{"gene":"ESM1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1996,"finding":"ESM1 (endocan) is a novel endothelial cell-specific secreted protein of ~20 kDa, encoded by a single gene, with a functional N-terminal hydrophobic signal sequence, constitutively expressed in HUVECs and lung tissue but not other cell lines tested. TNF-α and IL-1β upregulate ESM1 mRNA in a time-dependent manner, while IFN-γ inhibits TNF-α-induced ESM1 upregulation.","method":"Northern blot, RT-PCR, Southern blot, immunoprecipitation, immunoblotting, COS cell transfection, cytokine treatment of HUVECs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (immunoprecipitation, immunoblotting, Northern blot, transfection) in a single foundational study; replicated by subsequent work","pmids":["8702785"],"is_preprint":false},{"year":2005,"finding":"Endocan/ESM1 is a soluble dermatan sulphate proteoglycan of ~50 kDa, consisting of a 165-amino-acid polypeptide with a single dermatan sulphate chain covalently linked to serine-137, circulating freely in the bloodstream. Pro-angiogenic growth factors (VEGF, FGF-2, HGF/SF) and TNF-α increase endocan expression, synthesis, and secretion by endothelial cells.","method":"Biochemical characterization, ELISA, cell-based expression assays","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical characterization replicated across multiple labs; structural details (DS chain at Ser137) established by earlier work cited within","pmids":["16168566"],"is_preprint":false},{"year":2014,"finding":"Esm1 binds directly to fibronectin and thereby displaces fibronectin-bound VEGF-A165 (but not VEGF-A121), increasing VEGF-A165 bioavailability and enhancing VEGF-A signaling (phosphorylated Erk1/2). Esm1 knockout mice show delayed vascular outgrowth, reduced filopodia extension, ~40% decrease in leukocyte transmigration, and 30% decrease in VEGF-induced vascular permeability; cerebral edema from ischemic stroke is reduced by 50% in Esm1-KO mice.","method":"Esm1 knockout mouse generation and analysis, retinal vascular outgrowth assay, VEGF permeability assay, leukocyte transmigration assay, direct binding assay (Esm1–fibronectin), phospho-Erk1/2 immunostaining, stroke model","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo KO model with multiple phenotypic readouts, direct binding assay establishing mechanism, multiple orthogonal methods in a single rigorous study","pmids":["25057127"],"is_preprint":false},{"year":2006,"finding":"Hhex homeodomain protein is a direct transcriptional repressor of ESM-1. Hhex binds to an evolutionarily conserved Hhex response element (HRE1) in the ESM-1 promoter and represses its transcription; loss of Hhex in knockout embryos leads to increased ESM-1 expression, and overexpression of Hhex in endothelial cells downregulates ESM-1.","method":"Transient co-transfection assay, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis, chromatin immunoprecipitation (ChIP), Hhex-null mouse embryos","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — four orthogonal methods (EMSA, ChIP, mutagenesis, co-transfection reporter) in a single study establishing direct transcriptional repression","pmids":["16764824"],"is_preprint":false},{"year":2012,"finding":"ESM-1 activates the NF-κB/IκB pathway in colorectal cancer cells in an Akt-dependent manner. ESM-1 siRNA knockdown decreases phospho-Akt, -p38, -ERK1, -RSK1, -GSK-3α/β, and -HSP27, induces G1 cell cycle arrest via PTEN induction and cyclin D1 reduction, and inhibits cell migration and invasion. ESM-1 overexpression enhances proliferation through Akt-dependent NF-κB activation. ESM-1 was shown to interact directly with NF-κB and activate NF-κB promoter activity.","method":"siRNA knockdown, overexpression, phospho-MAPK array, cell cycle analysis, migration/invasion assays, NF-κB promoter reporter assay, co-immunoprecipitation (ESM-1/NF-κB interaction)","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA and overexpression with phospho-array and reporter assay; single lab, multiple methods but no structural validation","pmids":["22735811"],"is_preprint":false},{"year":2010,"finding":"ESM-1 siRNA knockdown in hepatocellular carcinoma SK-Hep1 cells decreases cell survival via NF-κB pathway inhibition, induces G1 cell cycle arrest through PTEN induction and cyclin D1 reduction, and inhibits cell migration and invasion.","method":"siRNA knockdown, cell viability assay, cell cycle analysis, migration/invasion assays, Western blot","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — consistent findings across colorectal and HCC contexts using siRNA; single lab, limited mechanistic depth","pmids":["20821239"],"is_preprint":false},{"year":2020,"finding":"Nuclear ESM1 (rather than cytosolic or secretory ESM1) directly interacts with the ARM domain of β-catenin to stabilize the β-catenin–TCF4 complex and facilitate transactivation of Wnt/β-catenin signaling targets, supporting prostate cancer stemness. Activated β-catenin in turn mediates nuclear entry of ESM1.","method":"Co-immunoprecipitation (ESM1–β-catenin ARM domain interaction), reporter assay, subcellular fractionation, loss-of-function and gain-of-function in prostate cancer cells, cancer stem cell assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing direct ARM-domain interaction, subcellular fractionation, multiple functional readouts, published in high-impact peer-reviewed journal","pmids":["33347625"],"is_preprint":false},{"year":2018,"finding":"ESM-1 is upregulated by intermittent hypoxia (IH) via the HIF-1α/VEGF pathway in HUVECs. ESM-1 promotes adhesion between monocytes and endothelial cells by enhancing ICAM-1 and VCAM-1 expression. HIF-1α shRNA and VEGFR inhibitor suppressed IH-induced ESM-1 expression.","method":"IH cell culture model, HIF-1α shRNA knockdown, VEGFR inhibitor treatment, ESM-1 siRNA/recombinant protein, adhesion assay, Western blot, ELISA","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA/inhibitor experiments with functional adhesion readout; single lab, pathway placement via genetic/pharmacological inhibition","pmids":["30144067"],"is_preprint":false},{"year":2016,"finding":"ESM1 is a downstream transcriptional target of NGFR (nerve growth factor receptor) in oral squamous cell carcinoma. NGF stimulation of NGFR+ cells increases ESM1 expression. ESM1 overexpression confers enhanced migratory, invasive, and metastatic phenotype; shRNA knockdown of ESM1 in NGFR-overexpressing OSCC cells abrogates tumor growth kinetics and invasive/metastatic properties associated with NGFR.","method":"Gene expression array, NGF stimulation, ESM1 overexpression, shRNA knockdown, migration/invasion assays, in vivo metastasis model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic epistasis (shRNA rescue of NGFR phenotype via ESM1), in vitro and in vivo, single lab","pmids":["27683113"],"is_preprint":false},{"year":2024,"finding":"In hypoxic ovarian cancer, HIF-1α transcriptionally upregulates ESM1. ESM1 acts as a mediator of PKM2 SUMOylation by facilitating interaction between PKM2 and UBA2 (a SUMO E2 enzyme), promoting PKM2 dimer formation. PKM2 dimers undergo nuclear translocation and phosphorylate STAT3, promoting the Warburg effect and vasculogenic mimicry. Shikonin inhibits the ESM1–PKM2 molecular interaction, preventing PKM2 dimerization and blocking glycolysis and fatty acid synthesis.","method":"GST pull-down, Co-immunoprecipitation, molecular docking, ECAR (extracellular acidification rate), tubule formation assay, transwell assay, RT-PCR, Western blot, immunofluorescence, xenograft model, LC-MS/MS","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — GST pull-down and Co-IP establishing direct ESM1–PKM2–UBA2 interactions, metabolic functional assays, in vivo validation, multiple orthogonal methods in one study","pmids":["38720298"],"is_preprint":false},{"year":2024,"finding":"ESM1 promotes gastric cancer EMT by enhancing EGFR/HER3 association and activating the EGFR/HER3-Akt pathway. A signal-peptide deletion mutant (ESM1-19del) showed the secreted form of ESM1 is required for pro-tumorigenic effects. ESM1 also interplays with angiopoietin-2 (ANGPT2) and Akt to promote EMT. Therapeutic peptides inhibited ESM1-induced EGFR/HER3-Akt/ANGPT2 signaling and cell motility.","method":"Signal-peptide deletion mutant, patient-derived organoids, xenograft models, EGFR/HER3 co-immunoprecipitation/association assay, Western blot, therapeutic peptide inhibition","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mutant construct clarifies secreted form requirement, EGFR/HER3 association assay, multiple functional assays; single lab","pmids":["39309430"],"is_preprint":false},{"year":2024,"finding":"ANGPTL4 interacts directly with ESM1 (verified by Co-IP and molecular docking). The ANGPTL4–ESM1 interaction promotes ANGPTL4 binding to lipoprotein lipase (LPL), leading to reprogrammed lipid metabolism and OC cell proliferation/migration. ESM1 may interfere with ANGPTL4 binding to integrin and VE-cadherin, stabilizing vascular integrity and promoting angiogenesis in the OC microenvironment.","method":"Co-immunoprecipitation, molecular docking, RNA sequencing, MTT, EdU, wound healing, transwell, xenograft, CAM assay, zebrafish model, Western blot","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and molecular docking establish interaction; multiple in vitro and in vivo functional assays; single lab","pmids":["38212795"],"is_preprint":false},{"year":2023,"finding":"ESM1 promotes gastric cancer angiogenesis and peritoneal metastasis by directly binding to c-Met on vascular endothelial cell membranes, activating the MAPK/ERK pathway and upregulating VEGFA, HIF1α, and MMP9 expression.","method":"Co-immunoprecipitation (ESM1–c-Met binding), in vitro angiogenesis assays, MAPK/ERK pathway Western blot, xenograft/peritoneal metastasis models, clinical tissue validation","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for direct binding, pathway activation by Western blot, in vivo validation; single lab","pmids":["38201620"],"is_preprint":false},{"year":2025,"finding":"SNORD3, a snoRNA upregulated by TNF-α and IL-17, physically interacts with EZH2 and competitively disrupts the association of EZH2 with RBBP4 within PRC2, diminishing H3K27me3 at the ESM1 gene promoter and relieving transcriptional repression of ESM1 in rheumatoid arthritis fibroblast-like synoviocytes. ESM1 upregulation by SNORD3 drives the aggressive transformation of RA-FLSs.","method":"RNA immunoprecipitation (SNORD3–EZH2 interaction), ChIP (H3K27me3 at ESM1 promoter), Co-IP (EZH2–RBBP4 disruption), siRNA knockdown, CIA mouse model, aptamer screening (SELEX) for ESM1","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — RIP for direct snoRNA–protein interaction, ChIP for epigenetic mark, Co-IP for complex disruption, in vivo mouse model; multiple orthogonal methods","pmids":["41223251"],"is_preprint":false},{"year":2025,"finding":"IRF5 promotes phosphorylation of STAT1 and STAT2 and their nuclear translocation in endothelial cells under salt-sensitive hypertension. The phospho-STAT1::pSTAT2 dimer directly binds to specific sites on the ESM1 promoter to enhance ESM1 transcription, as demonstrated by luciferase reporter assay and ChIP-qPCR.","method":"scRNA-seq, IRF5 knockdown, luciferase reporter assay, ChIP-qPCR, Western blot for nuclear pSTAT1/pSTAT2, DOCA-salt mouse model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and ChIP-qPCR establishing direct pSTAT1::pSTAT2 binding to