{"gene":"KL","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2000,"finding":"Adenoviral delivery of the membrane-form klotho gene to klotho-deficient (kl/kl) mice rescued multiple aging-like pathological phenotypes including gonadal atrophy, immune tissue atrophy, and loss of subcutaneous fat, and extended lifespan, establishing that Klotho protein expression is sufficient to reverse these premature-aging phenotypes.","method":"Adenoviral gene delivery in vivo; macroscopic and histological analysis of rescued tissues","journal":"The journal of gene medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function rescue with defined phenotypic readouts in multiple organs, single lab, no molecular mechanism dissected","pmids":["10953914"],"is_preprint":false},{"year":2020,"finding":"H3K27me3 (histone 3 lysine 27 trimethylation) is physically associated with the KL promoter region in renal tubule cells, and its levels increase in aged and KL-mutant mouse kidneys due to downregulation of the H3K27 demethylase JMJD3; inhibition of PRC2 (the H3K27 trimethyltransferase complex) decreased H3K27me3 and increased KL expression and promoter activity, identifying epigenetic silencing via PRC2/H3K27me3 as a mechanism for age-associated KL downregulation.","method":"Chromatin immunoprecipitation (ChIP)-qPCR; KL promoter activity assays; Western blot; PRC2 inhibitor treatment in primary renal tubule cells; aged WT and KL-mutant mouse kidney comparison","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR directly links H3K27me3 to KL promoter, functional rescue with PRC2 inhibitor, single lab with two orthogonal methods","pmids":["32223380"],"is_preprint":false},{"year":2020,"finding":"KL deficiency impairs SGK1 (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a signaling in the kidney, leading to upregulation of p53 and p16 (markers of cellular aging), indicating that Klotho regulates the SGK1/FOXO3 pathway to suppress kidney cell aging.","method":"Western blot analysis of SGK1/FOXO3a/p53/p16 in aged WT vs. KL-mutant mouse kidneys","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (Western blot), correlative pathway placement without direct perturbation of the pathway","pmids":["32223380"],"is_preprint":false},{"year":2023,"finding":"In cardiomyocytes under diabetic/metabolic stress, the FGF21/FGFR1–β-klotho (β-KL) signaling cascade is required for anti-inflammatory and proangiogenic responses; decreased FGFR1 and β-KL expression was found in human and mouse diabetic hearts, and reinforcing cardiac FGFR1 and β-KL expression alleviated pro-inflammatory responses and endothelial dysfunction; proteomics identified novel cardiomyocyte-derived factors regulated by FGFR1–β-KL signaling.","method":"In vivo mouse diabetic heart models; human diabetic heart tissue analysis; cardiac FGFR1/β-KL overexpression; proteomics","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with proteomics, multiple methods, single lab; note this is β-klotho (KLB) co-receptor context, but paper explicitly studies FGFR1–β-KL cascade","pmids":["37123894"],"is_preprint":false}],"current_model":"Klotho (KL) protein functions as an aging suppressor whose expression in renal tubule cells is epigenetically repressed during aging via PRC2-mediated H3K27me3 at its promoter; Klotho deficiency impairs SGK1/FOXO3 signaling and promotes cellular aging markers, while adenoviral restoration of Klotho in deficient mice rescues multiple aging-like phenotypes across several organs; additionally, β-klotho acts as a co-receptor for FGF21/FGFR1 signaling in cardiomyocytes to modulate inflammation and angiogenesis under metabolic stress."},"narrative":{"mechanistic_narrative":"Klotho (KL) functions as an aging-suppressor protein whose restoration is sufficient to reverse premature-aging pathology: adenoviral delivery of membrane-form klotho to klotho-deficient mice rescued gonadal atrophy, immune tissue atrophy, and loss of subcutaneous fat while extending lifespan [PMID:10953914]. In the kidney, KL expression is repressed during aging through epigenetic silencing, as H3K27me3 accumulates at the KL promoter in aged and KL-mutant kidneys owing to loss of the H3K27 demethylase JMJD3, and PRC2 inhibition reverses this repression to restore KL promoter activity and expression [PMID:32223380]. KL deficiency in turn impairs SGK1/FOXO3a signaling and elevates the senescence markers p53 and p16, linking KL to suppression of kidney cell aging [PMID:32223380]. Beyond the membrane-form aging-suppressor activity, the related β-klotho co-receptor supports FGF21/FGFR1 signaling in cardiomyocytes, where reinforcing cardiac FGFR1 and β-KL expression alleviates inflammation and endothelial dysfunction under diabetic/metabolic stress [PMID:37123894]. The downstream molecular mechanism by which Klotho protein engages the SGK1/FOXO3 axis has not been directly dissected in the available corpus.","teleology":[{"year":2000,"claim":"Established that Klotho protein is causally sufficient, not merely correlated, to reverse premature-aging phenotypes, defining KL as a functional aging suppressor.","evidence":"Adenoviral membrane-form klotho delivery into klotho-deficient (kl/kl) mice with histological and lifespan readouts","pmids":["10953914"],"confidence":"Medium","gaps":["No molecular mechanism for how Klotho rescues the phenotypes was dissected","Multi-organ rescue does not identify a tissue-of-action or direct molecular target","Single lab"]},{"year":2020,"claim":"Answered why KL expression declines with age by identifying PRC2/H3K27me3-mediated epigenetic silencing at the KL promoter as the repressive mechanism.","evidence":"ChIP-qPCR, KL promoter activity assays, PRC2 inhibitor treatment in primary renal tubule cells, aged WT vs KL-mutant kidney comparison","pmids":["32223380"],"confidence":"Medium","gaps":["Upstream