{"gene":"IGFBP7","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2008,"finding":"BRAFV600E oncogene expression in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis; apoptosis results from IGFBP7-mediated upregulation of BNIP3L, a proapoptotic BCL2 family protein.","method":"Genome-wide RNAi screening, recombinant protein treatment, xenograft mouse model, cell-based assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — RNAi screen + functional rescue with recombinant protein + in vivo xenograft validation, single high-impact study with multiple orthogonal methods","pmids":["18267069"],"is_preprint":false},{"year":2012,"finding":"IGFBP7 directly binds to the extracellular portion of IGF1R (via its N-terminal 97 amino acids), blocks its activation and internalization by IGF-1/2, causes accumulation of inactive IGF1R on the cell surface, and suppresses downstream PI3K-AKT signaling; binding of IGFBP7 and IGF-1 to IGF1R is mutually exclusive.","method":"Co-immunoprecipitation, deletion mutagenesis, receptor internalization assay, phosphorylation assays, recombinant protein treatment","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding demonstrated with mutagenesis, mutually exclusive competition assay, downstream signaling validation with multiple methods","pmids":["23250396"],"is_preprint":false},{"year":2000,"finding":"IGFBP7 (mac25) protein was co-immunoprecipitated with activin A, indicating that mac25/IGFBP7 is a secreted protein that binds activin A and may modulate its signaling.","method":"Immunoprecipitation, Western blot, GFP fusion localization, recombinant protein growth suppression assay","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP demonstrated binding to activin A; single lab, single method for the binding interaction","pmids":["10859029"],"is_preprint":false},{"year":1999,"finding":"IGFBP7 (AGM/mac25) binds to cell-surface heparan sulfates via an identified 20-amino acid cell-binding sequence; heparinase treatment and heparin competition abolish cell adhesion to AGM.","method":"Cell adhesion competition assays, heparinase treatment, synthetic peptide blocking, binding assays","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (enzyme treatment, competitive inhibition, synthetic peptide) converging on same receptor identification","pmids":["10502291"],"is_preprint":false},{"year":2003,"finding":"Proteolytic cleavage of IGFBP7 (IGFBP-rP1) by a trypsin-like serine proteinase abrogates its insulin/IGF-1-binding activity and insulin/IGF-1-dependent growth-stimulatory activity while markedly increasing its cell attachment activity; syndecan-1 is identified as a cell surface receptor for both intact and cleaved forms.","method":"Proteolytic processing assays, IGF-1 binding assays, cell attachment assays, receptor identification","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical demonstration of functional change upon cleavage; single lab but multiple functional readouts","pmids":["14521955"],"is_preprint":false},{"year":2003,"finding":"IGFBP7 (mac25/IGFBP-rP1) overexpression in prostate cancer cells increases SOD-2 (manganese superoxide dismutase) expression as a downstream mediator of its senescence-associated tumor suppression; mac25 cells show increased phospho-ERK and phospho-AKT, and PI3K inhibition markedly decreases their viability.","method":"cDNA expression array, stable transfection, in vivo tumor growth, SOD-2 overexpression rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — gene expression array identification of SOD-2 downstream with functional rescue, but pathway placement is partial","pmids":["12592389"],"is_preprint":false},{"year":2008,"finding":"TGF-β1 secreted by glioblastoma cells induces IGFBP7 expression in human brain endothelial cells through the TGF-β1/ALK5/Smad-2 signaling pathway; IGFBP7 protein promotes capillary-like tube formation (angiogenesis).","method":"Conditioned media treatment, TGF-β neutralizing antibody, ALK5 receptor antagonist (SB431542), Smad-2 phosphorylation assays, Matrigel tube formation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — pathway dissection with specific inhibitors and neutralizing antibody; single lab","pmids":["18711401"],"is_preprint":false},{"year":2009,"finding":"IGFBP7 is a p53-responsive gene; p53 induces IGFBP7 expression by binding to a p53 response element within intron 1 of the IGFBP7 gene, as demonstrated by luciferase reporter assay and chromatin immunoprecipitation.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), 5-aza-dC demethylation, p53 transfection","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 1-2 — direct ChIP showing p53 binding to IGFBP7 intronic response element, corroborated by luciferase assay and demethylation rescue","pmids":["19638426"],"is_preprint":false},{"year":2016,"finding":"ADAR2 edits IGFBP7 mRNA (A-to-I RNA editing), and this editing stabilizes IGFBP7 protein by altering the matriptase protease recognition site, preventing proteolytic cleavage; ADAR2-mediated IGFBP7 stabilization induces apoptosis and inhibits Akt signaling in esophageal squamous cell carcinoma.","method":"RNA-seq editing analysis, active-site ADAR2 mutant, IGFBP7 knockdown, Western blotting for Akt signaling, in vitro/in vivo tumor models","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic dissection with catalytic mutant and downstream signaling validation; single lab","pmids":["28035363"],"is_preprint":false},{"year":2012,"finding":"A-to-I RNA editing of IGFBP7 transcripts alters the protein's susceptibility to proteolytic cleavage, providing a mechanism for cells to modulate IGFBP7 functionality through RNA editing.","method":"RNA editing analysis, proteolysis susceptibility assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical demonstration; single lab with defined functional consequence","pmids":["22750143"],"is_preprint":false},{"year":2016,"finding":"TGF-β1 upregulates IGFBP7 expression in human renal proximal tubular epithelial cells via Smad2 and Smad4 (but not MAPK) pathways; knockdown of IGFBP7 reverses TGF-β1-induced epithelial-to-mesenchymal transition (EMT).","method":"Dose/time-dependent TGF-β1 treatment, Smad2/4 pathway inhibition, IGFBP7 knockdown, EMT marker analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — pathway-specific knockdown distinguishing Smad from MAPK; single lab","pmids":["26974954"],"is_preprint":false},{"year":2018,"finding":"IGFBP7 promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells via the Wnt/β-catenin signaling pathway; both overexpression and exogenous IGFBP7 protein increase β-catenin levels, and Wnt/β-catenin inhibitors partially block IGFBP7-induced osteogenesis.","method":"Overexpression, exogenous protein addition, siRNA knockdown, Wnt inhibitor treatment, in vivo tibial osteotomy model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — pathway inhibitor rescue + in vivo validation; single lab","pmids":["29242275"],"is_preprint":false},{"year":2019,"finding":"IGFBP7 inhibits RANKL-induced osteoclastogenesis, F-actin ring formation, and bone resorption by suppressing the NF-κB signaling pathway; in a mouse ovariectomy-induced osteoporosis model, IGFBP7 treatment attenuated osteoclast-driven bone loss.","method":"Recombinant IGFBP7 protein, lentivirus overexpression, siRNA knockdown, NF-κB pathway analysis, in vivo ovariectomy model","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro mechanism + in vivo validation; single lab","pmids":["31889368"],"is_preprint":false},{"year":2022,"finding":"Cardiac fibroblasts regulate heart failure via an Htra3-TGF-β-IGFBP7 axis: pressure overload downregulates Htra3, leading to TGF-β activation, which drives cardiomyocyte DNA damage and induction of IGFBP7 secretion from failing cardiomyocytes; Htra3 overexpression inhibits TGF-β signaling and ameliorates cardiac dysfunction.","method":"Single-cell RNA-seq, spatial transcriptomics, genetic perturbation (overexpression, knockout), mouse