{"gene":"CLCF1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"CLCF1 (NNT-1/BSF-3) is a second ligand for the tripartite CNTFR receptor complex and activates JAK-STAT, MAPK, and PI3K/Akt signaling pathways in various cell systems.","method":"Receptor binding and signal transduction assays in cell lines","journal":"Cytokine & growth factor reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathways assessed in cell systems, single review synthesizing functional studies but original experiments described; single lab context","pmids":["15450249"],"is_preprint":false},{"year":2004,"finding":"Cellular secretion of CLCF1 requires heteromeric complex formation with either cytokine-like factor-1 (CLF-1/CRLF1) or soluble CNTFR (sCNTFR) as chaperone partners.","method":"Co-expression and secretion assays","journal":"Cytokine & growth factor reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — secretion assays with defined co-expression partners, corroborated by later production studies; single lab","pmids":["15450249"],"is_preprint":false},{"year":1999,"finding":"NR6 (CLCF1 alias used for the soluble haemopoietin receptor; however this paper describes the soluble receptor CRLF1/NR6, not CLCF1 itself) — NOTE: This paper describes the receptor NR6, which is CRLF1, not CLCF1 directly. EXCLUDED from CLCF1 discoveries.","method":"N/A","journal":"N/A","confidence":"Low","confidence_rationale":"Excluded — NR6 in this paper refers to CRLF1 (cytokine receptor-like factor 1), not the cytokine CLCF1","pmids":["10359701"],"is_preprint":false},{"year":2012,"finding":"CLCF1-CNTFR signaling promotes growth of non-small cell lung cancer cells in vivo; CLCF1 is secreted by cancer-associated fibroblasts and directly stimulates tumor cell growth.","method":"In vivo xenograft studies, gene expression analysis, functional studies with CLCF1-CNTFR signaling inhibition","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional studies with gene expression analysis, single lab, multiple methods","pmids":["22962265"],"is_preprint":false},{"year":2015,"finding":"CLCF1 activates JAK/STAT3 phosphorylation in multiple cell types including podocytes, activates podocyte cytoskeletal remodeling (lamellipodia formation and loss of stress fibers), and increases glomerular albumin permeability in isolated rat glomeruli.","method":"In vitro phosphorylation assays, podocyte morphology imaging, isolated rat glomeruli permeability assay, in vivo injection with urinary albumin measurement","journal":"Journal of immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro signaling, cell morphology, ex vivo glomeruli, in vivo), replicated across cell and animal systems","pmids":["26146641"],"is_preprint":false},{"year":2019,"finding":"A high-affinity engineered soluble CNTFR decoy receptor (eCNTFR-Fc) sequesters CLCF1 and inhibits its oncogenic CNTFR signaling, suppressing tumor growth in xenograft and autochthonous KRAS-mutant lung adenocarcinoma mouse models; effectiveness correlated with KRAS GTPase-retaining mutations.","method":"Xenograft and GEM mouse models, eCNTFR-Fc treatment, correlation with KRAS mutation status","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo models, engineered decoy receptor with defined mechanism, replicated across model systems","pmids":["31700175"],"is_preprint":false},{"year":2019,"finding":"CLCF1 binds mouse mesenchymal stem cells (MSCs), triggers STAT1 and STAT3 phosphorylation, inhibits upregulation of master osteogenesis genes, and prevents osteoblast generation and mineralization.","method":"In vitro MSC differentiation assay, phosphorylation assays (Western blot), gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and signaling assays in primary cells, multiple readouts, single lab","pmids":["31248987"],"is_preprint":false},{"year":2020,"finding":"miR-30a-5p directly targets the CLCF1 3'UTR, suppressing CLCF1 expression; sorafenib-mediated suppression of miR-30a-5p leads to CLCF1 upregulation, which promotes aerobic glycolysis via PI3K/AKT signaling and downstream glycolytic gene activation in sorafenib-resistant HCC cells.","method":"Dual luciferase reporter assay (miR-30a-5p targeting CLCF1), ECAR glycolysis assay, Western blot for PI3K/AKT pathway, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct miRNA-target interaction, functional glycolysis assays, in vivo validation; single lab","pmids":["33097691"],"is_preprint":false},{"year":2021,"finding":"CLCF1 suppresses osteoclast differentiation by activating interferon signaling (STAT1 and IRF1 in macrophages) and suppressing NF-κB signaling; STAT1 blockade in macrophages abolished CLCF1's inhibitory effect on osteoclastogenesis in vitro.","method":"RANKL-stimulated monocyte differentiation assay, dentine slice resorption assay, ovariectomized and calvarial mouse models, Western blot for STAT1/IRF1, STAT1 blockade rescue experiment","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods, mechanism confirmed by rescue experiment (STAT1 blockade); single lab but comprehensive","pmids":["34364014"],"is_preprint":false},{"year":2023,"finding":"CLCF1 binds and activates CNTFR, augmenting STAT3 signaling, which transcriptionally inhibits PGC-1α and PGC-1β, thereby suppressing mitochondrial biogenesis and thermogenesis in brown adipocytes; adipocyte-specific CLCF1 transgenic mice show impaired energy expenditure and cold intolerance.","method":"Adipocyte-specific transgenic mouse model, CNTFR/STAT3 inhibition experiments, ChIP or transcriptional reporter for PGC-1α/1β, mitochondrial biogenesis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway (CNTFR→STAT3→PGC-1α/β→mitochondria) confirmed by inhibitor rescue, tissue-specific transgenic model, multiple orthogonal methods","pmids":["37549287"],"is_preprint":false},{"year":2018,"finding":"CLCF1 forms complexes with all three major isoforms of ApoE (co-immunoprecipitation and proximity assays) and co-purifies with plasma lipoproteins (VLDL and LDL) in mouse and human serum; CLCF1 complexed with VLDL shows significantly reduced STAT3 phosphorylation activity, and VLDL abrogates CLCF1's anti-angiogenic effects in an oxygen-induced retinopathy mouse model.","method":"Co-immunoprecipitation, proximity ligation assay, FPLC fractionation of serum, ligand blot assay, STAT3 phosphorylation assay, oxygen-induced retinopathy mouse model","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal binding assays (Co-IP, proximity, FPLC, ligand blot) plus functional consequence (reduced STAT3 signaling and in vivo anti-angiogenic activity), single lab but comprehensive","pmids":["29507344"],"is_preprint":false},{"year":2022,"finding":"CNTF stimulation of astrocytes induces Clcf1 expression; secreted Clcf1 from astrocytes promotes differentiation of oligodendrocyte precursor cells (OPCs), and this effect is blocked by a Clcf1 antibody.","method":"Cell culture stimulation assay, antibody neutralization experiment, differentiation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional differentiation assay with antibody blocking; limited mechanistic detail in abstract; single lab","pmids":["36334441"],"is_preprint":false},{"year":2023,"finding":"Clcf1 and Crlf1a are expressed in Müller glia of the light-damaged zebrafish retina; intravitreal CLCF1/CRLF1 injection protects rod photoreceptors from cell death and induces rod precursor cell proliferation; CNTFR, Clcf1, and Crlf1a are required for Müller glia proliferation after light damage.","method":"Zebrafish light-damage retina model, morpholino/genetic knockdown of