      \"pmids\": [\"33411693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KLB knockdown in muscle progenitor cells (MPCs) promotes myogenesis and mTOR activation, whereas FGF21 treatment inhibits myogenesis in a dose-dependent manner, establishing KLB as a mediator of impaired muscle development in IUGR through inhibition of mTOR signaling. These effects are conserved in both porcine and human fetal MPCs.\",\n      \"method\": \"KLB siRNA knockdown in fetal muscle progenitor cells; FGF21 treatment; fusion index measurement; myogenic transcript quantification; mTOR activity assays; in vitro human and pig fetal MPC cultures\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype plus FGF21 functional experiments, replicated across two species (pig and human), single lab\",\n      \"pmids\": [\"35081669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KLB is an upstream regulator of β-catenin signaling in hepatocellular carcinoma; KLB knockdown promotes HCC cell metastasis via β-catenin-driven EMT. HDAC3 acts as a deacetylase for KLB, and HDAC3 inhibitor-induced acetylation leads to KLB inactivation, blocking FGF21-KLB signaling and triggering EMT.\",\n      \"method\": \"KLB knockdown in Huh7 cells; migration/invasion assays; co-immunoprecipitation for acetylation; gene set variation analysis; in vitro and in vivo metastasis assays; HDAC3 inhibitor treatment\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — KD with defined phenotype, co-IP for PTM identification, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"37350415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In liver, KLB knockdown reduces the beneficial effects of ketogenic diet on hepatic steatosis, insulin resistance, and lipid metabolism, demonstrating that liver FGF21-KLB-FGFR1 signaling is required for KD-induced amelioration of fatty liver.\",\n      \"method\": \"Adeno-associated virus-mediated liver-specific KLB knockdown mice; ketogenic diet feeding; multi-omics; phenotypic assessment of hepatic steatosis and insulin resistance\",\n      \"journal\": \"Nutrition & diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — liver-specific KD with defined metabolic phenotype and multi-omics, single lab\",\n      \"pmids\": [\"38609395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLB overexpression in hepatocytes (HepG2 cells) reduces intracellular lipid accumulation in free fatty acid-loaded cells by modulating lipid metabolism gene expression, and counteracts LPS-induced inflammatory gene activation and NF-κB (p65) phosphorylation, establishing a cell-autonomous anti-lipogenic and anti-inflammatory role for KLB in hepatocytes.\",\n      \"method\": \"KLB overexpression in HepG2 cells; free fatty acid loading; lipid accumulation assays; gene expression analysis; LPS stimulation with NF-κB phosphorylation measurement\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — OE with defined cellular phenotypes (lipid and inflammatory), multiple readouts, single lab\",\n      \"pmids\": [\"41810430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KLB knockdown in HCC cells enhances expression of TFRC (a ferroptosis driver gene) and blocks the ferroptosis-inhibitory effect of FGF19, indicating that FGF19 inhibits ferroptosis in HCC cells through FGFR4-KLB co-receptor signaling.\",\n      \"method\": \"KLB knockdown; western blotting; reactive oxygen species (ROS) assay; TFRC expression measurement\",\n      \"journal\": \"Arab journal of gastroenterology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD with limited readouts (western blot, ROS assay), single lab, single study\",\n      \"pmids\": [\"41654439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FGF21 autocrinally drives lipolysis in cancer-associated adipocytes through upregulation of adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling; FGF21 deletion in adipose tissue impedes lipolysis, demonstrating that KLB is required for FGF21-mediated ATGL induction in adipocytes.\",\n      \"method\": \"FGF21 adipose-specific deletion; ATGL inhibition; FGFR1/KLB signaling pathway analysis; p38 pathway assessment; lipolysis assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, pathway placement inferred from KO and inhibition, mechanistic detail limited in abstract\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A discrete population of glutamatergic, Klb-expressing neurons in the nucleus of the solitary tract (NTS) mediates FGF21 action during dietary protein restriction; these neurons are directly activated by FGF21, and their selective ablation prevents metabolic adaptations (food intake, food choice, energy expenditure) to protein restriction, while chemogenetic activation is sufficient to drive these responses.