trigger for JMJD3 downregulation during aging is unknown","Restricted to renal tubule cells; not shown in other organs","Single lab"]},{"year":2020,"claim":"Placed KL upstream of the SGK1/FOXO3a senescence axis, connecting KL deficiency to cellular aging markers in the kidney.","evidence":"Western blot of SGK1/FOXO3a/p53/p16 in aged WT vs KL-mutant kidneys","pmids":["32223380"],"confidence":"Low","gaps":["Correlative pathway placement without direct perturbation of SGK1 or FOXO3a","Single method (Western blot)","No mechanism for how Klotho protein engages SGK1"]},{"year":2023,"claim":"Defined a distinct β-klotho co-receptor role in cardiomyocyte FGF21/FGFR1 signaling controlling inflammation and angiogenesis under metabolic stress.","evidence":"In vivo mouse diabetic heart models, human diabetic heart tissue, cardiac FGFR1/β-KL overexpression, proteomics","pmids":["37123894"],"confidence":"Medium","gaps":["This concerns β-klotho (KLB) co-receptor context rather than membrane KL","Cardiomyocyte-derived effector factors identified by proteomics are not functionally validated","Single lab"]},{"year":null,"claim":"How Klotho protein mechanistically couples to the SGK1/FOXO3 axis and whether the aging-suppressor and FGF co-receptor functions converge remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct molecular target of secreted/membrane Klotho identified in the corpus","No structural or biochemical mechanism for SGK1/FOXO3 regulation","Relationship between membrane KL and β-klotho functions not integrated"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1]}],"complexes":[],"partners":["FGFR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UEF7","full_name":"Klotho","aliases":[],"length_aa":1012,"mass_kda":116.2,"function":"May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D (By similarity). Essential factor for the specific interaction between FGF23 and FGFR1 (By similarity) The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UEF7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KL","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KL","total_profiled":1310},"omim":[{"mim_id":"621524","title":"WD REPEAT- AND SOCS BOX-CONTAINING PROTEIN 2; WSB2","url":"https://www.omim.org/entry/621524"},{"mim_id":"621521","title":"SCAFFOLDING CK1-ANCHORING PROTEIN E; SACK1E","url":"https://www.omim.org/entry/621521"},{"mim_id":"621520","title":"SCAFFOLDING CK1-ANCHORING PROTEIN C; SACK1C","url":"https://www.omim.org/entry/621520"},{"mim_id":"621519","title":"SCAFFOLDING CK1-ANCHORING PROTEIN B; SACK1B","url":"https://www.omim.org/entry/621519"},{"mim_id":"621393","title":"NEURODEVELOPMENTAL DISORDER WITH STRUCTURAL BRAIN ABNORMALITIES AND CRANIOFACIAL ABNORMALITIES; NEDBAC","url":"https://www.omim.org/entry/621393"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":120.2},{"tissue":"parathyroid gland","ntpm":127.3}],"url":"https://www.proteinatlas.org/search/KL"},"hgnc":{"alias_symbol":["KLA"],"prev_symbol":[]},"alphafold":{"accession":"Q9UEF7","domains":[{"cath_id":"3.20.20.80","chopping":"82-97_121-505","consensus_level":"medium","plddt":94.5051,"start":82,"end":505},{"cath_id":"3.20.20.80","chopping":"525-544_573-954","consensus_level":"medium","plddt":93.1496,"start":525,"end":954},{"cath_id":"-","chopping":"545-572","consensus_level":"medium","plddt":81.94,"start":545,"end":572}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UEF7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UEF7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UEF7-F1-predicted_aligned_error_v6.png","plddt_mean":89.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KL","jax_strain_url":"https://www.jax.org/strain/search?query=KL"},"sequence":{"accession":"Q9UEF7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UEF7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UEF7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UEF7"}},"corpus_meta":[{"pmid":"1698557","id":"PMC_1698557","title":"The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus.","date":"1990","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1698557","citation_count":1185,"is_preprint":false},{"pmid":"11818324","id":"PMC_11818324","title":"Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases.","date":"2002","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11818324","citation_count":339,"is_preprint":false},{"pmid":"22554854","id":"PMC_22554854","title":"Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases.","date":"2012","source":"Respiratory investigation","url":"https://pubmed.ncbi.nlm.nih.gov/22554854","citation_count":316,"is_preprint":false},{"pmid":"1378327","id":"PMC_1378327","title":"Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2.","date":"1992","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/1378327","citation_count":287,"is_preprint":false},{"pmid":"3411786","id":"PMC_3411786","title":"Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma.","date":"1988","source":"Japanese journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/3411786","citation_count":237,"is_preprint":false},{"pmid":"12959931","id":"PMC_12959931","title":"Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome.","date":"2003","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12959931","citation_count":155,"is_preprint":false},{"pmid":"17040248","id":"PMC_17040248","title":"Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases.","date":"2006","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17040248","citation_count":138,"is_preprint":false},{"pmid":"19286849","id":"PMC_19286849","title":"Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma.","date":"2009","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/19286849","citation_count":136,"is_preprint":false},{"pmid":"11069293","id":"PMC_11069293","title":"Y chromosomal fertility factors kl-2 and kl-3 of Drosophila melanogaster encode dynein heavy chain polypeptides.