Clcf1/Crlf1a/CNTFR, intravitreal injection of CLCF1/CRLF1 protein, cell proliferation and survival assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in vivo in zebrafish with defined cellular readouts; single lab","pmids":["36846595"],"is_preprint":false},{"year":2025,"finding":"The CRLF1/CLCF1 heterodimer (confirmed by fluorescence colocalization and co-immunoprecipitation) activates JAK/STAT3 signaling in nucleus pulposus cells, enhancing production of senescence-associated secretory phenotype (SASP) factors and accelerating cell senescence; CRLF1 knockdown reduces extracellular matrix degradation and NPC senescence in vitro and alleviates intervertebral disc degeneration in vivo.","method":"Co-immunoprecipitation, fluorescence colocalization, RNA-seq, in vitro NPC culture, in vivo rat disc degeneration model with pain behavior testing","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms heterodimer, JAK/STAT3 signaling mechanistically linked, in vitro and in vivo functional data; single lab","pmids":["39986601"],"is_preprint":false},{"year":2025,"finding":"MAFF and BACH1 heterodimers directly bind the CLCF1 promoter (identified by CUT&Tag) and transcriptionally activate CLCF1 expression; elevated CLCF1 subsequently activates STAT3 signaling to reduce hepatocyte apoptosis and inflammation in hepatic ischemia-reperfusion injury.","method":"CUT&Tag chromatin profiling, RNA sequencing, adenoviral MAFF overexpression/knockdown in mouse IRI model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag directly identifies MAFF/BACH1 as CLCF1 transcriptional regulators; functional downstream STAT3 signaling demonstrated; single lab","pmids":["40169936"],"is_preprint":false},{"year":2025,"finding":"CLCF1 interacts physically with IL12Rβ2 and promotes its degradation through the proteasome in a ubiquitination-independent manner, thereby reducing IL12Rβ2 surface expression and limiting Th1 (IFNγ) differentiation; Clcf1 knockout in hematopoietic cells results in increased IFNγ production by CD4+ T cells upon IL-12 stimulation.","method":"Hematopoietic-specific Clcf1 knockout mouse (Vav-Cre), T cell IFNγ measurement, co-immunoprecipitation of CLCF1 and IL12Rβ2, proteasome inhibitor rescue experiments","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout model, co-IP binding, proteasome rescue experiment; multiple orthogonal methods; single lab","pmids":["40628045"],"is_preprint":false},{"year":2025,"finding":"CLCF1 overexpression in high-glucose-stimulated glomerular endothelial cells activates JAK2/STAT3 signaling and promotes endothelial-to-mesenchymal transition (EndMT); CLCF1 knockdown attenuates HG-induced EndMT markers (α-SMA, vimentin), and re-activation of JAK2/STAT3 by colivelin rescues the phenotype in CLCF1-knockdown cells.","method":"siRNA knockdown and plasmid overexpression in HRGECs, Western blot for JAK2/STAT3 phosphorylation and EMT markers, colivelin rescue experiment","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression/knockdown with defined molecular readouts and pathway rescue; single lab","pmids":["40731368"],"is_preprint":false},{"year":2025,"finding":"CLCF1 regulates macrophage efferocytosis and modulates the NF-κB pathway in macrophages and microglia, controlling inflammation and promoting neuronal repair after CO poisoning; efferocytosis promotes M2 macrophage polarization (increased IL-10, reduced TNF-α and IL-1β).","method":"In vivo rat CO poisoning model, CLCF1 expression modulation, cytokine measurement, behavioral testing for cognitive outcomes","journal":"Brain, behavior, and immunity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — limited mechanistic detail in abstract; NF-κB pathway modulation asserted but mechanism not fully defined; single lab","pmids":["40081779"],"is_preprint":false},{"year":2024,"finding":"eCNTFR-Fc blockade of CLCF1-CNTFR signaling shifts the tumor microenvironment from immunosuppressive to immunostimulatory macrophage phenotype and increases activated T, NKT, and NK cells; combination with anti-PD1 is more effective than single-agent therapy in syngeneic allograft and GEM lung adenocarcinoma models.","method":"Syngeneic allograft model, GEM lung adenocarcinoma model, eCNTFR-Fc treatment, immune cell phenotyping","journal":"Research square","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo models with immune phenotyping; preprint status lowers confidence slightly; single lab","pmids":["38562778"],"is_preprint":true},{"year":2026,"finding":"Hepatic CLCF1 acting through CNTFR suppresses bile acid synthesis enzymes independently of FXR-SHP signaling, selectively enriches FXR-agonistic bile acids in the gut to activate the intestinal FXR-FGF15 axis, and remodels gut microbiota to favor Firmicutes; hepatocyte-specific CNTFR deletion worsens cholestasis, while AAV-mediated hepatic Clcf1 overexpression attenuates cholestatic injury in Mdr2-/- and DDC-fed mice.","method":"Hepatocyte-specific Cntfr knockout, AAV-mediated Clcf1 overexpression, bile acid profiling, intestinal FXR-FGF15 pathway measurement, gut microbiome analysis, gut-restricted FXR antagonism rescue","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological interventions with mechanistic pathway dissection; single lab but multiple orthogonal approaches","pmids":["41840139"],"is_preprint":false},{"year":2026,"finding":"eCNTFR-mediated blockade of CLCF1-CNTFR axis in HCC suppresses STAT3 signaling and TGF-β production in tumor cells, inhibiting tumor growth, stemness, and immunosuppressive TME formation; eCNTFR-armored GPC3 CAR-T cells show enhanced cytotoxicity and cytokine production.","method":"In vitro cytotoxicity assay, cytokine production measurement, xenograft mouse model, STAT3 and TGF-β signaling assays","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo methods with defined STAT3/TGF-β mechanistic readouts; single lab","pmids":["42102942"],"is_preprint":false},{"year":2031,"finding":"PRODUCTION NOTE: CLCF1 protein secretion requires co-expression with either CRLF1 or sCNTFR, which act as chaperones enabling CLCF1 to be secreted; CLCF1 alone is not secreted efficiently from mammalian expression systems.","method":"Transient co-expression in ExpiCHO-S and Expi293F cells, protein secretion measurement","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct production assay confirming CRLF1/sCNTFR dependence for CLCF1 secretion; single lab, consistent with earlier functional studies","pmids":["40393625"],"is_preprint":false},{"year":2003,"finding":"CLCF1 (NNT-1/BSF-3) mRNA expression in pituitary folliculostellate cells is induced by PKC-, PKA-, and ERK1/2-dependent mechanisms downstream of PACAP and VIP receptor activation; dexamethasone inhibits PKC-stimulated CLCF1 expression.","method":"Northern blot, pharmacological inhibitors (H-7, GF109203X, H-89, U0126), phorbol ester and cAMP stimulation, RT-PCR receptor identification","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological pathway inhibitors with Northern blot readout; single lab","pmids":["14605001"],"is_preprint":false}],"current_model":"CLCF1 is a secreted IL-6 family cytokine that requires complex formation with CRLF1 or soluble CNTFR for extracellular secretion; it signals primarily through the tripartite CNTFR/gp130/LIFRβ receptor complex to activate JAK-STAT (predominantly STAT3), MAPK, and PI3K/AKT pathways, and exerts pleiotropic effects including neurotrophic support, inhibition of brown adipose thermogenesis via STAT3-mediated suppression of PGC-1α/β, podocyte activation and glomerular permeability increase, suppression of osteoblastogenesis and osteoclastogenesis (the latter through STAT1/IFN signaling), promotion of aerobic glycolysis in cancer cells, immune modulation via proteasomal degradation of IL12Rβ2 to limit Th1 differentiation, and tumor-promoting effects through CAF-derived CNTFR signaling in lung and liver cancers."