{"gene":"C1QTNF7","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2008,"finding":"CTRP7 (C1QTNF-related protein 7) is a secreted glycoprotein that forms trimers as its basic structural unit when expressed in mammalian cells. CTRP7 forms heterotrimers with CTRP2 (CTRP2/CTRP7 heterotrimers), providing a mechanism to potentially generate functionally distinct ligands.","method":"Mammalian cell expression, biochemical characterization of secreted protein oligomeric states, co-expression and co-immunoprecipitation/secretion assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization of secreted protein oligomerization in mammalian cells with multiple CTRPs tested, single lab but multiple orthogonal methods described","pmids":["18783346"],"is_preprint":false},{"year":2017,"finding":"Genetic deletion of CTRP7 in mice fed a high-fat diet attenuated insulin resistance and enhanced glucose tolerance, reduced adipose tissue inflammation, and decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress, establishing CTRP7 as a contributor to obesity-linked metabolic dysfunction.","method":"Genetic loss-of-function mouse model (Ctrp7 knockout), metabolic phenotyping (glucose/insulin tolerance tests), adipose tissue inflammation markers, liver fibrosis and ER stress assays","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple defined cellular and metabolic phenotypic readouts, effects were diet-dependent and independent of body weight/metabolic rate","pmids":["28223291"],"is_preprint":false},{"year":2022,"finding":"CTRP7 overexpression in hepatocytes facilitated oxidative stress and suppressed the phosphorylation of insulin signaling molecules, placing CTRP7 as a promoter of hepatic insulin resistance via oxidative stress.","method":"In vitro hepatocyte overexpression, measurement of oxidative stress markers (ROS, SOD, GSH, MDA), western blotting of insulin signaling phosphorylation","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro functional assay with defined mechanistic readouts (oxidative stress markers + insulin signaling phosphorylation), single lab","pmids":["35368863"],"is_preprint":false},{"year":2022,"finding":"In vascular smooth muscle cells, BK channel α subunit deficiency reduces CTRP7 levels, and CTRP7 knockdown activates PI3K/Akt signaling; CTRP7 was identified as a downstream target of BK channels by RNA sequencing, placing CTRP7 in a BK channel → CTRP7 → PI3K/Akt axis regulating vascular remodeling.","method":"RNA sequencing of BK channel α subunit knockout (BK α−/−) rat aortas, qPCR verification, siRNA knockdown of CTRP7 in HUASMCs, PI3K/Akt pathway western blotting","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq pathway discovery combined with siRNA knockdown and defined signaling readout, single lab","pmids":["36514218"],"is_preprint":false},{"year":2025,"finding":"In pulmonary artery smooth muscle cells (PASMCs), IL-6 upregulates CTRP7 transcription (demonstrated by chromatin immunoprecipitation). CTRP7 in turn reduces expression of the prostacyclin analogue receptor (PTGIR) through Rab5a-mediated internalization, resulting in diminished responsiveness to selexipag (a prostacyclin analogue). AAV-mediated silencing of CTRP7 in pulmonary arteries of hypoxic PH mice mitigated reduced PTGIR expression and improved responses to selexipag.","method":"Chromatin immunoprecipitation (ChIP) for IL-6 binding to CTRP7 promoter in PASMCs; receptor internalization assay (Rab5a-mediated); AAV-mediated CTRP7 silencing in vivo; IL-6-R neutralizing antibody treatment in hypoxic PH mice; functional measurements (cardiac output, pulmonary artery resistance)","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal mechanistic methods (ChIP, receptor internalization assay, in vivo AAV silencing, pharmacological rescue) in both human cell and animal model, single lab but highly rigorous","pmids":["40504501"],"is_preprint":false}],"current_model":"C1QTNF7/CTRP7 is a secreted homotrimeric glycoprotein (also forming CTRP2/CTRP7 heterotrimers) that acts as a pro-metabolic stress factor: it is induced in the liver and adipose tissue by obesity and by IL-6 signaling; its genetic deletion in mice ameliorates obesity-linked insulin resistance, adipose inflammation, and hepatic ER/oxidative stress; in hepatocytes its overexpression drives oxidative stress and suppresses insulin signaling phosphorylation; in pulmonary artery smooth muscle cells it reduces prostacyclin receptor (PTGIR) surface expression through Rab5a-mediated internalization downstream of IL-6, thereby impairing responsiveness to prostacyclin analogues; and in vascular smooth muscle cells it acts downstream of BK channels to suppress PI3K/Akt-driven vascular remodeling."