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11069293","citation_count":128,"is_preprint":false},{"pmid":"9778516","id":"PMC_9778516","title":"Stage-specific expression of the Kit receptor and its ligand (KL) during male gametogenesis in the mouse: a Kit-KL interaction critical for meiosis.","date":"1998","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9778516","citation_count":127,"is_preprint":false},{"pmid":"15170923","id":"PMC_15170923","title":"Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis.","date":"2004","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/15170923","citation_count":102,"is_preprint":false},{"pmid":"19098446","id":"PMC_19098446","title":"ATRA and KL promote differentiation toward the meiotic program of male germ cells.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19098446","citation_count":102,"is_preprint":false},{"pmid":"32470148","id":"PMC_32470148","title":"Serum KL-6 concentrations as a novel biomarker of severe COVID-19.","date":"2020","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/32470148","citation_count":87,"is_preprint":false},{"pmid":"20459699","id":"PMC_20459699","title":"Prescreening based on the presence of CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe radiation pneumonitis after stereotactic radiotherapy.","date":"2010","source":"Radiation oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20459699","citation_count":86,"is_preprint":false},{"pmid":"911843","id":"PMC_911843","title":"DNA damage in ultraviolet-irradiated HeLa and CHO-Kl cells examined by alkaline lysis and hydroxyapatite chromatography.","date":"1977","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/911843","citation_count":82,"is_preprint":false},{"pmid":"21950266","id":"PMC_21950266","title":"KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis.","date":"2011","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21950266","citation_count":75,"is_preprint":false},{"pmid":"20158912","id":"PMC_20158912","title":"Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients.","date":"2010","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20158912","citation_count":74,"is_preprint":false},{"pmid":"21796888","id":"PMC_21796888","title":"Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement.","date":"2011","source":"Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG","url":"https://pubmed.ncbi.nlm.nih.gov/21796888","citation_count":71,"is_preprint":false},{"pmid":"9769294","id":"PMC_9769294","title":"Serum and bronchoalveolar fluid KL-6 levels in patients with pulmonary alveolar proteinosis.","date":"1998","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9769294","citation_count":70,"is_preprint":false},{"pmid":"14665489","id":"PMC_14665489","title":"Study of Clara cell 16, KL-6, and surfactant protein-D in serum as disease markers in pulmonary sarcoidosis.","date":"2003","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/14665489","citation_count":67,"is_preprint":false},{"pmid":"26481343","id":"PMC_26481343","title":"The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis.","date":"2015","source":"Respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26481343","citation_count":66,"is_preprint":false},{"pmid":"29317345","id":"PMC_29317345","title":"MUC1 aptamer-targeted DNA micelles for dual tumor therapy using doxorubicin and KLA peptide.","date":"2018","source":"Nanomedicine : nanotechnology, biology, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29317345","citation_count":60,"is_preprint":false},{"pmid":"10888708","id":"PMC_10888708","title":"Serum KL-6 in adult patients with polymyositis and dermatomyositis.","date":"2000","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10888708","citation_count":60,"is_preprint":false},{"pmid":"22995277","id":"PMC_22995277","title":"Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels.","date":"2012","source":"Respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22995277","citation_count":58,"is_preprint":false},{"pmid":"33586127","id":"PMC_33586127","title":"Serum KL-6, CA19-9, CA125 and CEA are Diagnostic Biomarkers for Rheumatoid Arthritis-Associated Interstitial Lung Disease in the Chinese Population.","date":"2021","source":"Rheumatology and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33586127","citation_count":58,"is_preprint":false},{"pmid":"28275485","id":"PMC_28275485","title":"Serum KL-6 and surfactant protein-D as monitoring and predictive markers of interstitial lung disease in patients with systemic sclerosis and mixed connective tissue disease.","date":"2017","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/28275485","citation_count":55,"is_preprint":false},{"pmid":"36869843","id":"PMC_36869843","title":"Auto-Kla: a novel web server to discriminate lysine lactylation sites using automated machine learning.","date":"2023","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/36869843","citation_count":54,"is_preprint":false},{"pmid":"8454204","id":"PMC_8454204","title":"The kl-3 loop of the Y chromosome of Drosophila melanogaster binds a tektin-like protein.","date":"1993","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8454204","citation_count":54,"is_preprint":false},{"pmid":"19570688","id":"PMC_19570688","title":"Differential cytokine/chemokines and KL-6 profiles in patients with different forms of tuberculosis.","date":"2009","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/19570688","citation_count":53,"is_preprint":false},{"pmid":"10953914","id":"PMC_10953914","title":"Improvement of multiple pathophysiological phenotypes of klotho (kl/kl) mice by adenovirus-mediated expression of the klotho