},"narrative":{"mechanistic_narrative":"CLCF1 (NNT-1/BSF-3) is a secreted IL-6-family cytokine that signals through the tripartite CNTFR receptor complex to activate JAK-STAT (predominantly STAT3), MAPK, and PI3K/AKT pathways across many cell types [PMID:15450249]. Efficient cellular secretion of CLCF1 depends on heteromeric complex formation with the soluble receptor CRLF1 (CLF-1) or soluble CNTFR, which act as obligate chaperones [PMID:15450249, PMID:40393625]. Through CNTFR-driven STAT3 signaling CLCF1 exerts pleiotropic context-dependent effects: it transcriptionally suppresses PGC-1α/β to inhibit mitochondrial biogenesis and thermogenesis in brown adipocytes [PMID:37549287], remodels podocyte cytoskeleton and increases glomerular albumin permeability [PMID:26146641], and drives endothelial-to-mesenchymal transition in glomerular endothelial cells via JAK2/STAT3 [PMID:40731368]. In bone, CLCF1 engages STAT1/IRF1 and interferon signaling to suppress both osteoblastogenesis [PMID:31248987] and osteoclastogenesis [PMID:34364014]. As a tumor-promoting factor, CLCF1 is secreted by cancer-associated fibroblasts to stimulate lung tumor growth through CNTFR [PMID:22962265], and supports aerobic glycolysis and sorafenib resistance in hepatocellular carcinoma via PI3K/AKT [PMID:33097691]; engineered soluble CNTFR decoy (eCNTFR-Fc) sequesters CLCF1, suppresses STAT3/TGF-β-driven tumor growth, and reshapes the immune microenvironment [PMID:31700175, PMID:42102942]. CLCF1 also limits Th1 differentiation by binding IL12Rβ2 and promoting its proteasomal, ubiquitination-independent degradation [PMID:40628045], and provides neurotrophic and protective support in the CNS by promoting oligodendrocyte precursor and Müller glia responses [PMID:36334441, PMID:36846595].","teleology":[{"year":2004,"claim":"Established CLCF1 as a functional CNTFR ligand and defined the requirement for chaperone-dependent secretion, answering how this cytokine reaches the extracellular space and which receptor it engages.","evidence":"Receptor binding, signal transduction, and co-expression secretion assays in cell lines","pmids":["15450249"],"confidence":"Medium","gaps":["Structural basis of CLCF1-CRLF1/sCNTFR complex not resolved","Relative physiological contributions of CRLF1 vs sCNTFR chaperones unclear"]},{"year":2012,"claim":"Showed CLCF1-CNTFR is a paracrine tumor-growth signal from cancer-associated fibroblasts, framing the cytokine as a stromal driver of lung cancer.","evidence":"In vivo xenografts, expression analysis, and signaling inhibition in NSCLC","pmids":["22962265"],"confidence":"Medium","gaps":["Downstream tumor-cell effectors not fully mapped","Generality across cancer types not addressed here"]},{"year":2015,"claim":"Demonstrated that CLCF1-driven STAT3 activation produces direct functional consequences in podocytes and glomerular permeability, linking the cytokine to renal filtration barrier biology.","evidence":"In vitro phosphorylation, podocyte morphology imaging, ex vivo glomeruli permeability, and in vivo albuminuria assays","pmids":["26146641"],"confidence":"High","gaps":["Receptor complex stoichiometry on podocytes not defined","In vivo source of CLCF1 in disease unclear"]},{"year":2019,"claim":"Resolved CLCF1's role in bone homeostasis, showing it suppresses osteoblastogenesis through STAT1/STAT3 in mesenchymal stem cells.","evidence":"MSC differentiation, Western blot phosphorylation, and gene expression assays","pmids":["31248987"],"confidence":"Medium","gaps":["Receptor identity on MSCs not confirmed","Balance between STAT1 and STAT3 contributions not dissected"]},{"year":2019,"claim":"Validated CLCF1-CNTFR as a druggable oncogenic axis using an engineered decoy receptor, with KRAS mutation status predicting response.","evidence":"Xenograft and GEM KRAS-mutant lung adenocarcinoma models with eCNTFR-Fc treatment","pmids":["31700175"],"confidence":"High","gaps":["Mechanism linking KRAS GTPase mutations to CLCF1 dependence unresolved"]},{"year":2021,"claim":"Defined a STAT1/IRF1 interferon-driven mechanism by which CLCF1 suppresses osteoclast differentiation, complementing its osteoblast effects.","evidence":"RANKL differentiation, dentine resorption, ovariectomized/calvarial models, and STAT1 blockade rescue","pmids":["34364014"],"confidence":"High","gaps":["How CLCF1 biases toward STAT1 vs STAT3 in different cells not explained"]},{"year":2023,"claim":"Established a CNTFR→STAT3→PGC-1α/β transcriptional axis through which CLCF1 suppresses brown adipose thermogenesis and energy expenditure.","evidence":"Adipocyte-specific transgenic mice, CNTFR/STAT3 inhibition, transcriptional and mitochondrial assays","pmids":["37549287"],"confidence":"High","gaps":["Endogenous regulation of adipose CLCF1 not defined","Relevance to human metabolic disease untested"]},{"year":2020,"claim":"Connected CLCF1 to cancer metabolism and drug resistance, showing miR-30a-5p-controlled CLCF1 drives aerobic glycolysis via PI3K/AKT in sorafenib-resistant HCC.","evidence":"Luciferase reporter, ECAR glycolysis assay, Western blot, and xenografts","pmids":["33097691"],"confidence":"Medium","gaps":["Receptor engagement in this autocrine setting not confirmed","Direct glycolytic gene targets only partially mapped"]},{"year":2018,"claim":"Revealed that lipoprotein and ApoE association modulates CLCF1 activity, providing a mechanism for extracellular regulation of its signaling.","evidence":"Co-IP, proximity ligation, FPLC fractionation, ligand blot, STAT3 assays, and oxygen-induced retinopathy model","pmids":["29507344"],"confidence":"High","gaps":["Physiological trigger of lipoprotein association unknown","Structural binding interface with ApoE/VLDL undefined"]},{"year":2025,"claim":"Identified a non-canonical immunoregulatory mechanism: CLCF1 binds IL12Rβ2 and drives its proteasomal degradation to restrain Th1 differentiation.","evidence":"Hematopoietic Clcf1 knockout mice, T cell IFNγ measurement, co-IP, and proteasome inhibitor rescue","pmids":["40628045"],"confidence":"Medium","gaps":["Ubiquitination-independent degradation route not molecularly defined","Whether this is CNTFR-independent not fully established"]},{"year":2025,"claim":"Extended CLCF1 transcriptional control and pathology, identifying MAFF/BACH1 as direct promoter activators and CLCF1-STAT3 as hepatoprotective in ischemia-reperfusion injury.","evidence":"CUT&Tag, RNA-seq, and adenoviral MAFF manipulation in mouse IRI","pmids":["40169936"],"confidence":"Medium","gaps":["Generality of MAFF/BACH1 regulation beyond liver unknown"]},{"year":2025,"claim":"Demonstrated CRLF1/CLCF1 heterodimer JAK/STAT3 signaling drives senescence and SASP in nucleus pulposus cells, implicating the axis in disc degeneration.","evidence":"Co-IP, fluorescence colocalization, RNA-seq, and in vivo rat disc degeneration model","pmids":["39986601"],"confidence":"Medium","gaps":["Relative roles of CRLF1 vs CLCF1 in signaling output not separated"]},{"year":2026,"claim":"Uncovered a hepatic CLCF1-CNTFR pathway that reshapes bile acid metabolism and gut microbiota to protect against cholestasis, broadening CLCF1's metabolic roles.","evidence":"Hepatocyte-specific Cntfr knockout, AAV Clcf1 