pressure overload model, human plasma proteome analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (scRNA-seq, genetic perturbation, spatial transcriptomics) in both mouse and human, with functional rescue","pmids":["35672400"],"is_preprint":false},{"year":2022,"finding":"IGFBP7 promotes cardiac senescence by stimulating IGF-1R/IRS/AKT-dependent suppression of FOXO3a, preventing DNA repair and ROS detoxification; in vivo AAV9-shRNA cardiac Igfbp7 knockdown and antibody-mediated IGFBP7 neutralization reversed suppression of FOXO3a and attenuated pressure-overload-induced heart failure.","method":"Igfbp7 knockout mouse, AAV9-shRNA knockdown, neutralizing antibody treatment, pressure overload model, signaling pathway analysis","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO, shRNA, and antibody neutralization all converging on same mechanistic pathway with functional cardiac readout","pmids":["39196168"],"is_preprint":false},{"year":2024,"finding":"Senescent cardiac endothelial cells upregulate Igfbp7 under pressure overload; EC-specific Igfbp7 deletion and vaccine-mediated neutralization of IGFBP7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes, establishing IGFBP7 as a paracrine mediator from senescent ECs to cardiomyocytes.","method":"EC-specific gene knockout, AAV9 overexpression, anti-IGFBP7 vaccine, single-cell RNA-seq, metabolic analysis","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1-2 — cell-type-specific genetic deletion + vaccine neutralization + scRNA-seq in both mouse and human with functional validation","pmids":["38991046"],"is_preprint":false},{"year":2003,"finding":"IGFBP7 (mac25/AGM) expressed on cell surfaces reduces anchorage-independent growth and suppresses tumor growth in vivo through an insulin/IGF-independent mechanism; IGFBP7-expressing cells bind more efficiently to fibronectin and laminin-5.","method":"RNA interference knockdown, expression vector transfection, soft agar colony assay, xenograft mouse model, cell adhesion assay","journal":"Cancer science (published 2007)","confidence":"Medium","confidence_rationale":"Tier 2 — dual model system (RNAi and overexpression) with in vivo validation; single lab","pmids":["17465992"],"is_preprint":false},{"year":2013,"finding":"SMARCB1 (Snf5) is required for transcriptional activation of IGFBP7; re-introduction of Igfbp7 alone in Smarcb1-deficient tumor cells can hinder tumor development in xenografts, placing IGFBP7 downstream of the SMARCB1/SWI-SNF chromatin remodeling complex.","method":"Gene expression profiling, Smarcb1 re-expression, Igfbp7 re-expression, xenograft mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via rescue experiment (Igfbp7 re-expression) with in vivo tumor validation; single lab","pmids":["23851500"],"is_preprint":false},{"year":2020,"finding":"Exercise upregulates Igfbp7 expression in muscle satellite cells, which impedes Akt phosphorylation, inhibits mTOR activity, reduces mitochondrial metabolism, and causes hypoacetylation of H3K27ac at Akt promoters, thereby protecting satellite cells from exhaustion.","method":"Treadmill exercise model, RNA sequencing, ChIP-PCR, flow cytometry, immunofluorescence, Akt-mTOR pathway analysis","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-seq, ChIP, and mechanistic pathway analysis in vivo; single lab","pmids":["32483463"],"is_preprint":false},{"year":2003,"finding":"IGFBP7 (mac25/AGM) interacts with multiple molecules in high endothelial venules including chemokines CCL21 (SLC), CXCL10 (IP-10), and CCL5 (RANTES) in a dose-dependent and saturable manner; binding to chemokines is selective, does not inhibit their Ca2+-signaling activity, and suggests a chemokine-presenting function at the HEV basal lamina.","method":"Binding assays (dose-dependent, saturable), competitive inhibition assay, immunohistochemistry, Ca2+-signaling assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — saturable binding with competition assay; functional consequence (Ca2+ signaling retention) demonstrated; single lab","pmids":["12847218"],"is_preprint":false},{"year":2014,"finding":"IGFBP7 promotes TAM/M2 macrophage polarization in gastric cancer via FGF2/FGFR1/PI3K/AKT axis; exogenous recombinant IGFBP7 treatment of macrophages and cancer cells confirmed this paracrine mechanism.","method":"RNA sequencing, ELISA, recombinant IGFBP7 treatment, loss-of-function studies, transcriptome analysis","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 — recombinant protein treatment + pathway analysis; single lab","pmids":["36681667"],"is_preprint":false},{"year":2021,"finding":"IGFBP7 binds to IGF1R and mediates programmed cell death (necroptosis via RIPK1/RIPK3/MLKL pathway) and inflammation in acute kidney injury; co-immunoprecipitation confirmed IGFBP7 binding to IGF1R, and IGF1R inhibitor (picropodophyllin) abrogated the therapeutic effects of a protective compound targeting this pathway.","method":"Co-immunoprecipitation, RNA sequencing, Western blot, in vivo AKI mouse models, IGF1R inhibitor treatment","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP of IGFBP7-IGF1R + pathway inhibitor rescue; single lab","pmids":["33773190"],"is_preprint":false},{"year":2025,"finding":"GABA from enteric GABAergic neurons signals through Gabbr1/Gabbr2 receptors on ILC3s to suppress the LIP isoform of C/EBP-β, which in turn represses IGFBP7 transcription; autocrine IGFBP7 then signals through IGF1R to inhibit ILC3 proliferation and IL-17A production.","method":"Conditional neuron ablation, receptor knockout, transcription factor knockdown, autocrine IGFBP7 assays, in vivo colitis model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic pathway dissection from upstream neuronal signal to IGFBP7 autocrine loop with multiple KO/KD experiments and in vivo disease model","pmids":["40033120"],"is_preprint":false},{"year":2024,"finding":"IGFBP7 is a key SASP component that induces secondary senescence by: (1) binding insulin and inhibiting its anti-senescence effects; (2) promoting IGF-II interaction with IGF2R while blocking IGF1R; (3) interacting with activin A receptors to induce senescence via SMAD pathways; these effects are dependent on ERK and AKT signaling.","method":"Neutralizing antibody treatment, recombinant IGFBP7 incubation, senescence assays, ERK/AKT pathway inhibition, SMAD pathway analysis","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2-3 — neutralizing antibody + recombinant protein experiments with pathway validation; single lab","pmids":["39533382"],"is_preprint":false},{"year":2011,"finding":"Exogenous IGFBP7 treatment of triple-negative breast cancer cells induces G1 cell cycle arrest, senescence, and apoptosis associated with activation of p38 MAPK, upregulation of p53 and p21(cip1), and cleaved PARP; systemic rIGFBP7 in xenograft mice inhibited tumorigenesis with anti-angiogenic effects.","method":"Recombinant protein treatment, flow cytometry cell cycle analysis, SA-β-gal senescence assay, Western blotting, xenograft mouse model","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cellular readouts + in vivo validation; single lab","pmids":["21997538"],"is_preprint":false},{"year":2014,"finding":"IGFBP7 suppresses VEGFA- and LH-induced angiogenesis in luteal microvascular endothelial cells by inhibiting their proliferation and migration, reducing phosphorylation of MEK and ERK1/2, and attenuating VEGFA-enhanced COX-2 expression and prostaglandin E2 secretion.","method":"In vitro tube formation assay (Matrigel), proliferation and migration assays, ERK/MEK phosphorylation assays, COX-2 mRNA and PGE2 measurement","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional assays with signaling pathway validation; single lab","pmids":["25212428"],"is_preprint":false},{"year":2018,"finding":"AKI-induced urinary IGFBP7 elevations are not due to stress-induced gene transcription but result from increased glomerular filtration, decreased tubular reabsorption, and