gene.","date":"2000","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10953914","citation_count":50,"is_preprint":false},{"pmid":"15654008","id":"PMC_15654008","title":"Serum KL-6 and surfactant proteins A and D in pediatric interstitial lung disease.","date":"2005","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/15654008","citation_count":49,"is_preprint":false},{"pmid":"34158479","id":"PMC_34158479","title":"KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34158479","citation_count":45,"is_preprint":false},{"pmid":"25619721","id":"PMC_25619721","title":"Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25619721","citation_count":43,"is_preprint":false},{"pmid":"21093413","id":"PMC_21093413","title":"Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21093413","citation_count":42,"is_preprint":false},{"pmid":"18595202","id":"PMC_18595202","title":"Serum surfactant protein-A, but not surfactant protein-D or KL-6, can predict preclinical lung damage induced by smoking.","date":"2008","source":"Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/18595202","citation_count":40,"is_preprint":false},{"pmid":"37903971","id":"PMC_37903971","title":"Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37903971","citation_count":38,"is_preprint":false},{"pmid":"30449228","id":"PMC_30449228","title":"Serum neopterin as well as ferritin, soluble interleukin-2 receptor, KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody-positive dermatomyositis.","date":"2019","source":"Modern rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/30449228","citation_count":38,"is_preprint":false},{"pmid":"32223380","id":"PMC_32223380","title":"Epigenetic Regulation of KL (Klotho) via H3K27me3 (Histone 3 Lysine [K] 27 Trimethylation) in Renal Tubule Cells.","date":"2020","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/32223380","citation_count":37,"is_preprint":false},{"pmid":"37950222","id":"PMC_37950222","title":"Lysine lactylation (Kla) might be a novel therapeutic target for breast cancer.","date":"2023","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37950222","citation_count":36,"is_preprint":false},{"pmid":"19900399","id":"PMC_19900399","title":"Potential-dependent membrane permeabilization and mitochondrial aggregation caused by anticancer polyarginine-KLA peptides.","date":"2009","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/19900399","citation_count":35,"is_preprint":false},{"pmid":"20103851","id":"PMC_20103851","title":"Clinicopathology of sialomucin: MUC1, particularly KL-6 mucin, in gastrointestinal, hepatic and pancreatic cancers.","date":"2009","source":"Bioscience trends","url":"https://pubmed.ncbi.nlm.nih.gov/20103851","citation_count":35,"is_preprint":false},{"pmid":"31794028","id":"PMC_31794028","title":"Lung ultrasound B-lines and serum KL-6 correlate with the severity of idiopathic inflammatory myositis-associated interstitial lung disease.","date":"2020","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31794028","citation_count":33,"is_preprint":false},{"pmid":"29397453","id":"PMC_29397453","title":"Synergistic effect of the pro-apoptosis peptide kla-TAT and the cationic anticancer peptide HPRP-A1.","date":"2018","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/29397453","citation_count":32,"is_preprint":false},{"pmid":"11478809","id":"PMC_11478809","title":"The paralemmin protein family: identification of paralemmin-2, an isoform differentially spliced to AKAP2/AKAP-KL, and of palmdelphin, a more distant cytosolic relative.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11478809","citation_count":31,"is_preprint":false},{"pmid":"32307698","id":"PMC_32307698","title":"Serum KL-6 levels in pulmonary Langerhans' cell histiocytosis.","date":"2020","source":"European journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32307698","citation_count":30,"is_preprint":false},{"pmid":"21569324","id":"PMC_21569324","title":"Ageing and long-term smoking affects KL-6 levels in the lung, induced sputum and plasma.","date":"2011","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21569324","citation_count":30,"is_preprint":false},{"pmid":"24289110","id":"PMC_24289110","title":"Correlation between mass transfer coefficient kLa and relevant operating parameters in cylindrical disposable shaken bioreactors on a bench-to-pilot scale.","date":"2013","source":"Journal of biological engineering","url":"https://pubmed.ncbi.nlm.nih.gov/24289110","citation_count":30,"is_preprint":false},{"pmid":"18085378","id":"PMC_18085378","title":"Immunohistochemical and immunoelectron microscopic studies of the localization of KL-6 and epithelial membrane antigen (EMA) in presumably normal pulmonary tissue and in interstitial pneumonia.","date":"2007","source":"Medical molecular morphology","url":"https://pubmed.ncbi.nlm.nih.gov/18085378","citation_count":30,"is_preprint":false},{"pmid":"15386618","id":"PMC_15386618","title":"Studies on the cellular uptake of substance P and lysine-rich, KLA-derived model peptides.","date":"2005","source":"Journal of molecular recognition : JMR","url":"https://pubmed.ncbi.nlm.nih.gov/15386618","citation_count":29,"is_preprint":false},{"pmid":"21474912","id":"PMC_21474912","title":"Levels of surfactant proteins A and D and KL-6 are elevated in the induced sputum of chronic obstructive pulmonary disease patients: a sequential sputum analysis.","date":"2011","source":"Respiration; international review of thoracic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21474912","citation_count":29,"is_preprint":false},{"pmid":"27108412","id":"PMC_27108412","title":"MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis.","date":"2016","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27108412","citation_count":28,"is_preprint":false},{"pmid":"22963039","id":"PMC_22963039","title":"The