overexpression, bile acid profiling, FXR-FGF15 measurement, and microbiome analysis","pmids":["41840139"],"confidence":"Medium","gaps":["Direct transcriptional targets controlling bile acid enzymes not identified","Mechanism of FXR-SHP independence unclear"]},{"year":null,"claim":"How CLCF1 selects between STAT3, STAT1, and proteasomal (IL12Rβ2) outputs across tissues, and the structural basis of its receptor and chaperone complexes, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the CLCF1-CNTFR-gp130-LIFR complex in the corpus","Determinants of cell-type-specific STAT bias unknown","Mechanism of CNTFR-independent signaling not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,10,21]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,15,18]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,9,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,20]}],"complexes":["CLCF1-CRLF1 heterodimer","CLCF1-sCNTFR complex","CNTFR/gp130/LIFR receptor complex"],"partners":["CRLF1","CNTFR","IL12RB2","APOE","GP130","LIFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBD9","full_name":"Cardiotrophin-like cytokine factor 1","aliases":["B-cell-stimulating factor 3","BSF-3","Novel neurotrophin-1","NNT-1"],"length_aa":225,"mass_kda":25.2,"function":"In complex with CRLF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development (Probable). Also stimulates B-cells. Binds to and activates the ILST/gp130 receptor","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UBD9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLCF1","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/CLCF1","total_profiled":1310},"omim":[{"mim_id":"610313","title":"CRISPONI/COLD-INDUCED SWEATING SYNDROME 2; CISS2","url":"https://www.omim.org/entry/610313"},{"mim_id":"607672","title":"CARDIOTROPHIN-LIKE CYTOKINE FACTOR 1; CLCF1","url":"https://www.omim.org/entry/607672"},{"mim_id":"604237","title":"CYTOKINE RECEPTOR-LIKE FACTOR 1; CRLF1","url":"https://www.omim.org/entry/604237"},{"mim_id":"272430","title":"CRISPONI/COLD-INDUCED SWEATING SYNDROME 1; CISS1","url":"https://www.omim.org/entry/272430"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CLCF1"},"hgnc":{"alias_symbol":["NNT1","BSF3","CLC","NR6","CISS2","BSF-3","NNT-1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBD9","domains":[{"cath_id":"1.20.1250.10","chopping":"35-208","consensus_level":"high","plddt":90.5702,"start":35,"end":208}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBD9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBD9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBD9-F1-predicted_aligned_error_v6.png","plddt_mean":81.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLCF1","jax_strain_url":"https://www.jax.org/strain/search?query=CLCF1"},"sequence":{"accession":"Q9UBD9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBD9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBD9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBD9"}},"corpus_meta":[{"pmid":"6312448","id":"PMC_6312448","title":"Platelet-derived growth factor stimulates Na+/H+ exchange and induces cytoplasmic alkalinization in NR6 cells.","date":"1983","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6312448","citation_count":156,"is_preprint":false},{"pmid":"22962265","id":"PMC_22962265","title":"Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer in vivo.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22962265","citation_count":119,"is_preprint":false},{"pmid":"33097691","id":"PMC_33097691","title":"The miR-30a-5p/CLCF1 axis regulates sorafenib resistance and aerobic glycolysis in hepatocellular carcinoma.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33097691","citation_count":73,"is_preprint":false},{"pmid":"26146641","id":"PMC_26146641","title":"Renal and Hematological Effects of CLCF-1, a B-Cell-Stimulating Cytokine of the IL-6 Family.","date":"2015","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/26146641","citation_count":70,"is_preprint":false},{"pmid":"10359701","id":"PMC_10359701","title":"Suckling defect in mice lacking the soluble haemopoietin receptor NR6.","date":"1999","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/10359701","citation_count":68,"is_preprint":false},{"pmid":"31700175","id":"PMC_31700175","title":"Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma.","date":"2019","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31700175","citation_count":63,"is_preprint":false},{"pmid":"1933876","id":"PMC_1933876","title":"Enhanced tumorigenesis of NR6 cells which express non-down-regulating epidermal growth factor receptors.","date":"1991","source":"Cancer 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Four new cases.","date":"2010","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/20400119","citation_count":26,"is_preprint":false},{"pmid":"37549287","id":"PMC_37549287","title":"CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37549287","citation_count":25,"is_preprint":false},{"pmid":"31248987","id":"PMC_31248987","title":"Cardiotrophin-like cytokine (CLCF1) modulates mesenchymal stem cell osteoblastic differentiation.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31248987","citation_count":16,"is_preprint":false},{"pmid":"34364014","id":"PMC_34364014","title":"Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates bone loss in osteoporosis mouse models by suppressing osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway.","date":"2021","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/34364014","citation_count":14,"is_preprint":false},{"pmid":"36846595","id":"PMC_36846595","title":"Clcf1/Crlf1a-mediated signaling is neuroprotective and required for Müller glia proliferation in the light-damaged zebrafish retina.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36846595","citation_count":13,"is_preprint":false},{"pmid":"29507344","id":"PMC_29507344","title":"Effect of human very low-density lipoproteins on cardiotrophin-like cytokine factor 1 (CLCF1) activity.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29507344","citation_count":12,"is_preprint":false},{"pmid":"7698257","id":"PMC_7698257","title":"Ligand-induced translocation of epidermal growth factor receptor to the nucleus of NR6/HER fibroblasts is serum dependent.","date":"1995","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/7698257","citation_count":12,"is_preprint":false},{"pmid":"14605001","id":"PMC_14605001","title":"Expression of novel neurotrophin-1/B-cell stimulating factor-3 (NNT-1/BSF-3) in murine pituitary folliculostellate TtT/GF cells: pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide-induced stimulation of NNT-1/BSF-3 is mediated by protein kinase A, protein kinase C, and extracellular-signal-regulated kinase1/2 pathways.","date":"2003","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/14605001","citation_count":11,"is_preprint":false},{"pmid":"39986601","id":"PMC_39986601","title":"CRLF1/CLCF1 heterodimer involvement in intervertebral disc degeneration via exacerbation of extracellular matrix degradation and nucleus pulposus cell senescence.","date":"2025","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/39986601","citation_count":9,"is_preprint":false},{"pmid":"21683644","id":"PMC_21683644","title":"Expression of Bcl2l1, Clcf1, IL-28ra and Pias1 in the mouse heart after single and repeated administration of chlorpromazine.","date":"2011","source":"Legal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/21683644","citation_count":8,"is_preprint":false},{"pmid":"40169936","id":"PMC_40169936","title":"MAFF alleviates hepatic ischemia-reperfusion injury by regulating the CLCF1/STAT3 signaling pathway.","date":"2025","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/40169936","citation_count":7,"is_preprint":false},{"pmid":"35530960","id":"PMC_35530960","title":"CLCF1 is up-regulated in renal ischemia reperfusion injury and may associate with FOXO3.