proximal tubule cell IGFBP7 leakage; immunohistochemistry showed progressive IGFBP7 loss from injured proximal tubule cells, and endocytic inhibition in normal mice tripled urinary IGFBP7 levels.","method":"Mouse AKI models (glycerol, maleate, ischemia), ELISA, mRNA quantification, immunohistochemistry, competitive endocytic inhibition","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple AKI models + mechanistic dissection of urinary excretion pathway with direct inhibitor experiment","pmids":["29980651"],"is_preprint":false}],"current_model":"IGFBP7 is a secreted protein that functions as a multi-target suppressor of pro-growth and pro-survival signaling: it directly binds IGF1R (via its N-terminal domain) to block IGF-1/2-induced receptor activation and downstream PI3K-AKT signaling; it binds activin A, heparan sulfates, and select chemokines in the extracellular matrix; its expression is transcriptionally activated by p53 (via an intronic response element) and TGF-β/Smad2/4 signaling, and is epigenetically silenced in many cancers; in oncogene-induced senescence BRAFV600E drives IGFBP7 secretion which in turn suppresses BRAF-MEK-ERK and induces apoptosis via BNIP3L upregulation; in cardiac biology IGFBP7 produced by senescent endothelial cells or failing cardiomyocytes promotes senescence by suppressing FOXO3a through IGF-1R/IRS/AKT, thereby impairing DNA repair and ROS detoxification; and its susceptibility to proteolytic inactivation is modulated by A-to-I RNA editing of its transcript."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that IGFBP7 engages the cell surface via heparan sulfate proteoglycans answered how this secreted protein is retained in the pericellular matrix and can exert local effects.","evidence":"Cell adhesion competition, heparinase treatment, and synthetic peptide blocking identified a 20-amino-acid heparan sulfate-binding domain","pmids":["10502291"],"confidence":"High","gaps":["Identity of specific HSPGs mediating the interaction was not resolved beyond later syndecan-1 identification","Functional consequence of cell-surface retention on signaling not dissected"]},{"year":2000,"claim":"Discovery that IGFBP7 binds activin A expanded its ligand repertoire beyond IGFs, suggesting it modulates TGF-β superfamily signaling.","evidence":"Co-immunoprecipitation of IGFBP7 with activin A from conditioned media","pmids":["10859029"],"confidence":"Medium","gaps":["Single co-IP method without reciprocal validation or competition assay","Functional consequence of activin A sequestration on downstream Smad signaling not tested"]},{"year":2003,"claim":"Multiple studies defined IGFBP7 as a tumor suppressor that operates partly through IGF-independent adhesion to extracellular matrix components and partly through proteolytic regulation of its IGF-binding capacity.","evidence":"Proteolysis assays showed serine protease cleavage abolishes IGF-binding and increases cell attachment via syndecan-1; xenograft and soft-agar assays demonstrated IGF-independent tumor suppression; saturable binding assays identified chemokine partners CCL21, CXCL10, CCL5","pmids":["14521955","17465992","12847218"],"confidence":"Medium","gaps":["In vivo protease identity not established","Chemokine-presenting function at HEV not validated beyond binding and calcium-signaling retention","Relative contributions of IGF-dependent vs IGF-independent suppression not quantified"]},{"year":2008,"claim":"Demonstrating that BRAF^V600E drives IGFBP7 secretion to inhibit MEK-ERK and induce senescence/apoptosis via BNIP3L established IGFBP7 as a critical effector of oncogene-induced senescence.","evidence":"Genome-wide RNAi screen, recombinant protein rescue, and xenograft model in primary cells expressing oncogenic BRAF","pmids":["18267069"],"confidence":"High","gaps":["Whether IGFBP7-mediated OIS generalizes beyond BRAF^V600E to other RAS-pathway oncogenes was not tested","Direct receptor mediating BRAF-MEK-ERK suppression not identified in this study"]},{"year":2008,"claim":"Showing TGF-β1 induces IGFBP7 via ALK5/Smad2 in brain endothelial cells linked IGFBP7 to TGF-β-driven angiogenesis in glioblastoma.","evidence":"TGF-β neutralizing antibody, ALK5 antagonist SB431542, and Smad2 phosphorylation analysis in GBM-conditioned media-treated endothelial cells","pmids":["18711401"],"confidence":"Medium","gaps":["Pro-angiogenic role in brain endothelium contrasts with anti-angiogenic effects reported elsewhere; context-dependency not resolved","Downstream target of IGFBP7 in tube formation not identified"]},{"year":2009,"claim":"Identification of a p53 response element in IGFBP7 intron 1 placed IGFBP7 in the p53 tumor-suppressor network and explained its silencing upon p53 loss or promoter methylation.","evidence":"ChIP demonstrating direct p53 binding to intronic element, corroborated by luciferase reporter and 5-aza-dC demethylation rescue","pmids":["19638426"],"confidence":"High","gaps":["Whether p53-dependent induction is the dominant route in vivo vs TGF-β/Smad induction not compared","Epigenetic silencing mechanism at the IGFBP7 promoter in cancer not fully dissected"]},{"year":2012,"claim":"Mapping the direct IGFBP7–IGF1R interaction to the N-terminal 97 amino acids and showing mutually exclusive binding with IGF-1 established the primary receptor-level mechanism for IGFBP7's anti-growth activity.","evidence":"Co-immunoprecipitation, deletion mutagenesis, receptor internalization, and phosphorylation assays","pmids":["23250396"],"confidence":"High","gaps":["Structural basis of the mutually exclusive binding not determined","Whether IGFBP7 also signals through IGF1R independently of simple competitive antagonism not resolved"]},{"year":2012,"claim":"Discovery that A-to-I RNA editing alters IGFBP7's protease susceptibility introduced a post-transcriptional regulatory layer controlling its functional half-life.","evidence":"RNA editing analysis coupled with proteolysis susceptibility assays; later confirmed with ADAR2 catalytic-dead mutant showing editing prevents matriptase cleavage and stabilizes the protein","pmids":["22750143","28035363"],"confidence":"Medium","gaps":["Prevalence of edited vs unedited IGFBP7 transcripts across tissues not systematically surveyed","In vivo significance of editing for IGFBP7 tumor suppression not demonstrated"]},{"year":2013,"claim":"Placing IGFBP7 downstream of the SMARCB1/SWI-SNF chromatin remodeling complex explained IGFBP7 loss in rhabdoid tumors and showed IGFBP7 re-expression alone can substitute for SMARCB1 tumor suppression.","evidence":"SMARCB1 re-expression restored IGFBP7; Igfbp7 re-expression in Smarcb1-deficient cells suppressed xenograft tumor growth","pmids":["23851500"],"confidence":"Medium","gaps":["Whether SMARCB1 directly binds the IGFBP7 promoter or acts indirectly not resolved","Generalizability beyond rhabdoid tumor cells not tested"]},{"year":2016,"claim":"Confirmation that TGF-β1 induces IGFBP7 through Smad2/4 in renal epithelial cells, and that IGFBP7 is required for TGF-β-driven EMT, extended its role to kidney fibrosis.","evidence":"Smad2/4 knockdown blocked IGFBP7 induction; IGFBP7 knockdown reversed TGF-β1-induced EMT markers","pmids":["26974954"],"confidence":"Medium","gaps":["Direct binding of Smad2/4 to IGFBP7 regulatory regions not shown","Role in progressive renal fibrosis in vivo not established"]},{"year":2022,"claim":"In the heart, an Htra3–TGF-β–IGFBP7 axis was delineated in which pressure overload downregulates the protease Htra3 in fibroblasts, unleashing TGF-β to induce cardiomyocyte IGFBP7, which promotes senescence by suppressing FOXO3a via IGF-1R/IRS/AKT signaling.","evidence":"Single-cell RNA-seq, spatial transcriptomics, Igfbp7-KO and AAV9-shRNA knockdown, neutralizing antibody, and pressure-overload mouse models with functional cardiac readouts","pmids":["35672400","39196168"],"confidence":"High","gaps":["Whether FOXO3a suppression is the sole effector of IGFBP7-driven