elevation of serum napsin A in idiopathic pulmonary fibrosis, compared with KL-6, surfactant protein-A and surfactant protein-D.","date":"2012","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22963039","citation_count":28,"is_preprint":false},{"pmid":"33672761","id":"PMC_33672761","title":"Serum KL-6 Could Represent a Reliable Indicator of Unfavourable Outcome in Patients with COVID-19 Pneumonia.","date":"2021","source":"International journal of environmental research and public health","url":"https://pubmed.ncbi.nlm.nih.gov/33672761","citation_count":28,"is_preprint":false},{"pmid":"30233844","id":"PMC_30233844","title":"Diagnostic value of KL-6 in idiopathic interstitial pneumonia.","date":"2018","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/30233844","citation_count":27,"is_preprint":false},{"pmid":"11694811","id":"PMC_11694811","title":"KL-6, surfactant protein A and D in bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis.","date":"2001","source":"Respiration; international review of thoracic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/11694811","citation_count":26,"is_preprint":false},{"pmid":"32078140","id":"PMC_32078140","title":"Bronchoalveolar lavage and serum KL-6 concentrations in chronic hypersensitivity pneumonitis: correlations with radiological and immunological features.","date":"2020","source":"Internal and emergency medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32078140","citation_count":26,"is_preprint":false},{"pmid":"16157978","id":"PMC_16157978","title":"KL-6 and surfactant proteins A and D in serum and bronchoalveolar lavage fluid in patients with acute eosinophilic pneumonia.","date":"2005","source":"Internal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/16157978","citation_count":26,"is_preprint":false},{"pmid":"36879786","id":"PMC_36879786","title":"Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study.","date":"2022","source":"The Lancet regional health. Western Pacific","url":"https://pubmed.ncbi.nlm.nih.gov/36879786","citation_count":25,"is_preprint":false},{"pmid":"21555868","id":"PMC_21555868","title":"Pneumocyte biomarkers KL-6 and surfactant protein D reflect the distinct findings of high-resolution computed tomography in nonspecific interstitial pneumonia.","date":"2011","source":"Respiration; international review of thoracic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21555868","citation_count":25,"is_preprint":false},{"pmid":"36413367","id":"PMC_36413367","title":"Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden.","date":"2022","source":"JAMA network open","url":"https://pubmed.ncbi.nlm.nih.gov/36413367","citation_count":24,"is_preprint":false},{"pmid":"12533025","id":"PMC_12533025","title":"KL/KIT co-expression in mouse fetal oocytes.","date":"2002","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/12533025","citation_count":24,"is_preprint":false},{"pmid":"33267857","id":"PMC_33267857","title":"Serum SP-A and KL-6 levels can predict the improvement and deterioration of patients with interstitial pneumonia with autoimmune features.","date":"2020","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33267857","citation_count":23,"is_preprint":false},{"pmid":"33427737","id":"PMC_33427737","title":"Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes.","date":"2021","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/33427737","citation_count":22,"is_preprint":false},{"pmid":"31703065","id":"PMC_31703065","title":"Coadministration of kla peptide with HPRP-A1 to enhance anticancer activity.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31703065","citation_count":20,"is_preprint":false},{"pmid":"26879611","id":"PMC_26879611","title":"[The expression and clinical role of KL-6 in serum and BALF of patients with different diffuse interstitial lung diseases].","date":"2016","source":"Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26879611","citation_count":20,"is_preprint":false},{"pmid":"35788062","id":"PMC_35788062","title":"YKL-40 and KL-6 Levels in Serum and Sputum of Patients Diagnosed With Hypersensitivity Pneumonitis.","date":"2022","source":"The journal of allergy and clinical immunology. In practice","url":"https://pubmed.ncbi.nlm.nih.gov/35788062","citation_count":19,"is_preprint":false},{"pmid":"25242856","id":"PMC_25242856","title":"A comparison of KL-6 and Clara cell protein as markers for predicting bronchopulmonary dysplasia in preterm infants.","date":"2014","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/25242856","citation_count":19,"is_preprint":false},{"pmid":"18430782","id":"PMC_18430782","title":"Drosophila melanogaster kl-3 and kl-5 Y-loops harbor triple-stranded nucleic acids.","date":"2008","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/18430782","citation_count":17,"is_preprint":false},{"pmid":"23123449","id":"PMC_23123449","title":"Phenethyl caffeate benzo[kl]xanthene lignan with DNA interacting properties induces DNA damage and apoptosis in colon cancer cells.","date":"2012","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23123449","citation_count":17,"is_preprint":false},{"pmid":"34401147","id":"PMC_34401147","title":"Association of serum KL-6 levels on COVID-19 severity: A cross-sectional study design with purposive sampling.","date":"2021","source":"Annals of medicine and surgery (2012)","url":"https://pubmed.ncbi.nlm.nih.gov/34401147","citation_count":17,"is_preprint":false},{"pmid":"19960788","id":"PMC_19960788","title":"Serum KL-6 as a novel disease marker in adolescent and adult cystic fibrosis.","date":"2009","source":"Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG","url":"https://pubmed.ncbi.nlm.nih.gov/19960788","citation_count":17,"is_preprint":false},{"pmid":"30389434","id":"PMC_30389434","title":"Anti-KL-6/MUC1 monoclonal antibody reverses resistance to trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity by capping MUC1.