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35530960","citation_count":7,"is_preprint":false},{"pmid":"11305595","id":"PMC_11305595","title":"Diesel exhaust particle-induced cell death of human leukemic promyelocytic cells HL-60 and their variant cells HL-NR6.","date":"2001","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/11305595","citation_count":6,"is_preprint":false},{"pmid":"8094619","id":"PMC_8094619","title":"Differential activity of the RVF enhancer element in the decreased expression of the neu oncogene in NR-6 cells versus parental Swiss Webster 3T3 cells.","date":"1993","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8094619","citation_count":6,"is_preprint":false},{"pmid":"36334441","id":"PMC_36334441","title":"CNTF induces Clcf1 in astrocytes to promote the differentiation of oligodendrocyte precursor cells.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36334441","citation_count":5,"is_preprint":false},{"pmid":"38562778","id":"PMC_38562778","title":"The CLCF1-CNTFR axis drives an immunosuppressive tumor microenvironment and blockade enhances the effects of established cancer therapies.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/38562778","citation_count":5,"is_preprint":false},{"pmid":"40081779","id":"PMC_40081779","title":"Regulation of macrophage efferocytosis by the CLCF1/NF-κB pathway improves neurological and cognitive impairment following CO poisoning.","date":"2025","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/40081779","citation_count":2,"is_preprint":false},{"pmid":"40628045","id":"PMC_40628045","title":"CLCF1 promotes IL12Rβ2 proteolysis and limits Th1 differentiation.","date":"2025","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/40628045","citation_count":1,"is_preprint":false},{"pmid":"40731368","id":"PMC_40731368","title":"CLCF1 contributes to high-glucose-induced EndMT by modulating JAK2/STAT3 signaling.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/40731368","citation_count":1,"is_preprint":false},{"pmid":"40393625","id":"PMC_40393625","title":"High-yield production of recombinant CLCF1 protein fused with human serum albumin in animal cells and toxicity evaluation in rodents.","date":"2025","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/40393625","citation_count":1,"is_preprint":false},{"pmid":"38842921","id":"PMC_38842921","title":"Reduced serum CLCF1 levels in hyperthyroidism patients and T3-treated mice.","date":"2024","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/38842921","citation_count":0,"is_preprint":false},{"pmid":"41662978","id":"PMC_41662978","title":"Insights into the regulation and signaling landscape of cardiotrophin-like cytokine factor 1 (CLCF1).","date":"2026","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41662978","citation_count":0,"is_preprint":false},{"pmid":"41840139","id":"PMC_41840139","title":"The secretory protein, CLCF1, improves cholestatic liver disease by inhibiting hepatic bile acid synthesis and promoting bile acid excretion.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41840139","citation_count":0,"is_preprint":false},{"pmid":"32512309","id":"PMC_32512309","title":"Crisponi syndrome/cold-induced sweating syndrome type 2: Reprogramming of CS/CISS2 individual derived fibroblasts into three clones of one iPSC line.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32512309","citation_count":0,"is_preprint":false},{"pmid":"41974852","id":"PMC_41974852","title":"Saikosaponin D and paeoniflorin improve the HCC immune microenvironment via CLCF1/PD-L1 mediated crosstalk between CAFs and tumor cells.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41974852","citation_count":0,"is_preprint":false},{"pmid":"41284622","id":"PMC_41284622","title":"CLCF1 Exercise-induced Myokine Protocol for Investigating RANKL/OPG Bone Protection Mechanisms in Postmenopausal Osteoporosis.","date":"2025","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/41284622","citation_count":0,"is_preprint":false},{"pmid":"42102942","id":"PMC_42102942","title":"Blockade of the CLCF1-CNTFR axis enhances the efficacy of GPC3 CAR-T cell therapy in hepatocellular carcinoma.","date":"2026","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/42102942","citation_count":0,"is_preprint":false},{"pmid":"41628867","id":"PMC_41628867","title":"Integrating metabolomics, network pharmacology and molecular dynamics simulations reveals that Xiehuang San targets CLCF1-STAT3 to restore insulin signaling in T2DM.","date":"2026","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41628867","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21665,"output_tokens":5765,"usd":0.075735,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14311,"output_tokens":4159,"usd":0.087765,"stage2_stop_reason":"end_turn"},"total_usd":0.1635,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"CLCF1 (NNT-1/BSF-3) is a second ligand for the tripartite CNTFR receptor complex and activates JAK-STAT, MAPK, and PI3K/Akt signaling pathways in various cell systems.\",\n      \"method\": \"Receptor binding and signal transduction assays in cell lines\",\n      \"journal\": \"Cytokine & growth factor reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathways assessed in cell systems, single review synthesizing functional studies but original experiments described; single lab context\",\n      \"pmids\": [\"15450249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cellular secretion of CLCF1 requires heteromeric complex formation with either cytokine-like factor-1 (CLF-1/CRLF1) or soluble CNTFR (sCNTFR) as chaperone partners.\",\n      \"method\": \"Co-expression and secretion assays\",\n      \"journal\": \"Cytokine & growth factor reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — secretion assays with defined co-expression partners, corroborated by later production studies; single lab\",\n      \"pmids\": [\"15450249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NR6 (CLCF1 alias used for the soluble haemopoietin receptor; however this paper describes the soluble receptor CRLF1/NR6, not CLCF1 itself) — NOTE: This paper describes the receptor NR6, which is CRLF1, not CLCF1 directly. EXCLUDED from CLCF1 discoveries.\",\n      \"method\": \"N/A\",\n      \"journal\": \"N/A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Excluded — NR6 in this paper refers to CRLF1 (cytokine receptor-like factor 1), not the cytokine CLCF1\",\n      \"pmids\": [\"10359701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CLCF1-CNTFR signaling promotes growth of non-small cell lung cancer cells in vivo; CLCF1 is secreted by cancer-associated fibroblasts and directly stimulates tumor cell growth.\",\n      \"method\": \"In vivo xenograft studies, gene expression analysis, functional studies with CLCF1-CNTFR signaling inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional studies with gene expression analysis, single lab, multiple methods\",\n      \"pmids\": [\"22962265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CLCF1 activates JAK/STAT3 phosphorylation in multiple cell types including podocytes, activates podocyte cytoskeletal remodeling (lamellipodia formation and loss of stress fibers), and increases glomerular albumin permeability in isolated rat glomeruli.