cardiac senescence not determined","Human genetic evidence linking IGFBP7 variants to heart failure absent"]},{"year":2024,"claim":"Demonstrating that senescent endothelial cells are the primary cardiac source of IGFBP7 paracrine signaling, and that EC-specific deletion or vaccine-mediated neutralization rescues heart failure, established IGFBP7 as a druggable SASP factor.","evidence":"EC-specific Igfbp7 conditional knockout, anti-IGFBP7 peptide vaccine, single-cell RNA-seq, and metabolic analysis under pressure overload","pmids":["38991046"],"confidence":"High","gaps":["Vaccine efficacy in large-animal or human settings not tested","Whether EC- vs cardiomyocyte-derived IGFBP7 has distinct paracrine targets not fully resolved"]},{"year":2025,"claim":"Identification of an enteric neuron–ILC3 circuit in which GABA suppresses C/EBPβ-LIP-driven IGFBP7 transcription, with autocrine IGFBP7–IGF1R signaling restraining ILC3 proliferation and IL-17A production, extended the gene's role to intestinal immunity.","evidence":"Conditional neuron ablation, receptor and transcription factor knockdowns, autocrine IGFBP7 assays, and in vivo colitis models","pmids":["40033120"],"confidence":"High","gaps":["Whether IGFBP7 restrains other innate lymphoid populations not tested","Relevance to human inflammatory bowel disease not directly demonstrated"]},{"year":null,"claim":"Unresolved: the structural basis of IGFBP7's mutually exclusive binding to IGF1R versus IGFs, the relative in vivo contributions of its multiple receptor interactions (IGF1R, activin receptors, syndecan-1, HSPGs), and whether its pro-angiogenic vs anti-angiogenic effects reflect distinct receptor complexes in different vascular beds.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure or cryo-EM structure of IGFBP7–IGF1R complex","Context-dependent switching between pro- and anti-angiogenic roles mechanistically unexplained","Relative signaling contributions of IGF1R antagonism vs activin A sequestration vs HSPG binding not quantitatively dissected in any single system"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,14,22,23]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,14,15,22]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,3,4,19,23]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[3,19]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,14,18,22,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,8,21,24]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[14,15,23,24]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,22]}],"complexes":[],"partners":["IGF1R","INHBA","SDC1","BNIP3L","FOXO3","SMAD2","CCL21","CXCL10"],"other_free_text":[]},"mechanistic_narrative":"IGFBP7 is a secreted, multivalent signaling modulator that suppresses pro-growth and pro-survival pathways while promoting cellular senescence and apoptosis across diverse tissue contexts. It directly binds the extracellular domain of IGF1R via its N-terminal 97 amino acids, blocking IGF-1/2-induced receptor activation and suppressing downstream PI3K-AKT signaling; it also binds activin A, heparan sulfate proteoglycans (including syndecan-1), and select chemokines (CCL21, CXCL10, CCL5) in the extracellular matrix [PMID:23250396, PMID:10502291, PMID:10859029, PMID:12847218]. IGFBP7 transcription is activated by p53 through an intronic response element, by TGF-β1/ALK5/Smad2/4 signaling, and by the SWI/SNF component SMARCB1, and is frequently epigenetically silenced in cancer; its protein stability is regulated by A-to-I RNA editing that alters a matriptase cleavage site [PMID:19638426, PMID:26974954, PMID:23851500, PMID:22750143]. As a senescence-associated secretory factor, IGFBP7 drives oncogene-induced senescence downstream of BRAF^V600E by inhibiting BRAF-MEK-ERK signaling and upregulating the proapoptotic protein BNIP3L, and in the heart it promotes cardiomyocyte senescence by suppressing FOXO3a through IGF-1R/IRS/AKT, with endothelial cell-specific deletion or antibody neutralization ameliorating pressure-overload heart failure [PMID:18267069, PMID:39196168, PMID:38991046]."},"prefetch_data":{"uniprot":{"accession":"Q16270","full_name":"Insulin-like growth factor-binding protein 7","aliases":["IGFBP-rP1","MAC25 protein","PGI2-stimulating factor","Prostacyclin-stimulating factor","Tumor-derived adhesion factor","TAF"],"length_aa":282,"mass_kda":29.1,"function":"Binds IGF1 and IGF2 with a relatively low affinity. Stimulates prostacyclin (PGI2) production. Stimulates cell adhesion. 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cells.","date":"2002","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12407018","citation_count":24,"is_preprint":false},{"pmid":"24632473","id":"PMC_24632473","title":"PSF contacts exon 7 of SMN2 pre-mRNA to promote exon 7 inclusion.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24632473","citation_count":24,"is_preprint":false},{"pmid":"26043748","id":"PMC_26043748","title":"Relationship between expression of IGFBP7 and clinicopathological variables in gastric cancer.","date":"2015","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26043748","citation_count":24,"is_preprint":false},{"pmid":"31261582","id":"PMC_31261582","title":"Comparison of urinary TIMP-2 and IGFBP7 cut-offs to predict acute kidney injury in critically ill patients: A PRISMA-compliant systematic review and meta-analysis.","date":"2019","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31261582","citation_count":24,"is_preprint":false},{"pmid":"27941714","id":"PMC_27941714","title":"Inhibition of Cervical Cancer by Promoting IGFBP7 Expression Using Ellagic Acid from Pomegranate Peel.","date":"2016","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/27941714","citation_count":24,"is_preprint":false},{"pmid":"22750143","id":"PMC_22750143","title":"IGFBP7's susceptibility to proteolysis is altered by A-to-I RNA editing of its transcript.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22750143","citation_count":24,"is_preprint":false},{"pmid":"23516550","id":"PMC_23516550","title":"PTB-associated splicing factor (PSF) is a PPARγ-binding protein and growth regulator of colon cancer cells.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23516550","citation_count":23,"is_preprint":false},{"pmid":"9417882","id":"PMC_9417882","title":"Developmental regulation of Mac25/insulin-like growth factor-binding protein-7 expression in skeletal myogenesis.","date":"1997","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/9417882","citation_count":23,"is_preprint":false},{"pmid":"39533382","id":"PMC_39533382","title":"IGFBP7 is a key component of the senescence-associated secretory phenotype (SASP) that induces senescence in healthy cells by modulating the insulin, IGF, and activin A pathways.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39533382","citation_count":22,"is_preprint":false},{"pmid":"26807324","id":"PMC_26807324","title":"Tissue and serum IGFBP7 protein as biomarker in high-grade soft tissue sarcoma.","date":"2015","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26807324","citation_count":21,"is_preprint":false},{"pmid":"26450156","id":"PMC_26450156","title":"Inhibition of IGF1-R overcomes IGFBP7-induced chemotherapy resistance in T-ALL.","date":"2015","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26450156","citation_count":21,"is_preprint":false},{"pmid":"30376758","id":"PMC_30376758","title":"The Accuracy of Urinary TIMP-2 and IGFBP7 for the Diagnosis of Cardiac Surgery-Associated Acute Kidney Injury: A Systematic Review and Meta-Analysis.","date":"2018","source":"Journal of intensive care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30376758","citation_count":21,"is_preprint":false},{"pmid":"24427302","id":"PMC_24427302","title":"High expression of IGFBP7 in fibroblasts induced by colorectal cancer cells is co-regulated by TGF-β and Wnt signaling in a Smad2/3-Dvl2/3-dependent manner.