ESM1 promoter; in vivo model; single lab","pmids":["40332339"],"is_preprint":false},{"year":2026,"finding":"ESM1's anticoagulant function depends on its covalently linked glycosaminoglycan (GAG) chains, which activate the thrombin inhibitor heparin cofactor II (HCII). Loss of esm1 in zebrafish causes vascular occlusion in the cardinal vein; esm1 overexpression dose-dependently reduces venous thrombosis and prolongs time-to-occlusion. Esm1 knockout in mice alters coagulation function, rescued by recombinant human ESM1 protein.","method":"Zebrafish esm1 knockout/overexpression (time-to-occlusion assay), mouse Esm1 knockout, recombinant human ESM1 rescue, in vitro thrombin inhibitor activation assays (HCII), ELISA","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanistic in vitro assay (HCII activation) combined with two in vivo models (zebrafish, mouse KO) and rescue experiment; multiple orthogonal methods","pmids":["41517829"],"is_preprint":false},{"year":2021,"finding":"ESM1 regulates endothelial cell function by controlling connexin 40 (CX40) and eNOS expression. ESM1 was identified as one of the highest expressed genes during endothelial cell differentiation from iPSCs and enhances angiogenesis and neovascularization in in vivo hindlimb ischemia models.","method":"iPS cell differentiation to endothelial cells, next-generation sequencing, ESM1 modulation (gain/loss of function), in vivo angiogenesis and hindlimb ischemia models, connexin 40 and eNOS Western blot/expression analysis","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vivo functional model with defined downstream targets (CX40, eNOS); single lab","pmids":["30372556"],"is_preprint":false},{"year":2021,"finding":"ESM1 (Esm1) promotes tube formation by HUVECs; Esm1 and Stc1 are produced by transplanted adipose-derived stem cells (ADSCs) under hypoxia and identified as angiogenic factors responsible for cardiac protective actions after myocardial infarction in rats.","method":"RNA sequencing of transplanted ADSCs, recombinant Esm1 tube formation assay, PKH-labeled cell tracking, echocardiography, histology","journal":"Circulation journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct tube formation assay with recombinant protein; in vivo cardiac model; single lab","pmids":["33716265"],"is_preprint":false},{"year":2023,"finding":"LIMK2 phosphorylates G3BP1 (identified by phosphoproteomics), and G3BP1 is required for ESM1 mRNA stability; G3BP1 knockdown reduces ESM1 mRNA levels. Ectopic ESM1 expression rescues LIMK2- or G3BP1-inhibition-induced suppression of melanoma growth and metastasis, placing ESM1 downstream of the LIMK2→G3BP1→ESM1 pathway.","method":"Phosphoproteomics (LIMK2 targets), RNA-seq (G3BP1 KD), mRNA stability assay, ESM1 rescue (ectopic expression), melanoma cell culture and mouse models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics identifies G3BP1 as LIMK2 target, mRNA stability assay, epistasis rescue; single lab, multiple methods","pmids":["36922679"],"is_preprint":false},{"year":2025,"finding":"ESM1 inhibits lipolysis by suppressing BECN1-mediated autophagy in ovarian cancer cells. IGF2BP3 (m6A reader) regulates ESM1 mRNA stability. ESM1-mediated KLF10 transcription regulates BECN1. BECN1 competitive binding with HSPA5 promotes ubiquitination/degradation of HMGCR, inhibiting cholesterol production. The IGF2BP3/ESM1/KLF10/BECN1 axis constitutes a positive feedback loop regulating lipid metabolism.","method":"mRNA sequencing, Co-IP, dual-luciferase reporter assay, actinomycin D treatment (mRNA stability), autophagy inhibitor (chloroquine), xenograft model, microarray analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple methods (Co-IP, reporter, mRNA stability, in vivo), but single lab and complex multi-step pathway","pmids":["40240362"],"is_preprint":false},{"year":2026,"finding":"TRIM28 stabilizes ESM1 by promoting its SUMOylation, inhibiting proteasomal degradation. Secreted ESM1 from bevacizumab-resistant ovarian cancer cells activates the ITGB1/FAK axis to induce neovascularization and bevacizumab resistance. TRIM28 overexpression promotes angiogenesis and Bev resistance via ESM1-mediated ITGB1/FAK activation in OC mouse models.","method":"Co-immunoprecipitation (TRIM28–ESM1, SUMOylation), proteasome inhibitor assay, ITGB1/FAK pathway Western blot, in vivo OC mouse models, conditioned medium angiogenesis assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for SUMOylation and interaction, pathway activation, in vivo model; single lab","pmids":["41649926"],"is_preprint":false},{"year":2025,"finding":"LSD1 promotes ESM1 transcription by binding to specific regulatory regions of the ESM1 gene and catalyzing H3K9me2 demethylation at the ESM1 promoter. ESM1 in turn regulates extravillous trophoblast function through EGFR/STAT3 and insulin receptor (IR) signaling pathways. This LSD1-ESM1-p-STAT3 axis is coordinately downregulated in recurrent spontaneous abortion patients.","method":"Chromatin immunoprecipitation (LSD1 binding, H3K9me2 at ESM1 promoter), RNA sequencing, Western blot, loss-of-function/gain-of-function, pharmacological inhibition (ORY-1001, metformin), mouse resorption model","journal":"Journal of assisted reproduction and genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct LSD1 binding and H3K27me2 mark at ESM1 locus, multi-omics, in vivo mouse model; single lab","pmids":["41984276"],"is_preprint":false},{"year":2025,"finding":"SOX4 binds to the ESM1 promoter and transcriptionally activates ESM1, promoting PI3K/AKT signaling activation and infantile hemangioma (IH) progression. ESM1 independently promotes tumor progression in IH 3D microtumor and animal experiments.","method":"RNA-seq, ChIP (SOX4 binding to ESM1 promoter), cell proliferation/migration/angiogenesis assays, 3D microtumor model, animal experiments","journal":"Precision clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP establishing direct SOX4–ESM1 promoter binding; in vivo model; single lab","pmids":["39507292"],"is_preprint":false},{"year":2025,"finding":"ESM1 upregulates ANGPTL4 expression, and the ESM1–ANGPTL4 axis maintains endothelial cell proliferation and lipid homeostasis by upregulating autophagy. ESM1 facilitates endothelial cell proliferation and mitigates palmitic acid-induced injury through ANGPTL4-mediated autophagy upregulation, an effect attenuated by ATG7 inhibition.","method":"Western blot (ESM1, ANGPTL4, autophagy proteins), MTT and EdU proliferation assays, MDC and pCMV-mCherry-GFP-LC3B staining (autophagic flux), Oil red O staining, ATG7 inhibition, atherosclerosis mouse model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — autophagic flux assays with mechanistic inhibitor, in vivo AS model; single lab","pmids":["40320451"],"is_preprint":false},{"year":2025,"finding":"Esm1-expressing endothelial tip cells inside intestinal villi give rise to arterial endothelium in the intestinal wall and mesenteric vasculature. This artery-forming process requires integrin β1 and signaling by VEGF-C and its receptor VEGFR3, established by genetic lineage tracing.","method":"Genetic lineage tracing (Esm1-Cre), immunohistochemistry, single-cell RNA sequencing, genetic epistasis (integrin β1 KO, VEGF-C/VEGFR3 pathway ablation), confocal imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic lineage tracing with in vivo epistasis (integrin β1, VEGFR3 knockouts), validated by scRNA-seq and IHC; multiple orthogonal approaches","pmids":["40998858"],"is_preprint":false},{"year":2025,"finding":"ESM1 promotes peripheral nerve regeneration by elevating phosphorylated MEK1/2 and ERK1/2 levels in Schwann cells. Recombinant ESM1 protein enhances Schwann cell viability, proliferation, and migration, supports angiogenesis, reduces apoptosis, and accelerates axon regeneration at the injury site.","method":"Recombinant ESM1 protein treatment, in vitro Schwann cell assays (viability, proliferation, migration), in vivo sciatic nerve injury model, Western blot (pMEK1/2, pERK1/2), transcriptomic profiling","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — recombinant protein with defined pathway readout (pMEK/ERK), in vitro and in vivo validation; single lab","pmids":["40992616"],"is_preprint":false},{"year":2026,"finding":"ESM1 and ANGPTL4 form a positive feedback loop, stabilizing FASN to promote trioleate (glycerol trioleate) synthesis in hepatocellular carcinoma cells. Trioleate activates the NF-κB/IL-17 pathway in HCC cells and upregulates CD99 in endothelial cells, driving angiogenesis. ESM1/ANGPTL4 knockdown suppresses tumor growth, rescued by trioleate supplementation.","method":"Co-immunoprecipitation, immunoprecipitation-mass spectrometry (IP-MS), RNA sequencing, metabolomics, tube formation assay, Western blot, xenograft model, tissue microarray","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and IP-MS for interactions, metabolomics, rescue experiment; single lab, multiple orthogonal methods","pmids":["41864037"],"is_preprint":false},{"year":2026,"finding":"ESM1 binds to ERBB2 to promote HSPB1 transcription, activating the FAK/SRC and NF-κB pathways, which inhibits ferroptosis and enhances cisplatin resistance in ovarian cancer cells.","method":"RNA sequencing after ESM1 KD, immunoprecipitation-mass spectrometry (IP-MS), Co-IP (ESM1–ERBB2), electron microscopy (ferroptosis), Western blot, tissue microarray, multiplex immunofluorescence","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and IP-MS establishing ESM1–ERBB2 direct interaction, pathway activation, ferroptosis readout; single lab","pmids":["42231975"],"is_preprint":false},{"year":2022,"finding":"In RT-R-TNBC cells, extracellular ATP activates P2Y2R, which transactivates VEGFR2 through Src phosphorylation, leading to ESM1 overexpression. This pathway activates PAK1, PKC, JNK, and p38 MAPKs, and the transcriptional regulator FoxO1 (nuclear localization promotes ESM1 transcription). VEGFR2 siRNA knockdown reduces ATP-induced ESM1 expression and associated signaling.","method":"P2Y2R knockdown, VEGFR2 siRNA, Src inhibitor, Western blot (pSrc, pVEGFR2), RT-PCR, FoxO1 localization assays, extracellular ATP treatment","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA epistasis placing P2Y2R→Src→VEGFR2→ESM1; multiple inhibitor/KD experiments; single lab","pmids":["37165911"],"is_preprint":false},{"year":2024,"finding":"Lactate upregulates ESM1 mRNA and protein expression in a concentration-dependent manner in cancer cells. ESM1 activates the Akt1–MDM2–p53 pathway to suppress DNA damage repair (DDR). Reduced DDR-generated dsDNA inactivates the cGAS-STING pathway, thereby inhibiting CD8+ T cell immune infiltration. ESM1 knockout in mice promotes CD8+ T cell infiltration into tumors.","method":"ESM1 shRNA/overexpression, lactate treatment, comet assay (DNA damage), flow cytometry (CD8+ T cells, apoptosis), Western blot (ESM1, Akt1, cGAS-STING pathway proteins), EdU staining, ESM1 whole-gene knockout mouse model, xenograft, IHC","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vivo KO model, mechanistic pathway Western blot, DNA damage assay; single lab","pmids":["41930148"],"is_preprint":false},{"year":2024,"finding":"BCL6 transcription factor upregulates ESM1 expression in hepatocellular carcinoma cells, which inhibits T lymphocyte (specifically CD4+ T cell) recruitment and activation through ICAM-1/LFA-1 signaling pathway, promoting cancer immune evasion.","method":"Transcription factor analysis, antibody depletion experiment (CD4+ vs CD8+ T cells), ESM1 expression modulation, ICAM-1/LFA-1 pathway analysis, in vivo HCC models","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — antibody depletion identifying CD4+ T cell specificity, pathway analysis linking ESM1 to ICAM-1/LFA-1; single lab","pmids":["38956432"],"is_preprint":false},{"year":2024,"finding":"In LUAD cells, ESM1 promotes fatty acid synthesis and angiogenesis by activating the AKT signaling pathway and upregulating SCD1 and FASN expression. Secreted ESM1 acts in a paracrine manner to promote endothelial cell proliferation, migration, lipid synthesis, and tube formation in the tumor microenvironment.","method":"MTT, EdU, wound healing, Oil red O, tubule formation assay, xenograft model, CAM model, Western blot (AKT, SCD1, FASN), ESM1 knockdown/overexpression","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — paracrine conditioned medium assay, AKT pathway Western blot, in vivo model; single lab","pmids":["39281564"],"is_preprint":false},{"year":2023,"finding":"Intermittent hypoxia (IH) upregulates ESM1 mRNA and protein in vascular endothelial cells via IH-induced downregulation of miR-181a1, not through transcriptional activation of the ESM1 promoter. Introduction of miR-181a1 mimic abolished IH-induced ESM1 upregulation, indicating post-transcriptional regulation.","method":"IH cell culture (HUEhT-1, UV2), real-time RT-PCR, ELISA, promoter activity assay, miR-181a1 mimic transfection","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter assay (negative result) combined with miRNA mimic rescue, consistent in two cell lines; single lab","pmids":["37968862"],"is_preprint":false},{"year":2024,"finding":"In vascular smooth muscle cells under high salt, TMEM16A upregulation increases ESM1 expression; ESM1 in turn upregulates VCAM-1, ICAM-1, and CXCL16. Silencing ESM1 attenuates VCAM-1, ICAM-1, and CXCL16, placing ESM1 downstream of TMEM16A in the vascular inflammation pathway.","method":"TMEM16A siRNA knockdown, ESM1 siRNA knockdown, transcriptome analysis, Western blot, in vitro high-salt VSMC model, in vivo hypertension mouse model","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic epistasis via siRNA double knockdown, transcriptome analysis; single lab","pmids":["36359280"],"is_preprint":false}],"current_model":"ESM1 (endocan) is a secreted dermatan sulphate proteoglycan expressed by vascular endothelial cells whose GAG chain activates heparin cofactor II (HCII) for anticoagulation; extracellularly, it binds fibronectin to displace and enhance VEGF-A165 bioavailability, binds c-Met and EGFR/HER3 on target cells to activate MAPK/ERK and Akt pathways promoting angiogenesis and EMT, and interacts with ANGPTL4 to reprogram lipid metabolism; intracellularly (when mislocalized to the nucleus), it stabilizes the β-catenin–TCF4 complex to drive Wnt signaling and cancer stemness; its transcription is directly repressed by Hhex and activated by pSTAT1::pSTAT2 dimers (downstream of IRF5), SOX4, HOXD4, SPI1, and LSD1 (via H3K9me2 demethylation), and is relieved from PRC2/H3K27me3 repression by SNORD3-mediated EZH2 disruption; post-translationally, ESM1 is stabilized by TRIM28-mediated SUMOylation; and during vascular development, Esm1-expressing tip cells serve as progenitors of intestinal and mesenteric arterial endothelium in a process requiring integrin β1 and VEGF-C/VEGFR3 signaling."},"narrative":{"mechanistic_narrative":"ESM1 (endocan) is an endothelial cell-specific secreted dermatan sulphate proteoglycan that governs vascular development, angiogenesis, coagulation, and inflammation, and is repeatedly co-opted by tumors to drive proliferation, metastasis, and immune evasion [PMID:8702785, PMID:16168566, PMID:25057127]. The mature protein is a ~50 kDa soluble proteoglycan carrying a single dermatan sulphate chain on serine-137 and is induced by pro-inflammatory cytokines (TNF-α, IL-1β) and pro-angiogenic growth factors (VEGF, FGF-2, HGF) [PMID:8702785, PMID:16168566]. Its glycosaminoglycan chains constitute an anticoagulant activity by activating the thrombin inhibitor heparin cofactor II, with loss of esm1 causing venous occlusion in zebrafish and altered coagulation in mice that is rescued by recombinant ESM1 [PMID:41517829]. In the vasculature, ESM1 binds fibronectin to displace and increase the bioavailability of VEGF-A165, enhancing VEGF/Erk signaling, filopodia extension, leukocyte transmigration, and vascular permeability [PMID:25057127], and Esm1-expressing endothelial tip cells act as progenitors of intestinal and mesenteric arterial endothelium in an integrin β1- and VEGF-C/VEGFR3-dependent manner [PMID:40998858]. As a secreted ligand, ESM1 engages multiple receptor tyrosine kinases—c-Met to activate MAPK/ERK and upregulate VEGFA, HIF1α, and MMP9 [PMID:38201620], EGFR/HER3 to activate the Akt pathway and drive EMT [PMID:39309430], and ERBB2 to induce HSPB1 and suppress ferroptosis [PMID:42231975]—while also forming positive feedback loops with ANGPTL4 that reprogram lipid metabolism and sustain angiogenesis [PMID:40320451, PMID:41864037]. ESM1 expression is controlled by a broad regulatory network: it is directly repressed by the homeodomain protein Hhex [PMID:16764824] and by PRC2/H3K27me3 (relieved when SNORD3 disrupts EZH2–RBBP4) [PMID:41223251], and is directly activated by pSTAT1::pSTAT2 dimers [PMID:40332339], SOX4 [PMID:39507292], and LSD1-mediated H3K9me2 demethylation [PMID:41984276]; it is further regulated post-transcriptionally via mRNA stability (G3BP1, IGF2BP3, miR-181a1) [PMID:36922679, PMID:40240362, PMID:37968862] and stabilized post-translationally by TRIM28-mediated SUMOylation [PMID:41649926]. In cancer, nuclear-localized ESM1 stabilizes the β-catenin–TCF4 complex to drive Wnt signaling and stemness [PMID:33347625], and ESM1 broadly activates Akt-dependent NF-κB signaling to promote proliferation and survival [PMID:22735811, PMID:20821239]; it also suppresses anti-tumor immunity by inactivating cGAS-STING and limiting CD8+ T cell infiltration [PMID:41930148].","teleology":[{"year":1996,"claim":"Establishing that ESM1 is a novel endothelial-specific secreted protein whose expression is cytokine-regulated defined it as a candidate mediator of vascular inflammation.","evidence":"Northern blot, immunoprecipitation, COS-cell transfection, and cytokine treatment of HUVECs","pmids":["8702785"],"confidence":"High","gaps":["No receptor or downstream signaling identified","Functional consequences of secretion not yet tested"]},{"year":2005,"claim":"Biochemical characterization resolved that endocan is a soluble dermatan sulphate proteoglycan with a single GAG chain on Ser137, distinguishing the functional glycoform from the core polypeptide.","evidence":"Biochemical characterization, ELISA, and cell-based expression assays","pmids":["16168566"],"confidence":"High","gaps":["Function of the GAG chain not yet assigned","Binding partners unknown"]},{"year":2006,"claim":"Identifying Hhex as a direct repressor binding a conserved promoter element established the first transcriptional control point for ESM1.","evidence":"EMSA, ChIP, site-directed mutagenesis, reporter assay, and Hhex-null mouse embryos","pmids":["16764824"],"confidence":"High","gaps":["Upstream signals controlling Hhex activity at ESM1 not defined","No activating factors identified at this stage"]},{"year":2014,"claim":"Demonstrating that Esm1 binds fibronectin to displace VEGF-A165 and that Esm1-KO mice have vascular defects established a direct molecular mechanism linking ESM1 to angiogenesis and permeability.","evidence":"Esm1 knockout mice, retinal vascular outgrowth, VEGF permeability and leukocyte transmigration assays, direct Esm1–fibronectin binding, stroke model","pmids":["25057127"],"confidence":"High","gaps":["VEGF-A165 specificity mechanism (vs A121) not structurally resolved","Role of the GAG chain in fibronectin binding unclear"]},{"year":2012,"claim":"Linking ESM-1 to Akt-dependent NF-κB activation and PTEN/cyclin D1 control in carcinoma cells extended its role from vasculature to direct regulation of tumor cell proliferation and invasion.","evidence":"siRNA/overexpression, phospho-MAPK array, cell cycle analysis, migration/invasion assays, NF-κB reporter and Co-IP in colorectal cancer cells (consistent HCC findings 2010)","pmids":["22735811","20821239"],"confidence":"Medium","gaps":["Direct ESM1–NF-κB interaction lacks structural validation","Whether secreted or intracellular ESM1 mediates the effect not resolved","Single lab"]},{"year":2020,"claim":"Discovery that nuclear ESM1 directly binds the β-catenin ARM domain to stabilize the β-catenin–TCF4 complex revealed a non-secretory, intracellular mode of action driving Wnt-dependent cancer stemness.","evidence":"Reciprocal Co-IP, subcellular fractionation, reporter assay, and stem cell assays in prostate cancer cells","pmids":["33347625"],"confidence":"High","gaps":["Mechanism routing a secreted proteoglycan to the nucleus incompletely defined","Whether the GAG chain is present on nuclear ESM1 unknown"]},{"year":2023,"claim":"Identification of c-Met as a direct ESM1 receptor on endothelial cells placed MAPK/ERK-driven angiogenesis and metastasis downstream of secreted ESM1.","evidence":"Co-IP for ESM1–c-Met binding, angiogenesis assays, MAPK/ERK Western blot, and peritoneal metastasis models","pmids":["38201620"],"confidence":"Medium","gaps":["Binding site on c-Met not mapped","Single lab"]},{"year":2024,"claim":"A series of studies established ESM1 as a multi-receptor secreted ligand (EGFR/HER3) and metabolic hub coupling RTK signaling, ANGPTL4/LPL lipid reprogramming, and PKM2 SUMOylation to tumor angiogenesis and the Warburg effect.","evidence":"Signal-peptide deletion mutant, EGFR/HER3 association assay, GST pull-down, Co-IP, and metabolic assays in gastric and ovarian cancer with xenografts","pmids":["39309430","38212795","38720298"],"confidence":"Medium","gaps":["Receptor selectivity across cancer types not unified","Direct vs indirect nature of some interactions (e.g. PKM2–UBA2 bridging) needs reconstitution","Single labs"]},{"year":2024,"claim":"Demonstrating that ESM1 suppresses CD8+ and CD4+ T cell infiltration via Akt1-MDM2-p53/cGAS-STING and ICAM-1/LFA-1 signaling defined a role in tumor immune evasion.","evidence":"ESM1 KO mice, antibody depletion of T cell subsets, comet assay, flow cytometry, and pathway Western blots in tumor models","pmids":["41930148","38956432"],"confidence":"Medium","gaps":["Whether immune effects are cell-autonomous or stromal not fully resolved","Single labs"]},{"year":2025,"claim":"Multiple studies delineated the transcriptional and epigenetic activation network for ESM1, identifying pSTAT1::pSTAT2 dimers, SOX4, and LSD1-mediated H3K9me2 demethylation as direct activators and SNORD3-mediated EZH2 disruption as a derepression mechanism.","evidence":"ChIP/ChIP-qPCR, luciferase reporters, RIP, and in vivo disease models (hypertension, hemangioma, RA, recurrent abortion)","pmids":["40332339","39507292","41984276","41223251"],"confidence":"Medium","gaps":["Combinatorial logic among activators and repressors not integrated","Tissue-specificity of each regulator unclear"]},{"year":2025,"claim":"Lineage tracing established that Esm1+ endothelial tip cells are bona fide arterial progenitors during gut and mesenteric vascular development, requiring integrin β1 and VEGF-C/VEGFR3 signaling.","evidence":"Esm1-Cre genetic lineage tracing, scRNA-seq, IHC, and genetic epistasis (integrin β1 