\",\n      \"method\": \"In vitro phosphorylation assays, podocyte morphology imaging, isolated rat glomeruli permeability assay, in vivo injection with urinary albumin measurement\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro signaling, cell morphology, ex vivo glomeruli, in vivo), replicated across cell and animal systems\",\n      \"pmids\": [\"26146641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A high-affinity engineered soluble CNTFR decoy receptor (eCNTFR-Fc) sequesters CLCF1 and inhibits its oncogenic CNTFR signaling, suppressing tumor growth in xenograft and autochthonous KRAS-mutant lung adenocarcinoma mouse models; effectiveness correlated with KRAS GTPase-retaining mutations.\",\n      \"method\": \"Xenograft and GEM mouse models, eCNTFR-Fc treatment, correlation with KRAS mutation status\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo models, engineered decoy receptor with defined mechanism, replicated across model systems\",\n      \"pmids\": [\"31700175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLCF1 binds mouse mesenchymal stem cells (MSCs), triggers STAT1 and STAT3 phosphorylation, inhibits upregulation of master osteogenesis genes, and prevents osteoblast generation and mineralization.\",\n      \"method\": \"In vitro MSC differentiation assay, phosphorylation assays (Western blot), gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and signaling assays in primary cells, multiple readouts, single lab\",\n      \"pmids\": [\"31248987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-30a-5p directly targets the CLCF1 3'UTR, suppressing CLCF1 expression; sorafenib-mediated suppression of miR-30a-5p leads to CLCF1 upregulation, which promotes aerobic glycolysis via PI3K/AKT signaling and downstream glycolytic gene activation in sorafenib-resistant HCC cells.\",\n      \"method\": \"Dual luciferase reporter assay (miR-30a-5p targeting CLCF1), ECAR glycolysis assay, Western blot for PI3K/AKT pathway, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct miRNA-target interaction, functional glycolysis assays, in vivo validation; single lab\",\n      \"pmids\": [\"33097691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CLCF1 suppresses osteoclast differentiation by activating interferon signaling (STAT1 and IRF1 in macrophages) and suppressing NF-κB signaling; STAT1 blockade in macrophages abolished CLCF1's inhibitory effect on osteoclastogenesis in vitro.\",\n      \"method\": \"RANKL-stimulated monocyte differentiation assay, dentine slice resorption assay, ovariectomized and calvarial mouse models, Western blot for STAT1/IRF1, STAT1 blockade rescue experiment\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods, mechanism confirmed by rescue experiment (STAT1 blockade); single lab but comprehensive\",\n      \"pmids\": [\"34364014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLCF1 binds and activates CNTFR, augmenting STAT3 signaling, which transcriptionally inhibits PGC-1α and PGC-1β, thereby suppressing mitochondrial biogenesis and thermogenesis in brown adipocytes; adipocyte-specific CLCF1 transgenic mice show impaired energy expenditure and cold intolerance.\",\n      \"method\": \"Adipocyte-specific transgenic mouse model, CNTFR/STAT3 inhibition experiments, ChIP or transcriptional reporter for PGC-1α/1β, mitochondrial biogenesis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway (CNTFR→STAT3→PGC-1α/β→mitochondria) confirmed by inhibitor rescue, tissue-specific transgenic model, multiple orthogonal methods\",\n      \"pmids\": [\"37549287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CLCF1 forms complexes with all three major isoforms of ApoE (co-immunoprecipitation and proximity assays) and co-purifies with plasma lipoproteins (VLDL and LDL) in mouse and human serum; CLCF1 complexed with VLDL shows significantly reduced STAT3 phosphorylation activity, and VLDL abrogates CLCF1's anti-angiogenic effects in an oxygen-induced retinopathy mouse model.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, FPLC fractionation of serum, ligand blot assay, STAT3 phosphorylation assay, oxygen-induced retinopathy mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal binding assays (Co-IP, proximity, FPLC, ligand blot) plus functional consequence (reduced STAT3 signaling and in vivo anti-angiogenic activity), single lab but comprehensive\",\n      \"pmids\": [\"29507344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CNTF stimulation of astrocytes induces Clcf1 expression; secreted Clcf1 from astrocytes promotes differentiation of oligodendrocyte precursor cells (OPCs), and this effect is blocked by a Clcf1 antibody.\",\n      \"method\": \"Cell culture stimulation assay, antibody neutralization experiment, differentiation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional differentiation assay with antibody blocking; limited mechanistic detail in abstract; single lab\",\n      \"pmids\": [\"36334441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Clcf1 and Crlf1a are expressed in Müller glia of the light-damaged zebrafish retina; intravitreal CLCF1/CRLF1 injection protects rod photoreceptors from cell death and induces rod precursor cell proliferation; CNTFR, Clcf1, and Crlf1a are required for Müller glia proliferation after light damage.\",\n      \"method\": \"Zebrafish light-damage retina model, morpholino/genetic knockdown of Clcf1/Crlf1a/CNTFR, intravitreal injection of CLCF1/CRLF1 protein, cell proliferation and survival assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in vivo in zebrafish with defined cellular readouts; single lab\",\n      \"pmids\": [\"36846595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The CRLF1/CLCF1 heterodimer (confirmed by fluorescence colocalization and co-immunoprecipitation) activates JAK/STAT3 signaling in nucleus pulposus cells, enhancing production of senescence-associated secretory phenotype (SASP) factors and accelerating cell senescence; CRLF1 knockdown reduces extracellular matrix degradation and NPC senescence in vitro and alleviates intervertebral disc degeneration in vivo.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence colocalization, RNA-seq, in vitro NPC culture, in vivo rat disc degeneration model with pain behavior testing\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms heterodimer, JAK/STAT3 signaling mechanistically linked, in vitro and in vivo functional data; single lab\",\n      \"pmids\": [\"39986601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAFF and BACH1 heterodimers directly bind the CLCF1 promoter (identified by CUT&Tag) and transcriptionally activate CLCF1 expression; elevated CLCF1 subsequently activates STAT3 signaling to reduce hepatocyte apoptosis and inflammation in hepatic ischemia-reperfusion injury.\",\n      \"method\": \"CUT&Tag chromatin profiling, RNA sequencing, adenoviral MAFF overexpression/knockdown in mouse IRI model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag directly identifies MAFF/BACH1 as CLCF1 transcriptional regulators; functional downstream STAT3 signaling demonstrated; single lab\",\n      \"pmids\": [\"40169936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLCF1 interacts physically with IL12Rβ2 and promotes its degradation through the proteasome in a ubiquitination-independent manner, thereby reducing IL12Rβ2 surface expression and limiting Th1 (IFNγ) differentiation; Clcf1 knockout in hematopoietic cells results in increased IFNγ production by CD4+ T cells upon IL-12 stimulation.