},"narrative":{"mechanistic_narrative":"C1QTNF7 (CTRP7) is a secreted glycoprotein that acts as a pro-metabolic and pro-vascular-remodeling stress factor, contributing to obesity-linked metabolic dysfunction and pulmonary vascular disease [PMID:28223291, PMID:40504501]. It assembles into homotrimers as its basic structural unit and can form heterotrimers with CTRP2, providing a route to generate distinct secreted ligands [PMID:18783346]. In a high-fat-diet mouse model, genetic deletion of CTRP7 attenuates insulin resistance, reduces adipose inflammation, and lowers hepatic fibrosis and ER/oxidative stress, establishing the protein as a driver of metabolic dysfunction [PMID:28223291]; consistent with this, hepatocyte overexpression promotes oxidative stress and suppresses insulin signaling phosphorylation [PMID:35368863]. In the vasculature, CTRP7 functions downstream of BK channels in an axis where its loss activates PI3K/Akt signaling governing vascular remodeling [PMID:36514218]. In pulmonary artery smooth muscle cells, IL-6 transcriptionally upregulates CTRP7, which then reduces surface PTGIR (prostacyclin receptor) through Rab5a-mediated internalization, blunting responsiveness to the prostacyclin analogue selexipag; AAV-mediated silencing of CTRP7 in hypoxic pulmonary hypertension mice restores PTGIR levels and drug response [PMID:40504501].","teleology":[{"year":2008,"claim":"Establishing CTRP7's biochemical nature as a secreted oligomeric protein defined the structural form in which it could act as a ligand and revealed combinatorial heterotrimer assembly with CTRP2.","evidence":"Mammalian cell expression and biochemical characterization of secreted oligomeric states, with co-expression and co-IP/secretion assays","pmids":["18783346"],"confidence":"Medium","gaps":["No receptor or downstream effector identified at this stage","Functional consequence of CTRP2/CTRP7 heterotrimers versus homotrimers not resolved","No tissue-level or physiological role established"]},{"year":2017,"claim":"A loss-of-function mouse model answered whether CTRP7 contributes to disease physiology, establishing it as a driver of obesity-linked insulin resistance, adipose inflammation, and hepatic stress.","evidence":"Ctrp7 knockout mice on high-fat diet with glucose/insulin tolerance tests, adipose inflammation markers, and liver fibrosis/ER stress assays","pmids":["28223291"],"confidence":"High","gaps":["Molecular mechanism connecting CTRP7 to insulin signaling not defined in this study","Receptor mediating metabolic effects unknown","Cell-autonomous versus systemic contributions not separated"]},{"year":2022,"claim":"Hepatocyte overexpression provided a cell-level mechanism, linking CTRP7 to oxidative stress and suppression of insulin signaling phosphorylation, consistent with the knockout metabolic phenotype.","evidence":"In vitro hepatocyte overexpression with oxidative stress markers (ROS, SOD, GSH, MDA) and western blotting of insulin signaling phosphorylation","pmids":["35368863"],"confidence":"Medium","gaps":["Receptor or signaling entry point through which CTRP7 acts not identified","Single lab in vitro overexpression, not reconciled with secreted-ligand biology","Direction of causality between oxidative stress and insulin signaling not dissected"]},{"year":2022,"claim":"Transcriptomic and knockdown work placed CTRP7 in a vascular signaling axis, showing it lies downstream of BK channels and restrains PI3K/Akt-driven remodeling.","evidence":"RNA-seq of BK channel α-subunit knockout rat aortas, qPCR, siRNA knockdown in human umbilical artery smooth muscle cells, and PI3K/Akt western blotting","pmids":["36514218"],"confidence":"Medium","gaps":["Mechanism by which BK channels regulate CTRP7 levels unknown","How secreted CTRP7 suppresses PI3K/Akt mechanistically not defined","In vivo vascular phenotype of CTRP7 perturbation not tested here"]},{"year":2025,"claim":"A multi-method study resolved a defined signaling cascade, showing IL-6 transcriptionally induces CTRP7, which drives Rab5a-mediated internalization of PTGIR and reduces prostacyclin-analogue responsiveness in pulmonary hypertension.","evidence":"ChIP for IL-6 at the CTRP7 promoter in PASMCs, Rab5a-mediated receptor internalization assay, in vivo AAV silencing and IL-6R antibody treatment in hypoxic PH mice with hemodynamic readouts","pmids":["40504501"],"confidence":"High","gaps":["Direct receptor through which secreted CTRP7 triggers Rab5a-mediated