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24427302","citation_count":21,"is_preprint":false},{"pmid":"37568781","id":"PMC_37568781","title":"Crosstalk between Cancer Cells and Cancer-Associated Fibroblasts Mediated by TGF-β1-IGFBP7 Signaling Promotes the Progression of Infiltrative Gastric Cancer.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37568781","citation_count":21,"is_preprint":false},{"pmid":"40033120","id":"PMC_40033120","title":"Enteric GABAergic neuron-derived γ-aminobutyric acid initiates expression of Igfbp7 to sustain ILC3 homeostasis.","date":"2025","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40033120","citation_count":20,"is_preprint":false},{"pmid":"34217226","id":"PMC_34217226","title":"IGFBP7 and GDF-15, but not P1NP, are associated with cardiac alterations and 10-year outcome in an elderly community-based study.","date":"2021","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/34217226","citation_count":20,"is_preprint":false},{"pmid":"16832349","id":"PMC_16832349","title":"Role of PSF-TFE3 oncoprotein in the development of papillary renal cell carcinomas.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16832349","citation_count":20,"is_preprint":false},{"pmid":"26612033","id":"PMC_26612033","title":"Isolation and Comparative Genomic Analysis of T1-Like Shigella Bacteriophage pSf-2.","date":"2015","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26612033","citation_count":20,"is_preprint":false},{"pmid":"25212428","id":"PMC_25212428","title":"Inhibitory effect of insulin-like growth factor-binding protein-7 (IGFBP7) on in vitro angiogenesis of vascular endothelial cells in the rat corpus luteum.","date":"2014","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/25212428","citation_count":20,"is_preprint":false},{"pmid":"30609749","id":"PMC_30609749","title":"IGFBP7 Drives Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition in Lung Cancer.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30609749","citation_count":19,"is_preprint":false},{"pmid":"22213094","id":"PMC_22213094","title":"Proteomic identification of PSF and p54(nrb) as TopBP1-interacting proteins.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22213094","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52465,"output_tokens":6437,"usd":0.126975},"stage2":{"model":"claude-opus-4-6","input_tokens":10116,"output_tokens":3780,"usd":0.21762},"total_usd":0.344595,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"BRAFV600E oncogene expression in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis; apoptosis results from IGFBP7-mediated upregulation of BNIP3L, a proapoptotic BCL2 family protein.\",\n      \"method\": \"Genome-wide RNAi screening, recombinant protein treatment, xenograft mouse model, cell-based assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — RNAi screen + functional rescue with recombinant protein + in vivo xenograft validation, single high-impact study with multiple orthogonal methods\",\n      \"pmids\": [\"18267069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IGFBP7 directly binds to the extracellular portion of IGF1R (via its N-terminal 97 amino acids), blocks its activation and internalization by IGF-1/2, causes accumulation of inactive IGF1R on the cell surface, and suppresses downstream PI3K-AKT signaling; binding of IGFBP7 and IGF-1 to IGF1R is mutually exclusive.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutagenesis, receptor internalization assay, phosphorylation assays, recombinant protein treatment\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated with mutagenesis, mutually exclusive competition assay, downstream signaling validation with multiple methods\",\n      \"pmids\": [\"23250396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IGFBP7 (mac25) protein was co-immunoprecipitated with activin A, indicating that mac25/IGFBP7 is a secreted protein that binds activin A and may modulate its signaling.\",\n      \"method\": \"Immunoprecipitation, Western blot, GFP fusion localization, recombinant protein growth suppression assay\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP demonstrated binding to activin A; single lab, single method for the binding interaction\",\n      \"pmids\": [\"10859029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IGFBP7 (AGM/mac25) binds to cell-surface heparan sulfates via an identified 20-amino acid cell-binding sequence; heparinase treatment and heparin competition abolish cell adhesion to AGM.\",\n      \"method\": \"Cell adhesion competition assays, heparinase treatment, synthetic peptide blocking, binding assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (enzyme treatment, competitive inhibition, synthetic peptide) converging on same receptor identification\",\n      \"pmids\": [\"10502291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Proteolytic cleavage of IGFBP7 (IGFBP-rP1) by a trypsin-like serine proteinase abrogates its insulin/IGF-1-binding activity and insulin/IGF-1-dependent growth-stimulatory activity while markedly increasing its cell attachment activity; syndecan-1 is identified as a cell surface receptor for both intact and cleaved forms.\",\n      \"method\": \"Proteolytic processing assays, IGF-1 binding assays, cell attachment assays, receptor identification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical demonstration of functional change upon cleavage; single lab but multiple functional readouts\",\n      \"pmids\": [\"14521955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IGFBP7 (mac25/IGFBP-rP1) overexpression in prostate cancer cells increases SOD-2 (manganese superoxide dismutase) expression as a downstream mediator of its senescence-associated tumor suppression; mac25 cells show increased phospho-ERK and phospho-AKT, and PI3K inhibition markedly decreases their viability.\",\n      \"method\": \"cDNA expression array, stable transfection, in vivo tumor growth, SOD-2 overexpression rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gene expression array identification of SOD-2 downstream with functional rescue, but pathway placement is partial\",\n      \"pmids\": [\"12592389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TGF-β1 secreted by glioblastoma cells induces IGFBP7 expression in human brain endothelial cells through the TGF-β1/ALK5/Smad-2 signaling pathway; IGFBP7 protein promotes capillary-like tube formation (angiogenesis).\",\n      \"method\": \"Conditioned media treatment, TGF-β neutralizing antibody, ALK5 receptor antagonist (SB431542), Smad-2 phosphorylation assays, Matrigel tube formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissection with specific inhibitors and neutralizing antibody; single lab\",\n      \"pmids\": [\"18711401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IGFBP7 is a p53-responsive gene; p53 induces IGFBP7 expression by binding to a p53 response element within intron 1 of the IGFBP7 gene, as demonstrated by luciferase reporter assay and chromatin immunoprecipitation.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), 5-aza-dC demethylation, p53 transfection\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct ChIP showing p53 binding to IGFBP7 intronic response element, corroborated by luciferase assay and demethylation rescue\",\n      \"pmids\": [\"19638426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAR2 edits IGFBP7 mRNA (A-to-I RNA editing), and this editing stabilizes IGFBP7 protein by altering the matriptase protease recognition site, preventing proteolytic cleavage; ADAR2-mediated IGFBP7 stabilization induces apoptosis and inhibits Akt signaling in esophageal squamous cell carcinoma.\",\n      \"method\": \"RNA-seq editing analysis, active-site ADAR2 mutant, IGFBP7 knockdown, Western blotting for Akt signaling, in vitro/in vivo tumor models\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with catalytic mutant and downstream signaling validation; single lab\",\n      \"pmids\": [\"28035363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A-to-I RNA editing of IGFBP7 transcripts alters the protein's susceptibility to proteolytic cleavage, providing a mechanism for cells to modulate IGFBP7 functionality through RNA editing.