\",\n      \"method\": \"Novel Klb-Flp mouse line; intersectional genetics; neuronal ablation; chemogenetic activation (DREADD); metabolic phenotyping during protein restriction\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint with cell-type-specific ablation and chemogenetic activation showing bidirectional control, multiple metabolic readouts\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KLB (β-Klotho) functions as an obligate co-receptor that enables FGF19 and FGF21 to bind and activate FGFR complexes (preferentially FGFR1-KLB for FGF21, and both FGFR1-KLB and FGFR4-KLB for FGF19); at the plasma membrane KLB forms a 1:1 heterocomplex with FGFR1 that transitions to a 1:2 signaling complex upon FGF21 binding; KLB expression in the brain (including NTS glutamatergic neurons) mediates FGF21's central effects on alcohol preference, energy balance, and protein restriction responses; in peripheral tissues KLB mediates FGF21/FGF19 regulation of lipid metabolism in liver and adipose, muscle development via mTOR, GnRH neuron function, and ferroptosis suppression in liver cancer cells, with KLB itself subject to acetylation/deacetylation by HDAC3 that modulates its activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLB (β-Klotho) is an obligate transmembrane co-receptor that confers receptor selectivity for the endocrine fibroblast growth factors FGF19 and FGF21, enabling them to bind and activate FGFR complexes—FGF21 binds the FGFR1-KLB complex with high affinity while FGF19 engages both FGFR1-KLB and FGFR4-KLB, whereas FGF1 signaling is KLB-independent [#0]. At the plasma membrane KLB and FGFR1c assemble as a preformed 1:1 heterocomplex that transitions to a 1:2 KLB-FGFR1c signaling complex upon FGF21-induced FGFR1c dimerization, a process modulated by association with the galectin lattice [#1]. Ligand engagement of KLB is governed by conserved C-terminal determinants of FGF19/FGF21 that are sufficient for binding and can be engineered into antagonists or super-agonists [#4]. Through this co-receptor function KLB transduces FGF21/FGF19 signals across central and peripheral tissues: brain and NTS glutamatergic KLB-expressing neurons mediate FGF21 control of alcohol preference and adaptation to dietary protein restriction [#2, #13], hypothalamic KLB is required for FGF21 signaling to GnRH neurons with loss-of-function KLB mutations causing congenital hypogonadotropic hypothorism in patients [#3], and liver and adipose KLB mediate FGF21/FGF19 regulation of lipid metabolism, hepatic steatosis, and inflammation [#9, #10]. KLB also restrains myogenesis through inhibition of mTOR in muscle progenitor cells [#7] and acts in hepatocellular carcinoma where it is deacetylated by HDAC3 and regulates β-catenin-driven EMT [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the core molecular function of KLB: it is the indispensable co-receptor that determines which FGFRs FGF19 and FGF21 can bind and activate, resolving how these endocrine FGFs achieve receptor selectivity.\",\n      \"evidence\": \"Quantitative binding kinetics, signaling assays, and early-response gene measurements in mice with KLB/FGFR1 ablation\",\n      \"pmids\": [\"22442730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the stoichiometry or membrane organization of the receptor complex\", \"Did not address tissue-specific downstream physiology\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the membrane architecture and assembly dynamics of the receptor complex, showing a preformed 1:1 KLB-FGFR1c heterocomplex converts to a 1:2 signaling complex on ligand binding and that the galectin lattice tunes signaling.\",\n      \"evidence\": \"FRAP, number-and-brightness analysis, galectin-3 co-IP, and live-cell imaging of tagged KLB and FGFR1c\",\n      \"pmids\": [\"22523080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the transition not determined\", \"Mechanism by which the galectin lattice restrains KLB mobility unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a physiological central role for KLB by showing brain KLB mediates FGF21's suppression of alcohol intake, defining a liver-brain endocrine axis.