PTGIR internalization not identified","Whether the same IL-6→CTRP7→PTGIR axis operates in the metabolic tissues is untested","Structural basis of CTRP7 action remains uncharacterized"]},{"year":null,"claim":"The cell-surface receptor(s) and direct molecular effectors that transduce secreted CTRP7 signaling across metabolic and vascular contexts remain unidentified.","evidence":"No discovery in the corpus identifies a direct CTRP7 receptor or binding partner beyond CTRP2 heterotrimer assembly","pmids":[],"confidence":"Low","gaps":["No receptor mediating CTRP7's metabolic or vascular effects identified","No structural model of CTRP7 trimers or heterotrimers","Unifying mechanism across liver, adipose, and pulmonary vasculature not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["C1QTNF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXJ2","full_name":"Complement C1q tumor necrosis factor-related protein 7","aliases":[],"length_aa":289,"mass_kda":30.7,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9BXJ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QTNF7","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/C1QTNF7","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/C1QTNF7"},"hgnc":{"alias_symbol":["CTRP7"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXJ2","domains":[{"cath_id":"2.60.120.40","chopping":"149-286","consensus_level":"high","plddt":91.1682,"start":149,"end":286}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXJ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXJ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXJ2-F1-predicted_aligned_error_v6.png","plddt_mean":73.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QTNF7","jax_strain_url":"https://www.jax.org/strain/search?query=C1QTNF7"},"sequence":{"accession":"Q9BXJ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXJ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXJ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXJ2"}},"corpus_meta":[{"pmid":"18783346","id":"PMC_18783346","title":"Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18783346","citation_count":340,"is_preprint":false},{"pmid":"29739312","id":"PMC_29739312","title":"Transcriptome analysis of adipose tissues from two fat-tailed sheep breeds reveals key genes involved in fat deposition.","date":"2018","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/29739312","citation_count":84,"is_preprint":false},{"pmid":"20585324","id":"PMC_20585324","title":"Genome-wide association study of conduct disorder symptomatology.","date":"2010","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/20585324","citation_count":67,"is_preprint":false},{"pmid":"28223291","id":"PMC_28223291","title":"CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress.","date":"2017","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/28223291","citation_count":46,"is_preprint":false},{"pmid":"26301107","id":"PMC_26301107","title":"Complex Inflammation mRNA-Related Response in ALS Is Region Dependent.","date":"2015","source":"Neural plasticity","url":"https://pubmed.ncbi.nlm.nih.gov/26301107","citation_count":25,"is_preprint":false},{"pmid":"17716811","id":"PMC_17716811","title":"Age-associated loss in adiponectin-activation by caloric restriction: lack of compensation by enhanced inducibility of adiponectin paralogs CTRP2 and CTRP7.","date":"2007","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17716811","citation_count":23,"is_preprint":false},{"pmid":"31965030","id":"PMC_31965030","title":"Implications of C1q/TNF-related protein superfamily in patients with coronary artery disease.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31965030","citation_count":23,"is_preprint":false},{"pmid":"24124410","id":"PMC_24124410","title":"Structure and Expression Analyses of SVA Elements in Relation to Functional Genes.","date":"2013","source":"Genomics & informatics","url":"https://pubmed.ncbi.nlm.nih.gov/24124410","citation_count":16,"is_preprint":false},{"pmid":"34693889","id":"PMC_34693889","title":"Selection of candidate genes for differences in fat metabolism between cattle subcutaneous and perirenal adipose tissue based on RNA-seq.","date":"2021","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34693889","citation_count":13,"is_preprint":false},{"pmid":"36330447","id":"PMC_36330447","title":"Integrated analysis of the whole transcriptome of skeletal muscle reveals the ceRNA regulatory network related to the formation of muscle fibers in Tan sheep.