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30389434","citation_count":16,"is_preprint":false},{"pmid":"29247834","id":"PMC_29247834","title":"The KL-VS polymorphism of KLOTHO gene is protective against retinopathy incidence in patients with type 1 diabetes.","date":"2017","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/29247834","citation_count":16,"is_preprint":false},{"pmid":"12924525","id":"PMC_12924525","title":"KL-6, a human MUC1 mucin, is expressed early in premature lung.","date":"2003","source":"Respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12924525","citation_count":16,"is_preprint":false},{"pmid":"16630141","id":"PMC_16630141","title":"Anti-tumor effect of the anti-KL-6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping.","date":"2006","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/16630141","citation_count":16,"is_preprint":false},{"pmid":"37123894","id":"PMC_37123894","title":"FGF21/FGFR1-β-KL cascade in cardiomyocytes modulates angiogenesis and inflammation under metabolic stress.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37123894","citation_count":15,"is_preprint":false},{"pmid":"24302189","id":"PMC_24302189","title":"KL-6 regulated the expression of HGF, collagen and myofibroblast differentiation.","date":"2013","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24302189","citation_count":15,"is_preprint":false},{"pmid":"34540037","id":"PMC_34540037","title":"The value of KL-6 in the diagnosis and assessment of interstitial lung disease.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34540037","citation_count":15,"is_preprint":false},{"pmid":"23672275","id":"PMC_23672275","title":"Bleomycin-induced pulmonary fibrosis is attenuated by an antibody against KL-6.","date":"2013","source":"Experimental lung research","url":"https://pubmed.ncbi.nlm.nih.gov/23672275","citation_count":15,"is_preprint":false},{"pmid":"39000606","id":"PMC_39000606","title":"KL-Biome (Postbiotic Formulation of Lactiplantibacillus plantarum KM2) Improves Dexamethasone-Induced Muscle Atrophy in Mice.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39000606","citation_count":14,"is_preprint":false},{"pmid":"39030746","id":"PMC_39030746","title":"KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults.","date":"2024","source":"Alzheimer's & dementia : the journal of the Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/39030746","citation_count":14,"is_preprint":false},{"pmid":"28447897","id":"PMC_28447897","title":"Specific hepatic stellate cell-penetrating peptide targeted delivery of a KLA peptide reduces collagen accumulation by inducing apoptosis.","date":"2017","source":"Journal of drug targeting","url":"https://pubmed.ncbi.nlm.nih.gov/28447897","citation_count":14,"is_preprint":false},{"pmid":"16645232","id":"PMC_16645232","title":"Simultaneous measurements of KL-6 and SP-D in patients undergoing thoracic radiotherapy.","date":"2006","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16645232","citation_count":14,"is_preprint":false},{"pmid":"21663735","id":"PMC_21663735","title":"Klotho KL-VS genotype is involved in blood pressure regulation.","date":"2011","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21663735","citation_count":14,"is_preprint":false},{"pmid":"19735643","id":"PMC_19735643","title":"Partitioning, dynamics, and orientation of lung surfactant peptide KL(4) in phospholipid bilayers.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19735643","citation_count":14,"is_preprint":false},{"pmid":"32966647","id":"PMC_32966647","title":"Krebs von den Lungen-6 (KL-6) is a pathophysiological biomarker of early-stage acute hypersensitivity pneumonitis among pigeon fanciers.","date":"2020","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32966647","citation_count":14,"is_preprint":false},{"pmid":"37409133","id":"PMC_37409133","title":"KL-6 levels in the connective tissue disease population: typical values and potential confounders-a retrospective, real-world study.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37409133","citation_count":13,"is_preprint":false},{"pmid":"21617869","id":"PMC_21617869","title":"Expression of KL-6/MUC1 in pancreatic cancer tissues and its potential involvement in tumor metastasis.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21617869","citation_count":13,"is_preprint":false},{"pmid":"28906002","id":"PMC_28906002","title":"Anti-inflammatory activities and glycerophospholipids metabolism in KLA-stimulated RAW 264.7 macrophage cells by diarylheptanoids from the rhizomes of Alpinia officinarum.","date":"2017","source":"Biomedical chromatography : BMC","url":"https://pubmed.ncbi.nlm.nih.gov/28906002","citation_count":13,"is_preprint":false},{"pmid":"19631667","id":"PMC_19631667","title":"Expression of KL-6 mucin, a human MUC1 mucin, in intrahepatic cholangiocarcinoma and its potential involvement in tumor cell adhesion and invasion.","date":"2009","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19631667","citation_count":13,"is_preprint":false},{"pmid":"2455378","id":"PMC_2455378","title":"Immunohistochemistry (S 100, KL 1) and human papillomavirus DNA hybridization on morbus Bowen and bowenoid papulosis.","date":"1988","source":"Virchows Archiv. A, Pathological anatomy and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/2455378","citation_count":13,"is_preprint":false},{"pmid":"25232251","id":"PMC_25232251","title":"Inhibition of KL-6/MUC1 glycosylation limits aggressive progression of pancreatic cancer.","date":"2014","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25232251","citation_count":12,"is_preprint":false},{"pmid":"23410752","id":"PMC_23410752","title":"A novel lung injury animal model using KL-6-measurable human MUC1-expressing mice.