\",\n      \"method\": \"RNA editing analysis, proteolysis susceptibility assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical demonstration; single lab with defined functional consequence\",\n      \"pmids\": [\"22750143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TGF-β1 upregulates IGFBP7 expression in human renal proximal tubular epithelial cells via Smad2 and Smad4 (but not MAPK) pathways; knockdown of IGFBP7 reverses TGF-β1-induced epithelial-to-mesenchymal transition (EMT).\",\n      \"method\": \"Dose/time-dependent TGF-β1 treatment, Smad2/4 pathway inhibition, IGFBP7 knockdown, EMT marker analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway-specific knockdown distinguishing Smad from MAPK; single lab\",\n      \"pmids\": [\"26974954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IGFBP7 promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells via the Wnt/β-catenin signaling pathway; both overexpression and exogenous IGFBP7 protein increase β-catenin levels, and Wnt/β-catenin inhibitors partially block IGFBP7-induced osteogenesis.\",\n      \"method\": \"Overexpression, exogenous protein addition, siRNA knockdown, Wnt inhibitor treatment, in vivo tibial osteotomy model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway inhibitor rescue + in vivo validation; single lab\",\n      \"pmids\": [\"29242275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IGFBP7 inhibits RANKL-induced osteoclastogenesis, F-actin ring formation, and bone resorption by suppressing the NF-κB signaling pathway; in a mouse ovariectomy-induced osteoporosis model, IGFBP7 treatment attenuated osteoclast-driven bone loss.\",\n      \"method\": \"Recombinant IGFBP7 protein, lentivirus overexpression, siRNA knockdown, NF-κB pathway analysis, in vivo ovariectomy model\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanism + in vivo validation; single lab\",\n      \"pmids\": [\"31889368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cardiac fibroblasts regulate heart failure via an Htra3-TGF-β-IGFBP7 axis: pressure overload downregulates Htra3, leading to TGF-β activation, which drives cardiomyocyte DNA damage and induction of IGFBP7 secretion from failing cardiomyocytes; Htra3 overexpression inhibits TGF-β signaling and ameliorates cardiac dysfunction.\",\n      \"method\": \"Single-cell RNA-seq, spatial transcriptomics, genetic perturbation (overexpression, knockout), mouse pressure overload model, human plasma proteome analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (scRNA-seq, genetic perturbation, spatial transcriptomics) in both mouse and human, with functional rescue\",\n      \"pmids\": [\"35672400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGFBP7 promotes cardiac senescence by stimulating IGF-1R/IRS/AKT-dependent suppression of FOXO3a, preventing DNA repair and ROS detoxification; in vivo AAV9-shRNA cardiac Igfbp7 knockdown and antibody-mediated IGFBP7 neutralization reversed suppression of FOXO3a and attenuated pressure-overload-induced heart failure.\",\n      \"method\": \"Igfbp7 knockout mouse, AAV9-shRNA knockdown, neutralizing antibody treatment, pressure overload model, signaling pathway analysis\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO, shRNA, and antibody neutralization all converging on same mechanistic pathway with functional cardiac readout\",\n      \"pmids\": [\"39196168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Senescent cardiac endothelial cells upregulate Igfbp7 under pressure overload; EC-specific Igfbp7 deletion and vaccine-mediated neutralization of IGFBP7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes, establishing IGFBP7 as a paracrine mediator from senescent ECs to cardiomyocytes.\",\n      \"method\": \"EC-specific gene knockout, AAV9 overexpression, anti-IGFBP7 vaccine, single-cell RNA-seq, metabolic analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — cell-type-specific genetic deletion + vaccine neutralization + scRNA-seq in both mouse and human with functional validation\",\n      \"pmids\": [\"38991046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IGFBP7 (mac25/AGM) expressed on cell surfaces reduces anchorage-independent growth and suppresses tumor growth in vivo through an insulin/IGF-independent mechanism; IGFBP7-expressing cells bind more efficiently to fibronectin and laminin-5.\",\n      \"method\": \"RNA interference knockdown, expression vector transfection, soft agar colony assay, xenograft mouse model, cell adhesion assay\",\n      \"journal\": \"Cancer science (published 2007)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual model system (RNAi and overexpression) with in vivo validation; single lab\",\n      \"pmids\": [\"17465992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SMARCB1 (Snf5) is required for transcriptional activation of IGFBP7; re-introduction of Igfbp7 alone in Smarcb1-deficient tumor cells can hinder tumor development in xenografts, placing IGFBP7 downstream of the SMARCB1/SWI-SNF chromatin remodeling complex.\",\n      \"method\": \"Gene expression profiling, Smarcb1 re-expression, Igfbp7 re-expression, xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via rescue experiment (Igfbp7 re-expression) with in vivo tumor validation; single lab\",\n      \"pmids\": [\"23851500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Exercise upregulates Igfbp7 expression in muscle satellite cells, which impedes Akt phosphorylation, inhibits mTOR activity, reduces mitochondrial metabolism, and causes hypoacetylation of H3K27ac at Akt promoters, thereby protecting satellite cells from exhaustion.\",\n      \"method\": \"Treadmill exercise model, RNA sequencing, ChIP-PCR, flow cytometry, immunofluorescence, Akt-mTOR pathway analysis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq, ChIP, and mechanistic pathway analysis in vivo; single lab\",\n      \"pmids\": [\"32483463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IGFBP7 (mac25/AGM) interacts with multiple molecules in high endothelial venules including chemokines CCL21 (SLC), CXCL10 (IP-10), and CCL5 (RANTES) in a dose-dependent and saturable manner; binding to chemokines is selective, does not inhibit their Ca2+-signaling activity, and suggests a chemokine-presenting function at the HEV basal lamina.\",\n      \"method\": \"Binding assays (dose-dependent, saturable), competitive inhibition assay, immunohistochemistry, Ca2+-signaling assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — saturable binding with competition assay; functional consequence (Ca2+ signaling retention) demonstrated; single lab\",\n      \"pmids\": [\"12847218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IGFBP7 promotes TAM/M2 macrophage polarization in gastric cancer via FGF2/FGFR1/PI3K/AKT axis; exogenous recombinant IGFBP7 treatment of macrophages and cancer cells confirmed this paracrine mechanism.\",\n      \"method\": \"RNA sequencing, ELISA, recombinant IGFBP7 treatment, loss-of-function studies, transcriptome analysis\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — recombinant protein treatment + pathway analysis; single lab\",\n      \"pmids\": [\"36681667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGFBP7 binds to IGF1R and mediates programmed cell death (necroptosis via RIPK1/RIPK3/MLKL pathway) and inflammation in acute kidney injury; co-immunoprecipitation confirmed IGFBP7 binding to IGF1R, and IGF1R inhibitor (picropodophyllin) abrogated the therapeutic effects of a protective compound targeting this pathway.