and VEGFR3 ablation)","pmids":["40998858"],"confidence":"High","gaps":["Whether ESM1 protein function (vs marker expression) is required for arterial fate not separated","Generality beyond intestinal/mesenteric beds unknown"]},{"year":2026,"claim":"Establishing that the GAG chain activates heparin cofactor II to inhibit thrombin assigned ESM1 a defined anticoagulant function and an in vivo role in preventing venous thrombosis.","evidence":"In vitro HCII activation assay, zebrafish esm1 KO/overexpression time-to-occlusion, mouse KO, and recombinant ESM1 rescue","pmids":["41517829"],"confidence":"High","gaps":["Relationship between anticoagulant and angiogenic functions of the same GAG chain not integrated","Physiological contexts requiring this activity in humans not defined"]},{"year":2026,"claim":"Identification of TRIM28-mediated SUMOylation as a stabilizer of ESM1 and ERBB2 as an additional receptor linked post-translational control to therapy resistance and ferroptosis suppression.","evidence":"Co-IP for SUMOylation and ESM1–ERBB2 interaction, proteasome inhibitor assays, IP-MS, and ovarian cancer mouse models","pmids":["41649926","42231975"],"confidence":"Medium","gaps":["SUMO acceptor sites on ESM1 not mapped","Single labs"]},{"year":null,"claim":"How the single dermatan sulphate chain mechanistically reconciles ESM1's distinct activities—anticoagulation, growth-factor displacement, and receptor engagement—and what governs the switch between secreted and nuclear ESM1 pools remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of ESM1 bound to any receptor or to fibronectin","Determinants of nuclear translocation undefined","Whether glycoform composition dictates partner selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[10,12,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[12,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,31]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,12,10,6]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[24,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[29,30,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,14,22,21]}],"complexes":[],"partners":["FN1","MET","EGFR","ERBB3","ERBB2","CTNNB1","ANGPTL4","PKM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NQ30","full_name":"Endothelial cell-specific molecule 1","aliases":[],"length_aa":184,"mass_kda":20.1,"function":"Involved in angiogenesis; promotes angiogenic sprouting. May have potent implications in lung endothelial cell-leukocyte interactions","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NQ30/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ESM1","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/ESM1","total_profiled":1310},"omim":[{"mim_id":"601521","title":"ENDOTHELIAL CELL-SPECIFIC MOLECULE 1; ESM1","url":"https://www.omim.org/entry/601521"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":18.6},{"tissue":"thyroid gland","ntpm":16.2}],"url":"https://www.proteinatlas.org/search/ESM1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NQ30","domains":[{"cath_id":"4.10.40","chopping":"40-113","consensus_level":"high","plddt":89.1469,"start":40,"end":113}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ30","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ30-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ30-F1-predicted_aligned_error_v6.png","plddt_mean":72.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ESM1","jax_strain_url":"https://www.jax.org/strain/search?query=ESM1"},"sequence":{"accession":"Q9NQ30","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQ30.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQ30/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ30"}},"corpus_meta":[{"pmid":"8702785","id":"PMC_8702785","title":"ESM-1 is a novel human endothelial cell-specific molecule expressed in lung and regulated by cytokines.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8702785","citation_count":328,"is_preprint":false},{"pmid":"16168566","id":"PMC_16168566","title":"Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy.","date":"2005","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16168566","citation_count":294,"is_preprint":false},{"pmid":"25057127","id":"PMC_25057127","title":"Esm1 modulates endothelial tip cell behavior and vascular permeability by enhancing VEGF bioavailability.","date":"2014","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/25057127","citation_count":197,"is_preprint":false},{"pmid":"11866539","id":"PMC_11866539","title":"Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM.","date":"2002","source":"Microvascular research","url":"https://pubmed.ncbi.nlm.nih.gov/11866539","citation_count":138,"is_preprint":false},{"pmid":"26894862","id":"PMC_26894862","title":"HULC long noncoding RNA silencing suppresses angiogenesis by regulating ESM-1 via the PI3K/Akt/mTOR signaling pathway in human gliomas.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26894862","citation_count":126,"is_preprint":false},{"pmid":"20102396","id":"PMC_20102396","title":"Vascular endocan (ESM-1) is markedly overexpressed in clear cell renal cell carcinoma.","date":"2010","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/20102396","citation_count":109,"is_preprint":false},{"pmid":"31734559","id":"PMC_31734559","title":"Exosomal MicroRNA-9-3p Secreted from BMSCs Downregulates ESM1 to Suppress the Development of Bladder Cancer.","date":"2019","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/31734559","citation_count":89,"is_preprint":false},{"pmid":"38720298","id":"PMC_38720298","title":"ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment.","date":"2024","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38720298","citation_count":83,"is_preprint":false},{"pmid":"31358545","id":"PMC_31358545","title":"ESM1 as a Marker of Macrotrabecular-Massive Hepatocellular Carcinoma.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/31358545","citation_count":80,"is_preprint":false},{"pmid":"22735811","id":"PMC_22735811","title":"ESM-1 regulates cell growth and metastatic process through activation of NF-κB in colorectal cancer.","date":"2012","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/22735811","citation_count":66,"is_preprint":false},{"pmid":"30144067","id":"PMC_30144067","title":"ESM-1 promotes adhesion between monocytes and endothelial cells under intermittent hypoxia.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30144067","citation_count":54,"is_preprint":false},{"pmid":"20383661","id":"PMC_20383661","title":"Overexpression of endothelial cell specific molecule-1 (ESM-1) in gastric cancer.","date":"2010","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20383661","citation_count":54,"is_preprint":false},{"pmid":"20821239","id":"PMC_20821239","title":"ESM-1 silencing decreased cell survival, migration, and invasion and modulated cell cycle progression in hepatocellular carcinoma.","date":"2010","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/20821239","citation_count":46,"is_preprint":false},{"pmid":"33347625","id":"PMC_33347625","title":"Direct interaction of β-catenin with nuclear ESM1 supports stemness of metastatic prostate cancer.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33347625","citation_count":40,"is_preprint":false},{"pmid":"34702798","id":"PMC_34702798","title":"Type V collagen alpha 1 chain promotes the malignancy of glioblastoma through PPRC1-ESM1 axis activation and extracellular matrix remodeling.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34702798","citation_count":39,"is_preprint":false},{"pmid":"23928407","id":"PMC_23928407","title":"ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma.","date":"2013","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/23928407","citation_count":38,"is_preprint":false},{"pmid":"38212795","id":"PMC_38212795","title":"ANGPTL4 accelerates ovarian serous cystadenocarcinoma carcinogenesis and angiogenesis in the tumor microenvironment by activating the JAK2/STAT3 pathway and interacting with ESM1.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38212795","citation_count":37,"is_preprint":false},{"pmid":"33650648","id":"PMC_33650648","title":"ESM1/HIF‑1α pathway modulates chronic intermittent hypoxia‑induced non‑small‑cell lung cancer proliferation, stemness and epithelial‑mesenchymal transition.","date":"2020","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/33650648","citation_count":35,"is_preprint":false},{"pmid":"33175267","id":"PMC_33175267","title":"Pan-cancer analysis identifies ESM1 as a novel oncogene for esophageal cancer.","date":"2020","source":"Esophagus : official journal of the Japan Esophageal Society","url":"https://pubmed.ncbi.nlm.nih.gov/33175267","citation_count":33,"is_preprint":false},{"pmid":"32466580","id":"PMC_32466580","title":"ESM-1 Overexpression is Involved in Increased Tumorigenesis of Radiotherapy-Resistant Breast Cancer Cells.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32466580","citation_count":30,"is_preprint":false},{"pmid":"26809958","id":"PMC_26809958","title":"A comparative analysis of ESM-1 and vascular endothelial cell marker (CD34/CD105) expression on pituitary adenoma invasion.","date":"2016","source":"Pituitary","url":"https://pubmed.ncbi.nlm.nih.gov/26809958","citation_count":29,"is_preprint":false},{"pmid":"38201620","id":"PMC_38201620","title":"ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38201620","citation_count":28,"is_preprint":false},{"pmid":"24108208","id":"PMC_24108208","title":"Plasma endothelial cell-specific molecule-1 (ESM-1) in management of community-acquired pneumonia.","date":"2014","source":"Clinical chemistry and laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24108208","citation_count":28,"is_preprint":false},{"pmid":"33987231","id":"PMC_33987231","title":"ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33987231","citation_count":27,"is_preprint":false},{"pmid":"30372556","id":"PMC_30372556","title":"Enhanced Function of Induced Pluripotent Stem Cell-Derived Endothelial Cells Through ESM1 Signaling.","date":"2018","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/30372556","citation_count":27,"is_preprint":false},{"pmid":"37100467","id":"PMC_37100467","title":"ESM1 promotes angiogenesis in colorectal cancer by activating PI3K/Akt/mTOR pathway, thus accelerating tumor progression.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37100467","citation_count":24,"is_preprint":false},{"pmid":"38897128","id":"PMC_38897128","title":"Lactate drives the ESM1-SCD1 axis to inhibit the antitumor CD8+ T-cell response by activating the Wnt/β-catenin pathway in ovarian cancer cells and inducing cisplatin resistance.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38897128","citation_count":23,"is_preprint":false},{"pmid":"31073279","id":"PMC_31073279","title":"Identification of ESM1 overexpressed in head and neck squamous cell carcinoma.","date":"2019","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31073279","citation_count":22,"is_preprint":false},{"pmid":"27683113","id":"PMC_27683113","title":"ESM1 mediates NGFR-induced invasion and metastasis in murine oral squamous cell carcinoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27683113","citation_count":21,"is_preprint":false},{"pmid":"33482820","id":"PMC_33482820","title":"Silenced lncRNA SNHG14 restrains the biological behaviors of bladder cancer cells via regulating microRNA-211-3p/ESM1 axis.