\",\n      \"evidence\": \"Brain-specific KLB knockout mice with alcohol preference testing plus exogenous FGF21 administration\",\n      \"pmids\": [\"27911795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific neuronal populations not identified\", \"Downstream neural circuitry unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked KLB to human reproductive disease by showing it is required for FGF21 signaling to GnRH neurons and that loss-of-function mutations cause congenital hypogonadotropic hypogonadism.\",\n      \"evidence\": \"CHH patient genetic screening, Klb knockout mice, GnRH neuron functional assays, and FGF21 brain-delivery tracking\",\n      \"pmids\": [\"28754744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FGF21 triggers GnRH release downstream of KLB not detailed\", \"Route of peripheral FGF21 access fully via circumventricular organs not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped the ligand-side determinants of KLB binding, showing FGF C-terminal sequences are sufficient and engineerable, enabling rational agonist/antagonist design.\",\n      \"evidence\": \"C-terminal peptide functional assays, alanine-scanning mutagenesis, and in vivo metabolic outcomes in obese mice; complemented by site-directed mutagenesis identifying FGF21 Y207 as critical for FGFR1-KLB affinity\",\n      \"pmids\": [\"29789271\", \"30317562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-crystal structure of KLB with the C-terminal peptides not reported\", \"Generalizability of single-residue tuning across both FGFR1 and FGFR4 contexts limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended KLB's central function beyond FGF21, showing neuronal KLB contributes to glucagon-receptor-agonist-induced weight loss, and revealed KLB as a mediator of muscle development via mTOR.\",\n      \"evidence\": \"Neuronal Klb conditional KO and central pharmacological antagonism with GCGR agonism; separately, KLB siRNA knockdown and FGF21 treatment in pig and human fetal muscle progenitor cells\",\n      \"pmids\": [\"33411693\", \"35081669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a GCGR agonist engages the central KLB pathway mechanistically unclear\", \"Direct demonstration that endogenous FGF21 drives the muscle phenotype in vivo lacking\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established peripheral metabolic and cancer-associated roles, showing liver KLB is required for ketogenic-diet amelioration of fatty liver and that KLB acts cell-autonomously as anti-lipogenic/anti-inflammatory in hepatocytes; also implicated KLB in tumor biology and PTM regulation.\",\n      \"evidence\": \"Liver-specific AAV KLB knockdown with ketogenic diet and multi-omics; KLB overexpression in HepG2 with FFA loading and LPS/NF-κB readouts; KLB knockdown with HDAC3 acetylation co-IP and metastasis assays in HCC\",\n      \"pmids\": [\"38609395\", \"41810430\", \"37350415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether acetylation/deacetylation directly alters ligand binding versus downstream output not resolved\", \"Connection between KLB co-receptor function and cell-autonomous anti-inflammatory effects unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the central circuit, identifying a discrete glutamatergic Klb-expressing NTS neuronal population that is necessary and sufficient for FGF21-driven metabolic adaptation to protein restriction.\",\n      \"evidence\": \"Klb-Flp mouse line, intersectional genetics, neuronal ablation, and chemogenetic activation during dietary protein restriction (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream projection targets of these NTS neurons not mapped\", \"Preprint, not yet peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KLB acetylation status, galectin-lattice association, and tissue-specific receptor partner availability are integrated to control the magnitude and selectivity of FGF19/FGF21 signaling in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the full ligand-KLB-FGFR signaling complex\", \"Causal role of KLB acetylation in physiological signaling not established in vivo\", \"Mechanism connecting co-receptor activity to ferroptosis suppression unconfirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\"KLB-FGFR1c co-receptor complex\", \"KLB-FGFR4 co-receptor complex\"],\n    \"partners\": [\"FGFR1\", \"FGFR4\", \"FGF21\", \"FGF19\", \"LGALS3\", \"HDAC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}