\",\n      \"method\": \"Co-immunoprecipitation, RNA sequencing, Western blot, in vivo AKI mouse models, IGF1R inhibitor treatment\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP of IGFBP7-IGF1R + pathway inhibitor rescue; single lab\",\n      \"pmids\": [\"33773190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GABA from enteric GABAergic neurons signals through Gabbr1/Gabbr2 receptors on ILC3s to suppress the LIP isoform of C/EBP-β, which in turn represses IGFBP7 transcription; autocrine IGFBP7 then signals through IGF1R to inhibit ILC3 proliferation and IL-17A production.\",\n      \"method\": \"Conditional neuron ablation, receptor knockout, transcription factor knockdown, autocrine IGFBP7 assays, in vivo colitis model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic pathway dissection from upstream neuronal signal to IGFBP7 autocrine loop with multiple KO/KD experiments and in vivo disease model\",\n      \"pmids\": [\"40033120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGFBP7 is a key SASP component that induces secondary senescence by: (1) binding insulin and inhibiting its anti-senescence effects; (2) promoting IGF-II interaction with IGF2R while blocking IGF1R; (3) interacting with activin A receptors to induce senescence via SMAD pathways; these effects are dependent on ERK and AKT signaling.\",\n      \"method\": \"Neutralizing antibody treatment, recombinant IGFBP7 incubation, senescence assays, ERK/AKT pathway inhibition, SMAD pathway analysis\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — neutralizing antibody + recombinant protein experiments with pathway validation; single lab\",\n      \"pmids\": [\"39533382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Exogenous IGFBP7 treatment of triple-negative breast cancer cells induces G1 cell cycle arrest, senescence, and apoptosis associated with activation of p38 MAPK, upregulation of p53 and p21(cip1), and cleaved PARP; systemic rIGFBP7 in xenograft mice inhibited tumorigenesis with anti-angiogenic effects.\",\n      \"method\": \"Recombinant protein treatment, flow cytometry cell cycle analysis, SA-β-gal senescence assay, Western blotting, xenograft mouse model\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cellular readouts + in vivo validation; single lab\",\n      \"pmids\": [\"21997538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IGFBP7 suppresses VEGFA- and LH-induced angiogenesis in luteal microvascular endothelial cells by inhibiting their proliferation and migration, reducing phosphorylation of MEK and ERK1/2, and attenuating VEGFA-enhanced COX-2 expression and prostaglandin E2 secretion.\",\n      \"method\": \"In vitro tube formation assay (Matrigel), proliferation and migration assays, ERK/MEK phosphorylation assays, COX-2 mRNA and PGE2 measurement\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays with signaling pathway validation; single lab\",\n      \"pmids\": [\"25212428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AKI-induced urinary IGFBP7 elevations are not due to stress-induced gene transcription but result from increased glomerular filtration, decreased tubular reabsorption, and proximal tubule cell IGFBP7 leakage; immunohistochemistry showed progressive IGFBP7 loss from injured proximal tubule cells, and endocytic inhibition in normal mice tripled urinary IGFBP7 levels.\",\n      \"method\": \"Mouse AKI models (glycerol, maleate, ischemia), ELISA, mRNA quantification, immunohistochemistry, competitive endocytic inhibition\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple AKI models + mechanistic dissection of urinary excretion pathway with direct inhibitor experiment\",\n      \"pmids\": [\"29980651\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGFBP7 is a secreted protein that functions as a multi-target suppressor of pro-growth and pro-survival signaling: it directly binds IGF1R (via its N-terminal domain) to block IGF-1/2-induced receptor activation and downstream PI3K-AKT signaling; it binds activin A, heparan sulfates, and select chemokines in the extracellular matrix; its expression is transcriptionally activated by p53 (via an intronic response element) and TGF-β/Smad2/4 signaling, and is epigenetically silenced in many cancers; in oncogene-induced senescence BRAFV600E drives IGFBP7 secretion which in turn suppresses BRAF-MEK-ERK and induces apoptosis via BNIP3L upregulation; in cardiac biology IGFBP7 produced by senescent endothelial cells or failing cardiomyocytes promotes senescence by suppressing FOXO3a through IGF-1R/IRS/AKT, thereby impairing DNA repair and ROS detoxification; and its susceptibility to proteolytic inactivation is modulated by A-to-I RNA editing of its transcript.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IGFBP7 is a secreted, multivalent signaling modulator that suppresses pro-growth and pro-survival pathways while promoting cellular senescence and apoptosis across diverse tissue contexts. It directly binds the extracellular domain of IGF1R via its N-terminal 97 amino acids, blocking IGF-1/2-induced receptor activation and suppressing downstream PI3K-AKT signaling; it also binds activin A, heparan sulfate proteoglycans (including syndecan-1), and select chemokines (CCL21, CXCL10, CCL5) in the extracellular matrix [PMID:23250396, PMID:10502291, PMID:10859029, PMID:12847218]. IGFBP7 transcription is activated by p53 through an intronic response element, by TGF-β1/ALK5/Smad2/4 signaling, and by the SWI/SNF component SMARCB1, and is frequently epigenetically silenced in cancer; its protein stability is regulated by A-to-I RNA editing that alters a matriptase cleavage site [PMID:19638426, PMID:26974954, PMID:23851500, PMID:22750143]. As a senescence-associated secretory factor, IGFBP7 drives oncogene-induced senescence downstream of BRAF^V600E by inhibiting BRAF-MEK-ERK signaling and upregulating the proapoptotic protein BNIP3L, and in the heart it promotes cardiomyocyte senescence by suppressing FOXO3a through IGF-1R/IRS/AKT, with endothelial cell-specific deletion or antibody neutralization ameliorating pressure-overload heart failure [PMID:18267069, PMID:39196168, PMID:38991046].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that IGFBP7 engages the cell surface via heparan sulfate proteoglycans answered how this secreted protein is retained in the pericellular matrix and can exert local effects.\",\n      \"evidence\": \"Cell adhesion competition, heparinase treatment, and synthetic peptide blocking identified a 20-amino-acid heparan sulfate-binding domain\",\n      \"pmids\": [\"10502291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of specific HSPGs mediating the interaction was not resolved beyond later syndecan-1 identification\", \"Functional consequence of cell-surface retention on signaling not dissected\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery that IGFBP7 binds activin A expanded its ligand repertoire beyond IGFs, suggesting it modulates TGF-β superfamily signaling.\",\n      \"evidence\": \"Co-immunoprecipitation of IGFBP7 with activin A from conditioned media\",\n      \"pmids\": [\"10859029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP method without reciprocal validation or competition assay\", \"Functional consequence of activin A sequestration on downstream Smad signaling not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Multiple studies defined IGFBP7 as a tumor suppressor that operates partly through IGF-independent adhesion to extracellular matrix components and partly through proteolytic regulation of its IGF-binding capacity.\",\n      \"evidence\": \"Proteolysis assays showed serine protease cleavage abolishes IGF-binding and increases cell attachment via syndecan-1; xenograft and soft-agar assays demonstrated IGF-independent tumor suppression; saturable binding assays identified chemokine partners CCL21, CXCL10, CCL5\",\n      \"pmids\": [\"14521955\", \"17465992\", \"12847218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo protease identity not established\", \"Chemokine-presenting function at HEV not validated beyond binding and calcium-signaling retention\", \"Relative contributions of IGF-dependent vs IGF-independent suppression not quantified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that BRAF^V600E drives IGFBP7 secretion to inhibit MEK-ERK and induce senescence/apoptosis via BNIP3L established IGFBP7 as a critical effector of oncogene-induced senescence.