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36330447","citation_count":11,"is_preprint":false},{"pmid":"35368863","id":"PMC_35368863","title":"CTRP7 Is a Biomarker Related to Insulin Resistance and Oxidative Stress: Cross-Sectional and Intervention Studies In Vivo and In Vitro.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/35368863","citation_count":9,"is_preprint":false},{"pmid":"36206604","id":"PMC_36206604","title":"Epigenetic and transcriptomic characterization of maternal-fetal interface in patients with recurrent miscarriage via an integrated multi-omics approach.","date":"2022","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36206604","citation_count":9,"is_preprint":false},{"pmid":"35603744","id":"PMC_35603744","title":"Gold Nanostars Combined with the Searched Antibody for Targeted Oral Squamous Cell Carcinoma Therapy.","date":"2022","source":"ACS biomaterials science & engineering","url":"https://pubmed.ncbi.nlm.nih.gov/35603744","citation_count":9,"is_preprint":false},{"pmid":"34914966","id":"PMC_34914966","title":"Where all the Roads Meet? A Crossover Perspective on Host Factors Regulating SARS-CoV-2 infection.","date":"2021","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34914966","citation_count":8,"is_preprint":false},{"pmid":"30287348","id":"PMC_30287348","title":"Characterization of four C1q/TNF-related proteins (CTRPs) from red-lip mullet (Liza haematocheila) and their transcriptional modulation in response to bacterial and pathogen-associated molecular pattern stimuli.","date":"2018","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30287348","citation_count":8,"is_preprint":false},{"pmid":"38726186","id":"PMC_38726186","title":"Combined serum CTRP7 and CTRP15 levels as a novel biomarker for insulin resistance and type 2 diabetes mellitus.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38726186","citation_count":5,"is_preprint":false},{"pmid":"36514218","id":"PMC_36514218","title":"Deletion of large-conductance calcium-activated potassium channels promotes vascular remodelling through the CTRP7-mediated PI3K/Akt signaling pathway.","date":"2022","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/36514218","citation_count":5,"is_preprint":false},{"pmid":"39372720","id":"PMC_39372720","title":"Identification of 10 differentially expressed genes involved in the tumorigenesis of cervical cancer via next-generation sequencing.","date":"2024","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/39372720","citation_count":3,"is_preprint":false},{"pmid":"40504501","id":"PMC_40504501","title":"CTRP7 as a molecular biomarker associating with responsiveness to pulmonary vasodilators: insights from human and animal studies in pulmonary arterial hypertension.","date":"2025","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/40504501","citation_count":2,"is_preprint":false},{"pmid":"40449578","id":"PMC_40449578","title":"Molecular and physiological adaptations of Scartelaos histophorus to air exposure: Implications for amphibious fish survival.","date":"2025","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/40449578","citation_count":0,"is_preprint":false},{"pmid":"38645867","id":"PMC_38645867","title":"[Screening for Characteristic Genes of Different Traditional Chinese Medicine Syndromes of Psoriasis Vulgaris: A Study Based on Bioinformatics and Machine Learning].","date":"2024","source":"Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. 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CTRP7 forms heterotrimers with CTRP2 (CTRP2/CTRP7 heterotrimers), providing a mechanism to potentially generate functionally distinct ligands.\",\n      \"method\": \"Mammalian cell expression, biochemical characterization of secreted protein oligomeric states, co-expression and co-immunoprecipitation/secretion assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization of secreted protein oligomerization in mammalian cells with multiple CTRPs tested, single lab but multiple orthogonal methods described\",\n      \"pmids\": [\"18783346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genetic deletion of CTRP7 in mice fed a high-fat diet attenuated insulin resistance and enhanced glucose tolerance, reduced adipose tissue inflammation, and decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress, establishing CTRP7 as a contributor to obesity-linked metabolic dysfunction.