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23410752","citation_count":12,"is_preprint":false},{"pmid":"38773736","id":"PMC_38773736","title":"Research progress of KL-6 in respiratory system diseases.","date":"2024","source":"Critical reviews in clinical laboratory sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38773736","citation_count":11,"is_preprint":false},{"pmid":"36505396","id":"PMC_36505396","title":"AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes.","date":"2022","source":"Alzheimer's & dementia (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/36505396","citation_count":11,"is_preprint":false},{"pmid":"21466814","id":"PMC_21466814","title":"Expression of KL-6/MUC1 in pancreatic ductal carcinoma and its potential relationship with β-catenin in tumor progression.","date":"2011","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21466814","citation_count":11,"is_preprint":false},{"pmid":"11530020","id":"PMC_11530020","title":"Domain and genomic sequence analysis of bdellin-KL, a leech-derived trypsin-plasmin inhibitor.","date":"2001","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11530020","citation_count":11,"is_preprint":false},{"pmid":"28370220","id":"PMC_28370220","title":"Impact of anti-tumor necrosis factor-α agents on serum levels of KL-6 and surfactant protein-D in patients with psoriasis.","date":"2017","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28370220","citation_count":11,"is_preprint":false},{"pmid":"39503345","id":"PMC_39503345","title":"Histone Lysine Lactylation (Kla)-induced BCAM Promotes OSCC Progression and Cis-Platinum Resistance.","date":"2024","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39503345","citation_count":10,"is_preprint":false},{"pmid":"39940859","id":"PMC_39940859","title":"Serum KL-6 and SP-D: Markers of Lung Function in Autoimmune-Related Interstitial Lung Diseases.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39940859","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55763,"output_tokens":1855,"usd":0.097557,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7932,"output_tokens":1772,"usd":0.04198,"stage2_stop_reason":"end_turn"},"total_usd":0.139537,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical KL gene (Klotho) and mechanistic findings. Let me classify each paper:\n\n- Papers about KL-6/MUC1 biomarker (ILD, lung disease): These are about a MUC1 mucin antigen detected by a monoclonal antibody called KL-6, NOT the Klotho (KL) gene. These should be EXCLUDED.\n- Papers about KL = Kit Ligand (Steel factor/SCF): Papers [1], [4], [10], [12], [61] - these are about the mouse Steel locus ligand, which is SCF/KITLG, NOT the Klotho gene KL. These should be EXCLUDED as a different gene (KITLG/SCF, not KL/Klotho).\n- Papers about Klotho gene (KL/KLA): Papers [30], [38], [32], [34], [60], [63], [73], [76], [81], [84], [95] - these are about the Klotho aging-suppressor gene.\n- Drosophila kl-2, kl-3, kl-5 fertility factors: Different genes, symbol collision - EXCLUDE.\n- KLA peptide (KLAKLAK)2: antimicrobial/anticancer peptide, not the gene - EXCLUDE.\n- Kla = lysine lactylation: post-translational modification nomenclature, not the gene - EXCLUDE.\n- KL-A167: anti-PD-L1 antibody drug - EXCLUDE.\n- KL(4) peptide: lung surfactant peptide - EXCLUDE.\n- KL-Biome: probiotic - EXCLUDE.\n- bdellin-KL: leech protein - EXCLUDE.\n\nNow let me focus on Klotho (KL) papers and extract mechanistic discoveries:\n\n- [30]: Adenoviral expression of klotho gene in klotho mutant mice - functional rescue\n- [38]: H3K27me3 regulation of KL gene expression\n- [76]: FGF21/FGFR1-β-KL cascade in cardiomyocytes\n- [32], [60], [63], [81], [84], [95]: KL-VS variant associations - mostly genetic association studies, not direct mechanistic experiments on the protein\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Adenoviral delivery of the membrane-form klotho gene to klotho-deficient (kl/kl) mice rescued multiple aging-like pathological phenotypes including gonadal atrophy, immune tissue atrophy, and loss of subcutaneous fat, and extended lifespan, establishing that Klotho protein expression is sufficient to reverse these premature-aging phenotypes.\",\n      \"method\": \"Adenoviral gene delivery in vivo; macroscopic and histological analysis of rescued tissues\",\n      \"journal\": \"The journal of gene medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function rescue with defined phenotypic readouts in multiple organs, single lab, no molecular mechanism dissected\",\n      \"pmids\": [\"10953914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"H3K27me3 (histone 3 lysine 27 trimethylation) is physically associated with the KL promoter region in renal tubule cells, and its levels increase in aged and KL-mutant mouse kidneys due to downregulation of the H3K27 demethylase JMJD3; inhibition of PRC2 (the H3K27 trimethyltransferase complex) decreased H3K27me3 and increased KL expression and promoter activity, identifying epigenetic silencing via PRC2/H3K27me3 as a mechanism for age-associated KL downregulation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP)-qPCR; KL promoter activity assays; Western blot; PRC2 inhibitor treatment in primary renal tubule cells; aged WT and KL-mutant mouse kidney comparison\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR directly links H3K27me3 to KL promoter, functional rescue with PRC2 inhibitor, single lab with two orthogonal methods\",\n      \"pmids\": [\"32223380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KL deficiency impairs SGK1 (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a signaling in the kidney, leading to upregulation of p53 and p16 (markers of cellular aging), indicating that Klotho regulates the SGK1/FOXO3 pathway to suppress kidney cell aging.