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33482820","citation_count":21,"is_preprint":false},{"pmid":"16764824","id":"PMC_16764824","title":"Hhex is a direct repressor of endothelial cell-specific molecule 1 (ESM-1).","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16764824","citation_count":21,"is_preprint":false},{"pmid":"33716265","id":"PMC_33716265","title":"Esm1 and Stc1 as Angiogenic Factors Responsible for Protective Actions of Adipose-Derived Stem Cell Sheets on Chronic Heart Failure After Rat Myocardial Infarction.","date":"2021","source":"Circulation journal : official journal of the Japanese Circulation Society","url":"https://pubmed.ncbi.nlm.nih.gov/33716265","citation_count":19,"is_preprint":false},{"pmid":"29024069","id":"PMC_29024069","title":"Functional analysis of ESM1 by siRNA knockdown in primary and metastatic head and neck cancer cells.","date":"2017","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29024069","citation_count":17,"is_preprint":false},{"pmid":"28533735","id":"PMC_28533735","title":"ESM-1 siRNA Knockdown Decreased Migration and Expression of CXCL3 in Prostate Cancer Cells.","date":"2017","source":"International journal of biomedical science : IJBS","url":"https://pubmed.ncbi.nlm.nih.gov/28533735","citation_count":17,"is_preprint":false},{"pmid":"31284875","id":"PMC_31284875","title":"ESM-1: A Novel Tumor Biomaker and its Research Advances.","date":"2019","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31284875","citation_count":15,"is_preprint":false},{"pmid":"36359280","id":"PMC_36359280","title":"Arctigenin Attenuates Vascular Inflammation Induced by High Salt through TMEM16A/ESM1/VCAM-1 Pathway.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/36359280","citation_count":15,"is_preprint":false},{"pmid":"35830780","id":"PMC_35830780","title":"Increasing circulating ESM-1 and adhesion molecules are associated with earlystage atherosclerosis in OSA patients:A cross-sectional study.","date":"2022","source":"Sleep medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35830780","citation_count":14,"is_preprint":false},{"pmid":"29416643","id":"PMC_29416643","title":"Clinical validation of serum endocan (ESM-1) as a potential biomarker in patients with renal cell carcinoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29416643","citation_count":14,"is_preprint":false},{"pmid":"31429753","id":"PMC_31429753","title":"Circulating ESM-1 levels are correlated with the presence of coronary artery disease in patients with obstructive sleep apnea.","date":"2019","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/31429753","citation_count":13,"is_preprint":false},{"pmid":"39309430","id":"PMC_39309430","title":"ESM1 facilitates the EGFR/HER3-triggered epithelial-to-mesenchymal transition and progression of gastric cancer via modulating interplay between Akt and angiopoietin-2 signaling.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39309430","citation_count":11,"is_preprint":false},{"pmid":"36922679","id":"PMC_36922679","title":"LIMK2 promotes melanoma tumor growth and metastasis through G3BP1-ESM1 pathway-mediated apoptosis inhibition.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36922679","citation_count":11,"is_preprint":false},{"pmid":"38956432","id":"PMC_38956432","title":"B cell lymphoma 6 promotes hepatocellular carcinoma progression by inhibiting tumor infiltrating CD4+T cell cytotoxicity through ESM1.","date":"2024","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38956432","citation_count":11,"is_preprint":false},{"pmid":"33206778","id":"PMC_33206778","title":"Endocan (ESM-1) levels in gingival crevicular fluid correlate with ICAM-1 and LFA-1 in periodontitis.","date":"2020","source":"Brazilian oral research","url":"https://pubmed.ncbi.nlm.nih.gov/33206778","citation_count":10,"is_preprint":false},{"pmid":"37476182","id":"PMC_37476182","title":"Targeting ESM1/ VEGFα signaling axis: a promising therapeutic avenue for angiogenesis in cervical squamous cell carcinoma.","date":"2023","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37476182","citation_count":9,"is_preprint":false},{"pmid":"40240362","id":"PMC_40240362","title":"IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40240362","citation_count":8,"is_preprint":false},{"pmid":"39929852","id":"PMC_39929852","title":"ESM1 promote proliferation, invasion and angiogenesis via Akt/mTOR and Ras pathway in kidney renal clear cell carcinoma.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39929852","citation_count":7,"is_preprint":false},{"pmid":"37715566","id":"PMC_37715566","title":"Novel specific anti-ESM1 antibodies overcome tumor bevacizumab resistance by suppressing angiogenesis and metastasis.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/37715566","citation_count":7,"is_preprint":false},{"pmid":"36117773","id":"PMC_36117773","title":"Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer.","date":"2022","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36117773","citation_count":6,"is_preprint":false},{"pmid":"23850961","id":"PMC_23850961","title":"Detection and mechanism of action of ESM-1 in rat kidney transplantation under various immune states.","date":"2013","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23850961","citation_count":6,"is_preprint":false},{"pmid":"36675388","id":"PMC_36675388","title":"Combination of Maternal Serum ESM-1 and PLGF with Uterine Artery Doppler PI for Predicting Preeclampsia.","date":"2023","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36675388","citation_count":6,"is_preprint":false},{"pmid":"26906498","id":"PMC_26906498","title":"Levels of endothelial cell-specific molecule-1 (ESM-1) in overt hypothyroidisim.","date":"2016","source":"Endocrine research","url":"https://pubmed.ncbi.nlm.nih.gov/26906498","citation_count":6,"is_preprint":false},{"pmid":"32710501","id":"PMC_32710501","title":"The Relationship Between the Level of Serum ESM-1 and Lp-PLA2 in Patients With Acute ST-Segment Elevation Myocardial Infarction.","date":"2020","source":"Clinical and translational science","url":"https://pubmed.ncbi.nlm.nih.gov/32710501","citation_count":6,"is_preprint":false},{"pmid":"37968862","id":"PMC_37968862","title":"Intermittent hypoxia increased the expression of ESM1 and ICAM-1 in vascular endothelial cells via the downregulation of microRNA-181a1.","date":"2023","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37968862","citation_count":5,"is_preprint":false},{"pmid":"39281564","id":"PMC_39281564","title":"The role of ESM1 in the lipids metabolic reprogramming and angiogenesis of lung adenocarcinoma cells.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39281564","citation_count":5,"is_preprint":false},{"pmid":"39507292","id":"PMC_39507292","title":"Targeting ESM1 via SOX4 promotes the progression of infantile hemangioma through the PI3K/AKT signaling pathway.","date":"2024","source":"Precision clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39507292","citation_count":5,"is_preprint":false},{"pmid":"40320451","id":"PMC_40320451","title":"Unveiling the protective role of ESM1 in endothelial cell proliferation and lipid reprogramming.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40320451","citation_count":4,"is_preprint":false},{"pmid":"40159545","id":"PMC_40159545","title":"Single-cell sequencing uncovers a high ESM1-expression endothelial cell subpopulation associated with bladder cancer progression and the immunosuppressive microenvironment.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40159545","citation_count":4,"is_preprint":false},{"pmid":"37455528","id":"PMC_37455528","title":"ESM-1 Mediates Cell Progression in Clear Cell Renal Cell Carcinoma by Affecting Wnt/β-Catenin Signalling Pathway.","date":"2023","source":"Archivos espanoles de urologia","url":"https://pubmed.ncbi.nlm.nih.gov/37455528","citation_count":4,"is_preprint":false},{"pmid":"37165911","id":"PMC_37165911","title":"P2Y2R‑mediated transactivation of VEGFR2 through Src phosphorylation is associated with ESM‑1 overexpression in radiotherapy‑resistant‑triple negative breast cancer cells.","date":"2023","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37165911","citation_count":4,"is_preprint":false},{"pmid":"40089962","id":"PMC_40089962","title":"ESM1 suppresses LncRNA GAS5/miR-23a-3p/PTEN axis to promote the cisplatin-chemotherapy resistance of ovarian cancer cells via activating the PI3K/AKT pathway.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40089962","citation_count":4,"is_preprint":false},{"pmid":"40998858","id":"PMC_40998858","title":"Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40998858","citation_count":3,"is_preprint":false},{"pmid":"19785952","id":"PMC_19785952","title":"[Expression of ESM-1 in hepatocellular carcinoma is associated with angiogenesis and tumor invasion].","date":"2009","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/19785952","citation_count":3,"is_preprint":false},{"pmid":"31516356","id":"PMC_31516356","title":"Polyphasic characterization of Delftia acidovorans ESM-1, a facultative methylotrophic bacterium isolated from rhizosphere of Eruca sativa.","date":"2018","source":"Saudi journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31516356","citation_count":3,"is_preprint":false},{"pmid":"37668411","id":"PMC_37668411","title":"EpCAM, Ki67, and ESM1 Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation.","date":"2023","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/37668411","citation_count":2,"is_preprint":false},{"pmid":"41223251","id":"PMC_41223251","title":"snoRNA Snord3 promotes rheumatoid arthritis by epigenetic regulation of ESM1 in fibroblast-like synoviocytes in mice.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41223251","citation_count":2,"is_preprint":false},{"pmid":"40332339","id":"PMC_40332339","title":"IRF5 Mediates Artery Inflammation in Salt-Sensitive Hypertension by Regulating STAT1 and STAT2 Phosphorylation to Increase ESM1 Transcription: Insights from Bioinformatics and Mechanistic Analysis.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40332339","citation_count":2,"is_preprint":false},{"pmid":"37605575","id":"PMC_37605575","title":"Identification of ESM1 as a Potential Biomarker Involving Drug Sensitivity and the Tumor Immune Microenvironment that Promotes Proliferation of Melanoma.","date":"2023","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/37605575","citation_count":2,"is_preprint":false},{"pmid":"36077661","id":"PMC_36077661","title":"P2Y2R-Mediated PAK1 Activation Is Involved in ESM-1 Overexpression in RT-R-MDA-MB-231 through FoxO1 Regulation.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36077661","citation_count":2,"is_preprint":false},{"pmid":"34925547","id":"PMC_34925547","title":"Serum Expression of ESM-1, HMWA, and AGEs and Its Relationship with Disease Severity in Patients with Gestational Hypertension.","date":"2021","source":"Computational and mathematical methods in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34925547","citation_count":2,"is_preprint":false},{"pmid":"40042932","id":"PMC_40042932","title":"ESM-1 and GBP-1 are associated with endothelial dysfunction: emerging biomarkers or key players in the pathophysiology of preeclampsia?","date":"2025","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40042932","citation_count":2,"is_preprint":false},{"pmid":"41649926","id":"PMC_41649926","title":"ESM1 SUMOylation mediates bevacizumab resistance in ovarian cancer through ITGB1-FAK-driven angiogenesis.","date":"2026","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41649926","citation_count":1,"is_preprint":false},{"pmid":"38601985","id":"PMC_38601985","title":"Esm-1 mediates transcriptional polarization associated with diabetic kidney disease.","date":"2024","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38601985","citation_count":1,"is_preprint":false},{"pmid":"41517829","id":"PMC_41517829","title":"Endothelial Cell-Specific Molecule-1 (ESM1): An Endogenous Anticoagulant and Protective Factor in Venous Thrombosis.