\",\n      \"method\": \"Hematopoietic-specific Clcf1 knockout mouse (Vav-Cre), T cell IFNγ measurement, co-immunoprecipitation of CLCF1 and IL12Rβ2, proteasome inhibitor rescue experiments\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout model, co-IP binding, proteasome rescue experiment; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"40628045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLCF1 overexpression in high-glucose-stimulated glomerular endothelial cells activates JAK2/STAT3 signaling and promotes endothelial-to-mesenchymal transition (EndMT); CLCF1 knockdown attenuates HG-induced EndMT markers (α-SMA, vimentin), and re-activation of JAK2/STAT3 by colivelin rescues the phenotype in CLCF1-knockdown cells.\",\n      \"method\": \"siRNA knockdown and plasmid overexpression in HRGECs, Western blot for JAK2/STAT3 phosphorylation and EMT markers, colivelin rescue experiment\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression/knockdown with defined molecular readouts and pathway rescue; single lab\",\n      \"pmids\": [\"40731368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLCF1 regulates macrophage efferocytosis and modulates the NF-κB pathway in macrophages and microglia, controlling inflammation and promoting neuronal repair after CO poisoning; efferocytosis promotes M2 macrophage polarization (increased IL-10, reduced TNF-α and IL-1β).\",\n      \"method\": \"In vivo rat CO poisoning model, CLCF1 expression modulation, cytokine measurement, behavioral testing for cognitive outcomes\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — limited mechanistic detail in abstract; NF-κB pathway modulation asserted but mechanism not fully defined; single lab\",\n      \"pmids\": [\"40081779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"eCNTFR-Fc blockade of CLCF1-CNTFR signaling shifts the tumor microenvironment from immunosuppressive to immunostimulatory macrophage phenotype and increases activated T, NKT, and NK cells; combination with anti-PD1 is more effective than single-agent therapy in syngeneic allograft and GEM lung adenocarcinoma models.\",\n      \"method\": \"Syngeneic allograft model, GEM lung adenocarcinoma model, eCNTFR-Fc treatment, immune cell phenotyping\",\n      \"journal\": \"Research square\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo models with immune phenotyping; preprint status lowers confidence slightly; single lab\",\n      \"pmids\": [\"38562778\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Hepatic CLCF1 acting through CNTFR suppresses bile acid synthesis enzymes independently of FXR-SHP signaling, selectively enriches FXR-agonistic bile acids in the gut to activate the intestinal FXR-FGF15 axis, and remodels gut microbiota to favor Firmicutes; hepatocyte-specific CNTFR deletion worsens cholestasis, while AAV-mediated hepatic Clcf1 overexpression attenuates cholestatic injury in Mdr2-/- and DDC-fed mice.\",\n      \"method\": \"Hepatocyte-specific Cntfr knockout, AAV-mediated Clcf1 overexpression, bile acid profiling, intestinal FXR-FGF15 pathway measurement, gut microbiome analysis, gut-restricted FXR antagonism rescue\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological interventions with mechanistic pathway dissection; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"41840139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"eCNTFR-mediated blockade of CLCF1-CNTFR axis in HCC suppresses STAT3 signaling and TGF-β production in tumor cells, inhibiting tumor growth, stemness, and immunosuppressive TME formation; eCNTFR-armored GPC3 CAR-T cells show enhanced cytotoxicity and cytokine production.\",\n      \"method\": \"In vitro cytotoxicity assay, cytokine production measurement, xenograft mouse model, STAT3 and TGF-β signaling assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo methods with defined STAT3/TGF-β mechanistic readouts; single lab\",\n      \"pmids\": [\"42102942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2031,\n      \"finding\": \"PRODUCTION NOTE: CLCF1 protein secretion requires co-expression with either CRLF1 or sCNTFR, which act as chaperones enabling CLCF1 to be secreted; CLCF1 alone is not secreted efficiently from mammalian expression systems.\",\n      \"method\": \"Transient co-expression in ExpiCHO-S and Expi293F cells, protein secretion measurement\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct production assay confirming CRLF1/sCNTFR dependence for CLCF1 secretion; single lab, consistent with earlier functional studies\",\n      \"pmids\": [\"40393625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CLCF1 (NNT-1/BSF-3) mRNA expression in pituitary folliculostellate cells is induced by PKC-, PKA-, and ERK1/2-dependent mechanisms downstream of PACAP and VIP receptor activation; dexamethasone inhibits PKC-stimulated CLCF1 expression.\",\n      \"method\": \"Northern blot, pharmacological inhibitors (H-7, GF109203X, H-89, U0126), phorbol ester and cAMP stimulation, RT-PCR receptor identification\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological pathway inhibitors with Northern blot readout; single lab\",\n      \"pmids\": [\"14605001\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLCF1 is a secreted IL-6 family cytokine that requires complex formation with CRLF1 or soluble CNTFR for extracellular secretion; it signals primarily through the tripartite CNTFR/gp130/LIFRβ receptor complex to activate JAK-STAT (predominantly STAT3), MAPK, and PI3K/AKT pathways, and exerts pleiotropic effects including neurotrophic support, inhibition of brown adipose thermogenesis via STAT3-mediated suppression of PGC-1α/β, podocyte activation and glomerular permeability increase, suppression of osteoblastogenesis and osteoclastogenesis (the latter through STAT1/IFN signaling), promotion of aerobic glycolysis in cancer cells, immune modulation via proteasomal degradation of IL12Rβ2 to limit Th1 differentiation, and tumor-promoting effects through CAF-derived CNTFR signaling in lung and liver cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLCF1 (NNT-1/BSF-3) is a secreted IL-6-family cytokine that signals through the tripartite CNTFR receptor complex to activate JAK-STAT (predominantly STAT3), MAPK, and PI3K/AKT pathways across many cell types [#0]. Efficient cellular secretion of CLCF1 depends on heteromeric complex formation with the soluble receptor CRLF1 (CLF-1) or soluble CNTFR, which act as obligate chaperones [#1, #21]. Through CNTFR-driven STAT3 signaling CLCF1 exerts pleiotropic context-dependent effects: it transcriptionally suppresses PGC-1\\u03b1/\\u03b2 to inhibit mitochondrial biogenesis and thermogenesis in brown adipocytes [#9], remodels podocyte cytoskeleton and increases glomerular albumin permeability [#4], and drives endothelial-to-mesenchymal transition in glomerular endothelial cells via JAK2/STAT3 [#16]. In bone, CLCF1 engages STAT1/IRF1 and interferon signaling to suppress both osteoblastogenesis [#6] and osteoclastogenesis [#8]. As a tumor-promoting factor, CLCF1 is secreted by cancer-associated fibroblasts to stimulate lung tumor growth through CNTFR [#3], and supports aerobic glycolysis and sorafenib resistance in hepatocellular carcinoma via PI3K/AKT [#7]; engineered soluble CNTFR decoy (eCNTFR-Fc) sequesters CLCF1, suppresses STAT3/TGF-\\u03b2-driven tumor growth, and reshapes the immune microenvironment [#5, #20]. CLCF1 also limits Th1 differentiation by binding IL12R\\u03b22 and promoting its proteasomal, ubiquitination-independent degradation [#15], and provides neurotrophic and protective support in the CNS by promoting oligodendrocyte precursor and M\\u00fcller glia responses [#11, #12].