\",\n      \"method\": \"Western blot analysis of SGK1/FOXO3a/p53/p16 in aged WT vs. KL-mutant mouse kidneys\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (Western blot), correlative pathway placement without direct perturbation of the pathway\",\n      \"pmids\": [\"32223380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In cardiomyocytes under diabetic/metabolic stress, the FGF21/FGFR1–β-klotho (β-KL) signaling cascade is required for anti-inflammatory and proangiogenic responses; decreased FGFR1 and β-KL expression was found in human and mouse diabetic hearts, and reinforcing cardiac FGFR1 and β-KL expression alleviated pro-inflammatory responses and endothelial dysfunction; proteomics identified novel cardiomyocyte-derived factors regulated by FGFR1–β-KL signaling.\",\n      \"method\": \"In vivo mouse diabetic heart models; human diabetic heart tissue analysis; cardiac FGFR1/β-KL overexpression; proteomics\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with proteomics, multiple methods, single lab; note this is β-klotho (KLB) co-receptor context, but paper explicitly studies FGFR1–β-KL cascade\",\n      \"pmids\": [\"37123894\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Klotho (KL) protein functions as an aging suppressor whose expression in renal tubule cells is epigenetically repressed during aging via PRC2-mediated H3K27me3 at its promoter; Klotho deficiency impairs SGK1/FOXO3 signaling and promotes cellular aging markers, while adenoviral restoration of Klotho in deficient mice rescues multiple aging-like phenotypes across several organs; additionally, β-klotho acts as a co-receptor for FGF21/FGFR1 signaling in cardiomyocytes to modulate inflammation and angiogenesis under metabolic stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Klotho (KL) functions as an aging-suppressor protein whose restoration is sufficient to reverse premature-aging pathology: adenoviral delivery of membrane-form klotho to klotho-deficient mice rescued gonadal atrophy, immune tissue atrophy, and loss of subcutaneous fat while extending lifespan [#0]. In the kidney, KL expression is repressed during aging through epigenetic silencing, as H3K27me3 accumulates at the KL promoter in aged and KL-mutant kidneys owing to loss of the H3K27 demethylase JMJD3, and PRC2 inhibition reverses this repression to restore KL promoter activity and expression [#1]. KL deficiency in turn impairs SGK1/FOXO3a signaling and elevates the senescence markers p53 and p16, linking KL to suppression of kidney cell aging [#2]. Beyond the membrane-form aging-suppressor activity, the related \\u03b2-klotho co-receptor supports FGF21/FGFR1 signaling in cardiomyocytes, where reinforcing cardiac FGFR1 and \\u03b2-KL expression alleviates inflammation and endothelial dysfunction under diabetic/metabolic stress [#3]. The downstream molecular mechanism by which Klotho protein engages the SGK1/FOXO3 axis has not been directly dissected in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that Klotho protein is causally sufficient, not merely correlated, to reverse premature-aging phenotypes, defining KL as a functional aging suppressor.\",\n      \"evidence\": \"Adenoviral membrane-form klotho delivery into klotho-deficient (kl/kl) mice with histological and lifespan readouts\",\n      \"pmids\": [\"10953914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for how Klotho rescues the phenotypes was dissected\", \"Multi-organ rescue does not identify a tissue-of-action or direct molecular target\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Answered why KL expression declines with age by identifying PRC2/H3K27me3-mediated epigenetic silencing at the KL promoter as the repressive mechanism.\",\n      \"evidence\": \"ChIP-qPCR, KL promoter activity assays, PRC2 inhibitor treatment in primary renal tubule cells, aged WT vs KL-mutant kidney comparison\",\n      \"pmids\": [\"32223380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream trigger for JMJD3 downregulation during aging is unknown\", \"Restricted to renal tubule cells; not shown in other organs\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed KL upstream of the SGK1/FOXO3a senescence axis, connecting KL deficiency to cellular aging markers in the kidney.\",\n      \"evidence\": \"Western blot of SGK1/FOXO3a/p53/p16 in aged WT vs KL-mutant kidneys\",\n      \"pmids\": [\"32223380\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative pathway placement without direct perturbation of SGK1 or FOXO3a\", \"Single method (Western blot)\", \"No mechanism for how Klotho protein engages SGK1\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a distinct \\u03b2-klotho co-receptor role in cardiomyocyte FGF21/FGFR1 signaling controlling inflammation and angiogenesis under metabolic stress.\",\n      \"evidence\": \"In vivo mouse diabetic heart models, human diabetic heart tissue, cardiac FGFR1/\\u03b2-KL overexpression, proteomics\",\n      \"pmids\": [\"37123894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"This concerns \\u03b2-klotho (KLB) co-receptor context rather than membrane KL\", \"Cardiomyocyte-derived effector factors identified by proteomics are not functionally validated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Klotho protein mechanistically couples to the SGK1/FOXO3 axis and whether the aging-suppressor and FGF co-receptor functions converge remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct molecular target of secreted/membrane Klotho identified in the corpus\", \"No structural or biochemical mechanism for SGK1/FOXO3 regulation\", \"Relationship between membrane KL and \\u03b2-klotho functions not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FGFR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}