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41517829","citation_count":0,"is_preprint":false},{"pmid":"38626010","id":"PMC_38626010","title":"Functional analysis of ESM1 by shRNA-mediated knockdown of its expression in papillary thyroid cancer cells.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38626010","citation_count":0,"is_preprint":false},{"pmid":"36993439","id":"PMC_36993439","title":"Esm-1 mediates transcriptional polarization associated with diabetic kidney disease.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36993439","citation_count":0,"is_preprint":false},{"pmid":"41864037","id":"PMC_41864037","title":"ESM1 drives cancer angiogenesis and bevacizumab resistance via trioleate synthesis.","date":"2026","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/41864037","citation_count":0,"is_preprint":false},{"pmid":"41366275","id":"PMC_41366275","title":"Multi-omics profiling identifies ESM1 as a key mediator of immunoevasion through the SPP1 pathway in bladder cancer.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41366275","citation_count":0,"is_preprint":false},{"pmid":"40854419","id":"PMC_40854419","title":"HOXD4-mediated transcriptional activation of ESM1 drives glioblastoma progression in human tumor cells and mouse models.","date":"2025","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/40854419","citation_count":0,"is_preprint":false},{"pmid":"41930148","id":"PMC_41930148","title":"Lactic Acid Drives ESM1 to Attenuate DNA Damage and CD8+ T Cell Infiltration in Cancer.","date":"2026","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/41930148","citation_count":0,"is_preprint":false},{"pmid":"39507447","id":"PMC_39507447","title":"Erratum to ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway.","date":"2024","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39507447","citation_count":0,"is_preprint":false},{"pmid":"40992616","id":"PMC_40992616","title":"Elevated ESM1 facilitates peripheral nerve regeneration via enhancing Schwann cell activity and developing a pro-regenerative microenvironment.","date":"2025","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40992616","citation_count":0,"is_preprint":false},{"pmid":"41984276","id":"PMC_41984276","title":"LSD1-ESM1 regulates extravillous trophoblast function through metabolic reprogramming in recurrent spontaneous abortion.","date":"2026","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41984276","citation_count":0,"is_preprint":false},{"pmid":"42231975","id":"PMC_42231975","title":"ESM1 drives cisplatin resistance and ferroptosis resistance via ERBB2/FAK/SRC/HSPB1/NF-κB signaling in ovarian cancer.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42231975","citation_count":0,"is_preprint":false},{"pmid":"41791304","id":"PMC_41791304","title":"CuET inhibits Ewing sarcoma of bone progression through modulation of the ESM1-MAPK/ERK signaling axis.","date":"2026","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41791304","citation_count":0,"is_preprint":false},{"pmid":"41693648","id":"PMC_41693648","title":"PRDM1 Knockdown Promotes Ferroptosis and Sunitinib Sensitivity by Modulating the PI3K/Akt Signaling Through Inhibition of ESM1 Transcription in Renal Cell Carcinoma.","date":"2026","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41693648","citation_count":0,"is_preprint":false},{"pmid":"38094421","id":"PMC_38094421","title":"Retracted: Serum Expression of ESM-1, HMWA, and AGEs and Its Relationship with Disease Severity in Patients with Gestational Hypertension.","date":"2023","source":"Computational and mathematical methods in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38094421","citation_count":0,"is_preprint":false},{"pmid":"40764585","id":"PMC_40764585","title":"Serum expression of ESM-1 and Syndecan-1 and its relationship with disease severity in children with Mycoplasma pneumoniae pneumonia.","date":"2025","source":"Italian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40764585","citation_count":0,"is_preprint":false},{"pmid":"40045860","id":"PMC_40045860","title":"ESM-1 Promotes the Process of Diabetic Nephropathy by Promoting the Expression of CXCL3.","date":"2025","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40045860","citation_count":0,"is_preprint":false},{"pmid":"41578817","id":"PMC_41578817","title":"Assessment of Serum Endothelial Cell-Specific Molecule-1 (ESM-1, Endocan) Levels in Patients with Diabetic Retinopathy.","date":"2025","source":"The Eurasian journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41578817","citation_count":0,"is_preprint":false},{"pmid":"40426985","id":"PMC_40426985","title":"Changes in Gingival Crevicular Fluid Endocan (ESM-1) Levels as a Potential Biomarker After Non-Surgical Periodontal Treatment in Periodontitis Patients.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/40426985","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.16.682838","title":"Attenuation of endothelial glycocalyx shedding and endocan modulation by Sulodexide in murine models of anaphylaxis","date":"2025-10-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.16.682838","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.17.643802","title":"An endothelial specific mouse model for the capillary malformation mutation Gnaq p.R183Q","date":"2025-03-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.17.643802","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.07.636864","title":"Seven blood biomarkers are associated with TGF-β and VHL-HIF signaling in patients with clear cell renal cell carcinoma","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.07.636864","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.13.632837","title":"Zonal endothelial cell heterogeneity underlies murine renal vascular development","date":"2025-01-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.13.632837","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51227,"output_tokens":9775,"usd":0.150153,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20071,"output_tokens":4985,"usd":0.11249,"stage2_stop_reason":"end_turn"},"total_usd":0.262643,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"ESM1 (endocan) is a novel endothelial cell-specific secreted protein of ~20 kDa, encoded by a single gene, with a functional N-terminal hydrophobic signal sequence, constitutively expressed in HUVECs and lung tissue but not other cell lines tested. TNF-α and IL-1β upregulate ESM1 mRNA in a time-dependent manner, while IFN-γ inhibits TNF-α-induced ESM1 upregulation.\",\n      \"method\": \"Northern blot, RT-PCR, Southern blot, immunoprecipitation, immunoblotting, COS cell transfection, cytokine treatment of HUVECs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (immunoprecipitation, immunoblotting, Northern blot, transfection) in a single foundational study; replicated by subsequent work\",\n      \"pmids\": [\"8702785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Endocan/ESM1 is a soluble dermatan sulphate proteoglycan of ~50 kDa, consisting of a 165-amino-acid polypeptide with a single dermatan sulphate chain covalently linked to serine-137, circulating freely in the bloodstream. Pro-angiogenic growth factors (VEGF, FGF-2, HGF/SF) and TNF-α increase endocan expression, synthesis, and secretion by endothelial cells.\",\n      \"method\": \"Biochemical characterization, ELISA, cell-based expression assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical characterization replicated across multiple labs; structural details (DS chain at Ser137) established by earlier work cited within\",\n      \"pmids\": [\"16168566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Esm1 binds directly to fibronectin and thereby displaces fibronectin-bound VEGF-A165 (but not VEGF-A121), increasing VEGF-A165 bioavailability and enhancing VEGF-A signaling (phosphorylated Erk1/2). Esm1 knockout mice show delayed vascular outgrowth, reduced filopodia extension, ~40% decrease in leukocyte transmigration, and 30% decrease in VEGF-induced vascular permeability; cerebral edema from ischemic stroke is reduced by 50% in Esm1-KO mice.\",\n      \"method\": \"Esm1 knockout mouse generation and analysis, retinal vascular outgrowth assay, VEGF permeability assay, leukocyte transmigration assay, direct binding assay (Esm1–fibronectin), phospho-Erk1/2 immunostaining, stroke model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo KO model with multiple phenotypic readouts, direct binding assay establishing mechanism, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"25057127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Hhex homeodomain protein is a direct transcriptional repressor of ESM-1. Hhex binds to an evolutionarily conserved Hhex response element (HRE1) in the ESM-1 promoter and represses its transcription; loss of Hhex in knockout embryos leads to increased ESM-1 expression, and overexpression of Hhex in endothelial cells downregulates ESM-1.\",\n      \"method\": \"Transient co-transfection assay, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis, chromatin immunoprecipitation (ChIP), Hhex-null mouse embryos\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — four orthogonal methods (EMSA, ChIP, mutagenesis, co-transfection reporter) in a single study establishing direct transcriptional repression\",\n      \"pmids\": [\"16764824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ESM-1 activates the NF-κB/IκB pathway in colorectal cancer cells in an Akt-dependent manner. ESM-1 siRNA knockdown decreases phospho-Akt, -p38, -ERK1, -RSK1, -GSK-3α/β, and -HSP27, induces G1 cell cycle arrest via PTEN induction and cyclin D1 reduction, and inhibits cell migration and invasion. ESM-1 overexpression enhances proliferation through Akt-dependent NF-κB activation. ESM-1 was shown to interact directly with NF-κB and activate NF-κB promoter activity.\",\n      \"method\": \"siRNA knockdown, overexpression, phospho-MAPK array, cell cycle analysis, migration/invasion assays, NF-κB promoter reporter assay, co-immunoprecipitation (ESM-1/NF-κB interaction)\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA and overexpression with phospho-array and reporter assay; single lab, multiple methods but no structural validation\",\n      \"pmids\": [\"22735811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ESM-1 siRNA knockdown in hepatocellular carcinoma SK-Hep1 cells decreases cell survival via NF-κB pathway inhibition, induces G1 cell cycle arrest through PTEN induction and cyclin D1 reduction, and inhibits cell migration and invasion.\",\n      \"method\": \"siRNA knockdown, cell viability assay, cell cycle analysis, migration/invasion assays, Western blot\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — consistent findings across colorectal and HCC contexts using siRNA; single lab, limited mechanistic depth\",\n      \"pmids\": [\"20821239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nuclear ESM1 (rather than cytosolic or secretory ESM1) directly interacts with the ARM domain of β-catenin to stabilize the β-catenin–TCF4 complex and facilitate transactivation of Wnt/β-catenin signaling targets, supporting prostate cancer stemness. Activated β-catenin in turn mediates nuclear entry of ESM1.