\",\n      \"method\": \"Genetic loss-of-function mouse model (Ctrp7 knockout), metabolic phenotyping (glucose/insulin tolerance tests), adipose tissue inflammation markers, liver fibrosis and ER stress assays\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple defined cellular and metabolic phenotypic readouts, effects were diet-dependent and independent of body weight/metabolic rate\",\n      \"pmids\": [\"28223291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP7 overexpression in hepatocytes facilitated oxidative stress and suppressed the phosphorylation of insulin signaling molecules, placing CTRP7 as a promoter of hepatic insulin resistance via oxidative stress.\",\n      \"method\": \"In vitro hepatocyte overexpression, measurement of oxidative stress markers (ROS, SOD, GSH, MDA), western blotting of insulin signaling phosphorylation\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro functional assay with defined mechanistic readouts (oxidative stress markers + insulin signaling phosphorylation), single lab\",\n      \"pmids\": [\"35368863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In vascular smooth muscle cells, BK channel α subunit deficiency reduces CTRP7 levels, and CTRP7 knockdown activates PI3K/Akt signaling; CTRP7 was identified as a downstream target of BK channels by RNA sequencing, placing CTRP7 in a BK channel → CTRP7 → PI3K/Akt axis regulating vascular remodeling.\",\n      \"method\": \"RNA sequencing of BK channel α subunit knockout (BK α−/−) rat aortas, qPCR verification, siRNA knockdown of CTRP7 in HUASMCs, PI3K/Akt pathway western blotting\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq pathway discovery combined with siRNA knockdown and defined signaling readout, single lab\",\n      \"pmids\": [\"36514218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In pulmonary artery smooth muscle cells (PASMCs), IL-6 upregulates CTRP7 transcription (demonstrated by chromatin immunoprecipitation). CTRP7 in turn reduces expression of the prostacyclin analogue receptor (PTGIR) through Rab5a-mediated internalization, resulting in diminished responsiveness to selexipag (a prostacyclin analogue). AAV-mediated silencing of CTRP7 in pulmonary arteries of hypoxic PH mice mitigated reduced PTGIR expression and improved responses to selexipag.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for IL-6 binding to CTRP7 promoter in PASMCs; receptor internalization assay (Rab5a-mediated); AAV-mediated CTRP7 silencing in vivo; IL-6-R neutralizing antibody treatment in hypoxic PH mice; functional measurements (cardiac output, pulmonary artery resistance)\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal mechanistic methods (ChIP, receptor internalization assay, in vivo AAV silencing, pharmacological rescue) in both human cell and animal model, single lab but highly rigorous\",\n      \"pmids\": [\"40504501\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QTNF7/CTRP7 is a secreted homotrimeric glycoprotein (also forming CTRP2/CTRP7 heterotrimers) that acts as a pro-metabolic stress factor: it is induced in the liver and adipose tissue by obesity and by IL-6 signaling; its genetic deletion in mice ameliorates obesity-linked insulin resistance, adipose inflammation, and hepatic ER/oxidative stress; in hepatocytes its overexpression drives oxidative stress and suppresses insulin signaling phosphorylation; in pulmonary artery smooth muscle cells it reduces prostacyclin receptor (PTGIR) surface expression through Rab5a-mediated internalization downstream of IL-6, thereby impairing responsiveness to prostacyclin analogues; and in vascular smooth muscle cells it acts downstream of BK channels to suppress PI3K/Akt-driven vascular remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QTNF7 (CTRP7) is a secreted glycoprotein that acts as a pro-metabolic and pro-vascular-remodeling stress factor, contributing to obesity-linked metabolic dysfunction and pulmonary vascular disease [#1, #4]. It assembles into homotrimers as its basic structural unit and can form heterotrimers with CTRP2, providing a route to generate distinct secreted ligands [#0]. In a high-fat-diet mouse model, genetic deletion of CTRP7 attenuates insulin resistance, reduces adipose inflammation, and lowers hepatic fibrosis and ER/oxidative stress, establishing the protein as a driver of metabolic dysfunction [#1]; consistent with this, hepatocyte overexpression promotes oxidative stress and suppresses insulin signaling phosphorylation [#2]. In the vasculature, CTRP7 functions downstream of BK channels in an axis where its loss activates PI3K/Akt signaling governing vascular remodeling [#3]. In pulmonary artery smooth muscle cells, IL-6 transcriptionally upregulates CTRP7, which then reduces surface PTGIR (prostacyclin receptor) through Rab5a-mediated internalization, blunting responsiveness to the prostacyclin analogue selexipag; AAV-mediated silencing of CTRP7 in hypoxic pulmonary hypertension mice restores PTGIR levels and drug response [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing CTRP7's biochemical nature as a secreted oligomeric protein defined the structural form in which it could act as a ligand and revealed combinatorial heterotrimer assembly with CTRP2.