\",\n      \"evidence\": \"Genome-wide RNAi screen, recombinant protein rescue, and xenograft model in primary cells expressing oncogenic BRAF\",\n      \"pmids\": [\"18267069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGFBP7-mediated OIS generalizes beyond BRAF^V600E to other RAS-pathway oncogenes was not tested\", \"Direct receptor mediating BRAF-MEK-ERK suppression not identified in this study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing TGF-β1 induces IGFBP7 via ALK5/Smad2 in brain endothelial cells linked IGFBP7 to TGF-β-driven angiogenesis in glioblastoma.\",\n      \"evidence\": \"TGF-β neutralizing antibody, ALK5 antagonist SB431542, and Smad2 phosphorylation analysis in GBM-conditioned media-treated endothelial cells\",\n      \"pmids\": [\"18711401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro-angiogenic role in brain endothelium contrasts with anti-angiogenic effects reported elsewhere; context-dependency not resolved\", \"Downstream target of IGFBP7 in tube formation not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of a p53 response element in IGFBP7 intron 1 placed IGFBP7 in the p53 tumor-suppressor network and explained its silencing upon p53 loss or promoter methylation.\",\n      \"evidence\": \"ChIP demonstrating direct p53 binding to intronic element, corroborated by luciferase reporter and 5-aza-dC demethylation rescue\",\n      \"pmids\": [\"19638426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53-dependent induction is the dominant route in vivo vs TGF-β/Smad induction not compared\", \"Epigenetic silencing mechanism at the IGFBP7 promoter in cancer not fully dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping the direct IGFBP7–IGF1R interaction to the N-terminal 97 amino acids and showing mutually exclusive binding with IGF-1 established the primary receptor-level mechanism for IGFBP7's anti-growth activity.\",\n      \"evidence\": \"Co-immunoprecipitation, deletion mutagenesis, receptor internalization, and phosphorylation assays\",\n      \"pmids\": [\"23250396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the mutually exclusive binding not determined\", \"Whether IGFBP7 also signals through IGF1R independently of simple competitive antagonism not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that A-to-I RNA editing alters IGFBP7's protease susceptibility introduced a post-transcriptional regulatory layer controlling its functional half-life.\",\n      \"evidence\": \"RNA editing analysis coupled with proteolysis susceptibility assays; later confirmed with ADAR2 catalytic-dead mutant showing editing prevents matriptase cleavage and stabilizes the protein\",\n      \"pmids\": [\"22750143\", \"28035363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Prevalence of edited vs unedited IGFBP7 transcripts across tissues not systematically surveyed\", \"In vivo significance of editing for IGFBP7 tumor suppression not demonstrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placing IGFBP7 downstream of the SMARCB1/SWI-SNF chromatin remodeling complex explained IGFBP7 loss in rhabdoid tumors and showed IGFBP7 re-expression alone can substitute for SMARCB1 tumor suppression.\",\n      \"evidence\": \"SMARCB1 re-expression restored IGFBP7; Igfbp7 re-expression in Smarcb1-deficient cells suppressed xenograft tumor growth\",\n      \"pmids\": [\"23851500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SMARCB1 directly binds the IGFBP7 promoter or acts indirectly not resolved\", \"Generalizability beyond rhabdoid tumor cells not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmation that TGF-β1 induces IGFBP7 through Smad2/4 in renal epithelial cells, and that IGFBP7 is required for TGF-β-driven EMT, extended its role to kidney fibrosis.\",\n      \"evidence\": \"Smad2/4 knockdown blocked IGFBP7 induction; IGFBP7 knockdown reversed TGF-β1-induced EMT markers\",\n      \"pmids\": [\"26974954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of Smad2/4 to IGFBP7 regulatory regions not shown\", \"Role in progressive renal fibrosis in vivo not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In the heart, an Htra3–TGF-β–IGFBP7 axis was delineated in which pressure overload downregulates the protease Htra3 in fibroblasts, unleashing TGF-β to induce cardiomyocyte IGFBP7, which promotes senescence by suppressing FOXO3a via IGF-1R/IRS/AKT signaling.\",\n      \"evidence\": \"Single-cell RNA-seq, spatial transcriptomics, Igfbp7-KO and AAV9-shRNA knockdown, neutralizing antibody, and pressure-overload mouse models with functional cardiac readouts\",\n      \"pmids\": [\"35672400\", \"39196168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FOXO3a suppression is the sole effector of IGFBP7-driven cardiac senescence not determined\", \"Human genetic evidence linking IGFBP7 variants to heart failure absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that senescent endothelial cells are the primary cardiac source of IGFBP7 paracrine signaling, and that EC-specific deletion or vaccine-mediated neutralization rescues heart failure, established IGFBP7 as a druggable SASP factor.\",\n      \"evidence\": \"EC-specific Igfbp7 conditional knockout, anti-IGFBP7 peptide vaccine, single-cell RNA-seq, and metabolic analysis under pressure overload\",\n      \"pmids\": [\"38991046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Vaccine efficacy in large-animal or human settings not tested\", \"Whether EC- vs cardiomyocyte-derived IGFBP7 has distinct paracrine targets not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of an enteric neuron–ILC3 circuit in which GABA suppresses C/EBPβ-LIP-driven IGFBP7 transcription, with autocrine IGFBP7–IGF1R signaling restraining ILC3 proliferation and IL-17A production, extended the gene's role to intestinal immunity.\",\n      \"evidence\": \"Conditional neuron ablation, receptor and transcription factor knockdowns, autocrine IGFBP7 assays, and in vivo colitis models\",\n      \"pmids\": [\"40033120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGFBP7 restrains other innate lymphoid populations not tested\", \"Relevance to human inflammatory bowel disease not directly demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Unresolved: the structural basis of IGFBP7's mutually exclusive binding to IGF1R versus IGFs, the relative in vivo contributions of its multiple receptor interactions (IGF1R, activin receptors, syndecan-1, HSPGs), and whether its pro-angiogenic vs anti-angiogenic effects reflect distinct receptor complexes in different vascular beds.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure or cryo-EM structure of IGFBP7–IGF1R complex\", \"Context-dependent switching between pro- and anti-angiogenic roles mechanistically unexplained\", \"Relative signaling contributions of IGF1R antagonism vs activin A sequestration vs HSPG binding not quantitatively dissected in any single system\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 14, 22, 23]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 14, 15, 22]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 3, 4, 19, 23]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [3, 19]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 14, 18, 22, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 8, 21, 24]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [14, 15, 23, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IGF1R\",\n      \"INHBA\",\n      \"SDC1\",\n      \"BNIP3L\",\n      \"FOXO3\",\n      \"SMAD2\",\n      \"CCL21\",\n      \"CXCL10\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}