\",\n      \"method\": \"Co-immunoprecipitation (ESM1–β-catenin ARM domain interaction), reporter assay, subcellular fractionation, loss-of-function and gain-of-function in prostate cancer cells, cancer stem cell assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing direct ARM-domain interaction, subcellular fractionation, multiple functional readouts, published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"33347625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ESM-1 is upregulated by intermittent hypoxia (IH) via the HIF-1α/VEGF pathway in HUVECs. ESM-1 promotes adhesion between monocytes and endothelial cells by enhancing ICAM-1 and VCAM-1 expression. HIF-1α shRNA and VEGFR inhibitor suppressed IH-induced ESM-1 expression.\",\n      \"method\": \"IH cell culture model, HIF-1α shRNA knockdown, VEGFR inhibitor treatment, ESM-1 siRNA/recombinant protein, adhesion assay, Western blot, ELISA\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA/inhibitor experiments with functional adhesion readout; single lab, pathway placement via genetic/pharmacological inhibition\",\n      \"pmids\": [\"30144067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ESM1 is a downstream transcriptional target of NGFR (nerve growth factor receptor) in oral squamous cell carcinoma. NGF stimulation of NGFR+ cells increases ESM1 expression. ESM1 overexpression confers enhanced migratory, invasive, and metastatic phenotype; shRNA knockdown of ESM1 in NGFR-overexpressing OSCC cells abrogates tumor growth kinetics and invasive/metastatic properties associated with NGFR.\",\n      \"method\": \"Gene expression array, NGF stimulation, ESM1 overexpression, shRNA knockdown, migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic epistasis (shRNA rescue of NGFR phenotype via ESM1), in vitro and in vivo, single lab\",\n      \"pmids\": [\"27683113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In hypoxic ovarian cancer, HIF-1α transcriptionally upregulates ESM1. ESM1 acts as a mediator of PKM2 SUMOylation by facilitating interaction between PKM2 and UBA2 (a SUMO E2 enzyme), promoting PKM2 dimer formation. PKM2 dimers undergo nuclear translocation and phosphorylate STAT3, promoting the Warburg effect and vasculogenic mimicry. Shikonin inhibits the ESM1–PKM2 molecular interaction, preventing PKM2 dimerization and blocking glycolysis and fatty acid synthesis.\",\n      \"method\": \"GST pull-down, Co-immunoprecipitation, molecular docking, ECAR (extracellular acidification rate), tubule formation assay, transwell assay, RT-PCR, Western blot, immunofluorescence, xenograft model, LC-MS/MS\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — GST pull-down and Co-IP establishing direct ESM1–PKM2–UBA2 interactions, metabolic functional assays, in vivo validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38720298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ESM1 promotes gastric cancer EMT by enhancing EGFR/HER3 association and activating the EGFR/HER3-Akt pathway. A signal-peptide deletion mutant (ESM1-19del) showed the secreted form of ESM1 is required for pro-tumorigenic effects. ESM1 also interplays with angiopoietin-2 (ANGPT2) and Akt to promote EMT. Therapeutic peptides inhibited ESM1-induced EGFR/HER3-Akt/ANGPT2 signaling and cell motility.\",\n      \"method\": \"Signal-peptide deletion mutant, patient-derived organoids, xenograft models, EGFR/HER3 co-immunoprecipitation/association assay, Western blot, therapeutic peptide inhibition\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mutant construct clarifies secreted form requirement, EGFR/HER3 association assay, multiple functional assays; single lab\",\n      \"pmids\": [\"39309430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANGPTL4 interacts directly with ESM1 (verified by Co-IP and molecular docking). The ANGPTL4–ESM1 interaction promotes ANGPTL4 binding to lipoprotein lipase (LPL), leading to reprogrammed lipid metabolism and OC cell proliferation/migration. ESM1 may interfere with ANGPTL4 binding to integrin and VE-cadherin, stabilizing vascular integrity and promoting angiogenesis in the OC microenvironment.\",\n      \"method\": \"Co-immunoprecipitation, molecular docking, RNA sequencing, MTT, EdU, wound healing, transwell, xenograft, CAM assay, zebrafish model, Western blot\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and molecular docking establish interaction; multiple in vitro and in vivo functional assays; single lab\",\n      \"pmids\": [\"38212795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ESM1 promotes gastric cancer angiogenesis and peritoneal metastasis by directly binding to c-Met on vascular endothelial cell membranes, activating the MAPK/ERK pathway and upregulating VEGFA, HIF1α, and MMP9 expression.\",\n      \"method\": \"Co-immunoprecipitation (ESM1–c-Met binding), in vitro angiogenesis assays, MAPK/ERK pathway Western blot, xenograft/peritoneal metastasis models, clinical tissue validation\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for direct binding, pathway activation by Western blot, in vivo validation; single lab\",\n      \"pmids\": [\"38201620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNORD3, a snoRNA upregulated by TNF-α and IL-17, physically interacts with EZH2 and competitively disrupts the association of EZH2 with RBBP4 within PRC2, diminishing H3K27me3 at the ESM1 gene promoter and relieving transcriptional repression of ESM1 in rheumatoid arthritis fibroblast-like synoviocytes. ESM1 upregulation by SNORD3 drives the aggressive transformation of RA-FLSs.\",\n      \"method\": \"RNA immunoprecipitation (SNORD3–EZH2 interaction), ChIP (H3K27me3 at ESM1 promoter), Co-IP (EZH2–RBBP4 disruption), siRNA knockdown, CIA mouse model, aptamer screening (SELEX) for ESM1\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — RIP for direct snoRNA–protein interaction, ChIP for epigenetic mark, Co-IP for complex disruption, in vivo mouse model; multiple orthogonal methods\",\n      \"pmids\": [\"41223251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRF5 promotes phosphorylation of STAT1 and STAT2 and their nuclear translocation in endothelial cells under salt-sensitive hypertension. The phospho-STAT1::pSTAT2 dimer directly binds to specific sites on the ESM1 promoter to enhance ESM1 transcription, as demonstrated by luciferase reporter assay and ChIP-qPCR.\",\n      \"method\": \"scRNA-seq, IRF5 knockdown, luciferase reporter assay, ChIP-qPCR, Western blot for nuclear pSTAT1/pSTAT2, DOCA-salt mouse model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and ChIP-qPCR establishing direct pSTAT1::pSTAT2 binding to ESM1 promoter; in vivo model; single lab\",\n      \"pmids\": [\"40332339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ESM1's anticoagulant function depends on its covalently linked glycosaminoglycan (GAG) chains, which activate the thrombin inhibitor heparin cofactor II (HCII). Loss of esm1 in zebrafish causes vascular occlusion in the cardinal vein; esm1 overexpression dose-dependently reduces venous thrombosis and prolongs time-to-occlusion. Esm1 knockout in mice alters coagulation function, rescued by recombinant human ESM1 protein.\",\n      \"method\": \"Zebrafish esm1 knockout/overexpression (time-to-occlusion assay), mouse Esm1 knockout, recombinant human ESM1 rescue, in vitro thrombin inhibitor activation assays (HCII), ELISA\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanistic in vitro assay (HCII activation) combined with two in vivo models (zebrafish, mouse KO) and rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"41517829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ESM1 regulates endothelial cell function by controlling connexin 40 (CX40) and eNOS expression. ESM1 was identified as one of the highest expressed genes during endothelial cell differentiation from iPSCs and enhances angiogenesis and neovascularization in in vivo hindlimb ischemia models.\",\n      \"method\": \"iPS cell differentiation to endothelial cells, next-generation sequencing, ESM1 modulation (gain/loss of function), in vivo angiogenesis and hindlimb ischemia models, connexin 40 and eNOS Western blot/expression analysis\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vivo functional model with defined downstream targets (CX40, eNOS); single lab\",\n      \"pmids\": [\"30372556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ESM1 (Esm1) promotes tube formation by HUVECs; Esm1 and Stc1 are produced by transplanted adipose-derived stem cells (ADSCs) under hypoxia and identified as angiogenic factors responsible for cardiac protective actions after myocardial infarction in rats.\",\n      \"method\": \"RNA sequencing of transplanted ADSCs, recombinant Esm1 tube formation assay, PKH-labeled cell tracking, echocardiography, histology\",\n      \"journal\": \"Circulation journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct tube formation assay with recombinant protein; in vivo cardiac model; single lab\",\n      \"pmids\": [\"33716265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LIMK2 phosphorylates G3BP1 (identified by phosphoproteomics), and G3BP1 is required for ESM1 mRNA stability; G3BP1 knockdown reduces ESM1 mRNA levels. Ectopic ESM1 expression rescues LIMK2- or G3BP1-inhibition-induced suppression of melanoma growth and metastasis, placing ESM1 downstream of the LIMK2→G3BP1→ESM1 pathway.\",\n      \"method\": \"Phosphoproteomics (LIMK2 targets), RNA-seq (G3BP1 KD), mRNA stability assay, ESM1 rescue (ectopic expression), melanoma cell culture and mouse models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics identifies G3BP1 as LIMK2 target, mRNA stability assay, epistasis rescue; single lab, multiple methods\",\n      \"pmids\": [\"36922679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ESM1 inhibits lipolysis by suppressing BECN1-mediated autophagy in ovarian cancer cells. IGF2BP3 (m6A reader) regulates ESM1 mRNA stability. ESM1-mediated KLF10 transcription regulates BECN1. BECN1 competitive binding with HSPA5 promotes ubiquitination/degradation of HMGCR, inhibiting cholesterol production. The IGF2BP3/ESM1/KLF10/BECN1 axis constitutes a positive feedback loop regulating lipid metabolism.\",\n      \"method\": \"mRNA sequencing, Co-IP, dual-luciferase reporter assay, actinomycin D treatment (mRNA stability), autophagy inhibitor (chloroquine), xenograft model, microarray analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple methods (Co-IP, reporter, mRNA stability, in vivo), but single lab and complex multi-step pathway\",\n      \"pmids\": [\"40240362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM28 stabilizes ESM1 by promoting its SUMOylation, inhibiting proteasomal degradation. Secreted ESM1 from bevacizumab-resistant ovarian cancer cells activates the ITGB1/FAK axis to induce neovascularization and bevacizumab resistance. TRIM28 overexpression promotes angiogenesis and Bev resistance via ESM1-mediated ITGB1/FAK activation in OC mouse models.