\",\n      \"evidence\": \"Mammalian cell expression and biochemical characterization of secreted oligomeric states, with co-expression and co-IP/secretion assays\",\n      \"pmids\": [\"18783346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No receptor or downstream effector identified at this stage\",\n        \"Functional consequence of CTRP2/CTRP7 heterotrimers versus homotrimers not resolved\",\n        \"No tissue-level or physiological role established\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A loss-of-function mouse model answered whether CTRP7 contributes to disease physiology, establishing it as a driver of obesity-linked insulin resistance, adipose inflammation, and hepatic stress.\",\n      \"evidence\": \"Ctrp7 knockout mice on high-fat diet with glucose/insulin tolerance tests, adipose inflammation markers, and liver fibrosis/ER stress assays\",\n      \"pmids\": [\"28223291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism connecting CTRP7 to insulin signaling not defined in this study\",\n        \"Receptor mediating metabolic effects unknown\",\n        \"Cell-autonomous versus systemic contributions not separated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Hepatocyte overexpression provided a cell-level mechanism, linking CTRP7 to oxidative stress and suppression of insulin signaling phosphorylation, consistent with the knockout metabolic phenotype.\",\n      \"evidence\": \"In vitro hepatocyte overexpression with oxidative stress markers (ROS, SOD, GSH, MDA) and western blotting of insulin signaling phosphorylation\",\n      \"pmids\": [\"35368863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Receptor or signaling entry point through which CTRP7 acts not identified\",\n        \"Single lab in vitro overexpression, not reconciled with secreted-ligand biology\",\n        \"Direction of causality between oxidative stress and insulin signaling not dissected\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Transcriptomic and knockdown work placed CTRP7 in a vascular signaling axis, showing it lies downstream of BK channels and restrains PI3K/Akt-driven remodeling.\",\n      \"evidence\": \"RNA-seq of BK channel \\u03b1-subunit knockout rat aortas, qPCR, siRNA knockdown in human umbilical artery smooth muscle cells, and PI3K/Akt western blotting\",\n      \"pmids\": [\"36514218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which BK channels regulate CTRP7 levels unknown\",\n        \"How secreted CTRP7 suppresses PI3K/Akt mechanistically not defined\",\n        \"In vivo vascular phenotype of CTRP7 perturbation not tested here\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A multi-method study resolved a defined signaling cascade, showing IL-6 transcriptionally induces CTRP7, which drives Rab5a-mediated internalization of PTGIR and reduces prostacyclin-analogue responsiveness in pulmonary hypertension.\",\n      \"evidence\": \"ChIP for IL-6 at the CTRP7 promoter in PASMCs, Rab5a-mediated receptor internalization assay, in vivo AAV silencing and IL-6R antibody treatment in hypoxic PH mice with hemodynamic readouts\",\n      \"pmids\": [\"40504501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct receptor through which secreted CTRP7 triggers Rab5a-mediated PTGIR internalization not identified\",\n        \"Whether the same IL-6\\u2192CTRP7\\u2192PTGIR axis operates in the metabolic tissues is untested\",\n        \"Structural basis of CTRP7 action remains uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cell-surface receptor(s) and direct molecular effectors that transduce secreted CTRP7 signaling across metabolic and vascular contexts remain unidentified.\",\n      \"evidence\": \"No discovery in the corpus identifies a direct CTRP7 receptor or binding partner beyond CTRP2 heterotrimer assembly\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No receptor mediating CTRP7's metabolic or vascular effects identified\",\n        \"No structural model of CTRP7 trimers or heterotrimers\",\n        \"Unifying mechanism across liver, adipose, and pulmonary vasculature not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"C1QTNF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}