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established CLCF1 as a functional CNTFR ligand and defined the requirement for chaperone-dependent secretion, answering how this cytokine reaches the extracellular space and which receptor it engages.\",\n      \"evidence\": \"Receptor binding, signal transduction, and co-expression secretion assays in cell lines\",\n      \"pmids\": [\"15450249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CLCF1-CRLF1/sCNTFR complex not resolved\", \"Relative physiological contributions of CRLF1 vs sCNTFR chaperones unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed CLCF1-CNTFR is a paracrine tumor-growth signal from cancer-associated fibroblasts, framing the cytokine as a stromal driver of lung cancer.\",\n      \"evidence\": \"In vivo xenografts, expression analysis, and signaling inhibition in NSCLC\",\n      \"pmids\": [\"22962265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream tumor-cell effectors not fully mapped\", \"Generality across cancer types not addressed here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that CLCF1-driven STAT3 activation produces direct functional consequences in podocytes and glomerular permeability, linking the cytokine to renal filtration barrier biology.\",\n      \"evidence\": \"In vitro phosphorylation, podocyte morphology imaging, ex vivo glomeruli permeability, and in vivo albuminuria assays\",\n      \"pmids\": [\"26146641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor complex stoichiometry on podocytes not defined\", \"In vivo source of CLCF1 in disease unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved CLCF1's role in bone homeostasis, showing it suppresses osteoblastogenesis through STAT1/STAT3 in mesenchymal stem cells.\",\n      \"evidence\": \"MSC differentiation, Western blot phosphorylation, and gene expression assays\",\n      \"pmids\": [\"31248987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor identity on MSCs not confirmed\", \"Balance between STAT1 and STAT3 contributions not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validated CLCF1-CNTFR as a druggable oncogenic axis using an engineered decoy receptor, with KRAS mutation status predicting response.\",\n      \"evidence\": \"Xenograft and GEM KRAS-mutant lung adenocarcinoma models with eCNTFR-Fc treatment\",\n      \"pmids\": [\"31700175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking KRAS GTPase mutations to CLCF1 dependence unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a STAT1/IRF1 interferon-driven mechanism by which CLCF1 suppresses osteoclast differentiation, complementing its osteoblast effects.\",\n      \"evidence\": \"RANKL differentiation, dentine resorption, ovariectomized/calvarial models, and STAT1 blockade rescue\",\n      \"pmids\": [\"34364014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CLCF1 biases toward STAT1 vs STAT3 in different cells not explained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a CNTFR\\u2192STAT3\\u2192PGC-1\\u03b1/\\u03b2 transcriptional axis through which CLCF1 suppresses brown adipose thermogenesis and energy expenditure.\",\n      \"evidence\": \"Adipocyte-specific transgenic mice, CNTFR/STAT3 inhibition, transcriptional and mitochondrial assays\",\n      \"pmids\": [\"37549287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulation of adipose CLCF1 not defined\", \"Relevance to human metabolic disease untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected CLCF1 to cancer metabolism and drug resistance, showing miR-30a-5p-controlled CLCF1 drives aerobic glycolysis via PI3K/AKT in sorafenib-resistant HCC.\",\n      \"evidence\": \"Luciferase reporter, ECAR glycolysis assay, Western blot, and xenografts\",\n      \"pmids\": [\"33097691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor engagement in this autocrine setting not confirmed\", \"Direct glycolytic gene targets only partially mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed that lipoprotein and ApoE association modulates CLCF1 activity, providing a mechanism for extracellular regulation of its signaling.\",\n      \"evidence\": \"Co-IP, proximity ligation, FPLC fractionation, ligand blot, STAT3 assays, and oxygen-induced retinopathy model\",\n      \"pmids\": [\"29507344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of lipoprotein association unknown\", \"Structural binding interface with ApoE/VLDL undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a non-canonical immunoregulatory mechanism: CLCF1 binds IL12R\\u03b22 and drives its proteasomal degradation to restrain Th1 differentiation.\",\n      \"evidence\": \"Hematopoietic Clcf1 knockout mice, T cell IFN\\u03b3 measurement, co-IP, and proteasome inhibitor rescue\",\n      \"pmids\": [\"40628045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination-independent degradation route not molecularly defined\", \"Whether this is CNTFR-independent not fully established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended CLCF1 transcriptional control and pathology, identifying MAFF/BACH1 as direct promoter activators and CLCF1-STAT3 as hepatoprotective in ischemia-reperfusion injury.\",\n      \"evidence\": \"CUT&Tag, RNA-seq, and adenoviral MAFF manipulation in mouse IRI\",\n      \"pmids\": [\"40169936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of MAFF/BACH1 regulation beyond liver unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated CRLF1/CLCF1 heterodimer JAK/STAT3 signaling drives senescence and SASP in nucleus pulposus cells, implicating the axis in disc degeneration.\",\n      \"evidence\": \"Co-IP, fluorescence colocalization, RNA-seq, and in vivo rat disc degeneration model\",\n      \"pmids\": [\"39986601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative roles of CRLF1 vs CLCF1 in signaling output not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Uncovered a hepatic CLCF1-CNTFR pathway that reshapes bile acid metabolism and gut microbiota to protect against cholestasis, broadening CLCF1's metabolic roles.\",\n      \"evidence\": \"Hepatocyte-specific Cntfr knockout, AAV Clcf1 overexpression, bile acid profiling, FXR-FGF15 measurement, and microbiome analysis\",\n      \"pmids\": [\"41840139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets controlling bile acid enzymes not identified\", \"Mechanism of FXR-SHP independence unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CLCF1 selects between STAT3, STAT1, and proteasomal (IL12R\\u03b22) outputs across tissues, and the structural basis of its receptor and chaperone complexes, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the CLCF1-CNTFR-gp130-LIFR complex in the corpus\", \"Determinants of cell-type-specific STAT bias unknown\", \"Mechanism of CNTFR-independent signaling not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 10, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 15, 18]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 9, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 20]}\n    ],\n    \"complexes\": [\"CLCF1-CRLF1 heterodimer\", \"CLCF1-sCNTFR complex\", \"CNTFR/gp130/LIFR receptor complex\"],\n    \"partners\": [\"CRLF1\", \"CNTFR\", \"IL12RB2\", \"APOE\", \"gp130\", \"LIFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}