\",\n      \"method\": \"Co-immunoprecipitation (TRIM28–ESM1, SUMOylation), proteasome inhibitor assay, ITGB1/FAK pathway Western blot, in vivo OC mouse models, conditioned medium angiogenesis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for SUMOylation and interaction, pathway activation, in vivo model; single lab\",\n      \"pmids\": [\"41649926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LSD1 promotes ESM1 transcription by binding to specific regulatory regions of the ESM1 gene and catalyzing H3K9me2 demethylation at the ESM1 promoter. ESM1 in turn regulates extravillous trophoblast function through EGFR/STAT3 and insulin receptor (IR) signaling pathways. This LSD1-ESM1-p-STAT3 axis is coordinately downregulated in recurrent spontaneous abortion patients.\",\n      \"method\": \"Chromatin immunoprecipitation (LSD1 binding, H3K9me2 at ESM1 promoter), RNA sequencing, Western blot, loss-of-function/gain-of-function, pharmacological inhibition (ORY-1001, metformin), mouse resorption model\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct LSD1 binding and H3K27me2 mark at ESM1 locus, multi-omics, in vivo mouse model; single lab\",\n      \"pmids\": [\"41984276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOX4 binds to the ESM1 promoter and transcriptionally activates ESM1, promoting PI3K/AKT signaling activation and infantile hemangioma (IH) progression. ESM1 independently promotes tumor progression in IH 3D microtumor and animal experiments.\",\n      \"method\": \"RNA-seq, ChIP (SOX4 binding to ESM1 promoter), cell proliferation/migration/angiogenesis assays, 3D microtumor model, animal experiments\",\n      \"journal\": \"Precision clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP establishing direct SOX4–ESM1 promoter binding; in vivo model; single lab\",\n      \"pmids\": [\"39507292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ESM1 upregulates ANGPTL4 expression, and the ESM1–ANGPTL4 axis maintains endothelial cell proliferation and lipid homeostasis by upregulating autophagy. ESM1 facilitates endothelial cell proliferation and mitigates palmitic acid-induced injury through ANGPTL4-mediated autophagy upregulation, an effect attenuated by ATG7 inhibition.\",\n      \"method\": \"Western blot (ESM1, ANGPTL4, autophagy proteins), MTT and EdU proliferation assays, MDC and pCMV-mCherry-GFP-LC3B staining (autophagic flux), Oil red O staining, ATG7 inhibition, atherosclerosis mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — autophagic flux assays with mechanistic inhibitor, in vivo AS model; single lab\",\n      \"pmids\": [\"40320451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Esm1-expressing endothelial tip cells inside intestinal villi give rise to arterial endothelium in the intestinal wall and mesenteric vasculature. This artery-forming process requires integrin β1 and signaling by VEGF-C and its receptor VEGFR3, established by genetic lineage tracing.\",\n      \"method\": \"Genetic lineage tracing (Esm1-Cre), immunohistochemistry, single-cell RNA sequencing, genetic epistasis (integrin β1 KO, VEGF-C/VEGFR3 pathway ablation), confocal imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic lineage tracing with in vivo epistasis (integrin β1, VEGFR3 knockouts), validated by scRNA-seq and IHC; multiple orthogonal approaches\",\n      \"pmids\": [\"40998858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ESM1 promotes peripheral nerve regeneration by elevating phosphorylated MEK1/2 and ERK1/2 levels in Schwann cells. Recombinant ESM1 protein enhances Schwann cell viability, proliferation, and migration, supports angiogenesis, reduces apoptosis, and accelerates axon regeneration at the injury site.\",\n      \"method\": \"Recombinant ESM1 protein treatment, in vitro Schwann cell assays (viability, proliferation, migration), in vivo sciatic nerve injury model, Western blot (pMEK1/2, pERK1/2), transcriptomic profiling\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — recombinant protein with defined pathway readout (pMEK/ERK), in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"40992616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ESM1 and ANGPTL4 form a positive feedback loop, stabilizing FASN to promote trioleate (glycerol trioleate) synthesis in hepatocellular carcinoma cells. Trioleate activates the NF-κB/IL-17 pathway in HCC cells and upregulates CD99 in endothelial cells, driving angiogenesis. ESM1/ANGPTL4 knockdown suppresses tumor growth, rescued by trioleate supplementation.\",\n      \"method\": \"Co-immunoprecipitation, immunoprecipitation-mass spectrometry (IP-MS), RNA sequencing, metabolomics, tube formation assay, Western blot, xenograft model, tissue microarray\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and IP-MS for interactions, metabolomics, rescue experiment; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41864037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ESM1 binds to ERBB2 to promote HSPB1 transcription, activating the FAK/SRC and NF-κB pathways, which inhibits ferroptosis and enhances cisplatin resistance in ovarian cancer cells.\",\n      \"method\": \"RNA sequencing after ESM1 KD, immunoprecipitation-mass spectrometry (IP-MS), Co-IP (ESM1–ERBB2), electron microscopy (ferroptosis), Western blot, tissue microarray, multiplex immunofluorescence\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and IP-MS establishing ESM1–ERBB2 direct interaction, pathway activation, ferroptosis readout; single lab\",\n      \"pmids\": [\"42231975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In RT-R-TNBC cells, extracellular ATP activates P2Y2R, which transactivates VEGFR2 through Src phosphorylation, leading to ESM1 overexpression. This pathway activates PAK1, PKC, JNK, and p38 MAPKs, and the transcriptional regulator FoxO1 (nuclear localization promotes ESM1 transcription). VEGFR2 siRNA knockdown reduces ATP-induced ESM1 expression and associated signaling.\",\n      \"method\": \"P2Y2R knockdown, VEGFR2 siRNA, Src inhibitor, Western blot (pSrc, pVEGFR2), RT-PCR, FoxO1 localization assays, extracellular ATP treatment\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA epistasis placing P2Y2R→Src→VEGFR2→ESM1; multiple inhibitor/KD experiments; single lab\",\n      \"pmids\": [\"37165911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lactate upregulates ESM1 mRNA and protein expression in a concentration-dependent manner in cancer cells. ESM1 activates the Akt1–MDM2–p53 pathway to suppress DNA damage repair (DDR). Reduced DDR-generated dsDNA inactivates the cGAS-STING pathway, thereby inhibiting CD8+ T cell immune infiltration. ESM1 knockout in mice promotes CD8+ T cell infiltration into tumors.\",\n      \"method\": \"ESM1 shRNA/overexpression, lactate treatment, comet assay (DNA damage), flow cytometry (CD8+ T cells, apoptosis), Western blot (ESM1, Akt1, cGAS-STING pathway proteins), EdU staining, ESM1 whole-gene knockout mouse model, xenograft, IHC\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vivo KO model, mechanistic pathway Western blot, DNA damage assay; single lab\",\n      \"pmids\": [\"41930148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BCL6 transcription factor upregulates ESM1 expression in hepatocellular carcinoma cells, which inhibits T lymphocyte (specifically CD4+ T cell) recruitment and activation through ICAM-1/LFA-1 signaling pathway, promoting cancer immune evasion.\",\n      \"method\": \"Transcription factor analysis, antibody depletion experiment (CD4+ vs CD8+ T cells), ESM1 expression modulation, ICAM-1/LFA-1 pathway analysis, in vivo HCC models\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — antibody depletion identifying CD4+ T cell specificity, pathway analysis linking ESM1 to ICAM-1/LFA-1; single lab\",\n      \"pmids\": [\"38956432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In LUAD cells, ESM1 promotes fatty acid synthesis and angiogenesis by activating the AKT signaling pathway and upregulating SCD1 and FASN expression. Secreted ESM1 acts in a paracrine manner to promote endothelial cell proliferation, migration, lipid synthesis, and tube formation in the tumor microenvironment.\",\n      \"method\": \"MTT, EdU, wound healing, Oil red O, tubule formation assay, xenograft model, CAM model, Western blot (AKT, SCD1, FASN), ESM1 knockdown/overexpression\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — paracrine conditioned medium assay, AKT pathway Western blot, in vivo model; single lab\",\n      \"pmids\": [\"39281564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intermittent hypoxia (IH) upregulates ESM1 mRNA and protein in vascular endothelial cells via IH-induced downregulation of miR-181a1, not through transcriptional activation of the ESM1 promoter. Introduction of miR-181a1 mimic abolished IH-induced ESM1 upregulation, indicating post-transcriptional regulation.\",\n      \"method\": \"IH cell culture (HUEhT-1, UV2), real-time RT-PCR, ELISA, promoter activity assay, miR-181a1 mimic transfection\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter assay (negative result) combined with miRNA mimic rescue, consistent in two cell lines; single lab\",\n      \"pmids\": [\"37968862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vascular smooth muscle cells under high salt, TMEM16A upregulation increases ESM1 expression; ESM1 in turn upregulates VCAM-1, ICAM-1, and CXCL16. Silencing ESM1 attenuates VCAM-1, ICAM-1, and CXCL16, placing ESM1 downstream of TMEM16A in the vascular inflammation pathway.\",\n      \"method\": \"TMEM16A siRNA knockdown, ESM1 siRNA knockdown, transcriptome analysis, Western blot, in vitro high-salt VSMC model, in vivo hypertension mouse model\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic epistasis via siRNA double knockdown, transcriptome analysis; single lab\",\n      \"pmids\": [\"36359280\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ESM1 (endocan) is a secreted dermatan sulphate proteoglycan expressed by vascular endothelial cells whose GAG chain activates heparin cofactor II (HCII) for anticoagulation; extracellularly, it binds fibronectin to displace and enhance VEGF-A165 bioavailability, binds c-Met and EGFR/HER3 on target cells to activate MAPK/ERK and Akt pathways promoting angiogenesis and EMT, and interacts with ANGPTL4 to reprogram lipid metabolism; intracellularly (when mislocalized to the nucleus), it stabilizes the β-catenin–TCF4 complex to drive Wnt signaling and cancer stemness; its transcription is directly repressed by Hhex and activated by pSTAT1::pSTAT2 dimers (downstream of IRF5), SOX4, HOXD4, SPI1, and LSD1 (via H3K9me2 demethylation), and is relieved from PRC2/H3K27me3 repression by SNORD3-mediated EZH2 disruption; post-translationally, ESM1 is stabilized by TRIM28-mediated SUMOylation; and during vascular development, Esm1-expressing tip cells serve as progenitors of intestinal and mesenteric arterial endothelium in a process requiring integrin β1 and VEGF-C/VEGFR3 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ESM1 (endocan) is an endothelial cell-specific secreted dermatan sulphate proteoglycan that governs vascular development, angiogenesis, coagulation, and inflammation, and is repeatedly co-opted by tumors to drive proliferation, metastasis, and immune evasion [#0, #1, #2]. The mature protein is a ~50 kDa soluble proteoglycan carrying a single dermatan sulphate chain on serine-137 and is induced by pro-inflammatory cytokines (TNF-\\u03b1, IL-1\\u03b2) and pro-angiogenic growth factors (VEGF, FGF-2, HGF) [#0, #1]. Its glycosaminoglycan chains constitute an anticoagulant activity by activating the thrombin inhibitor heparin cofactor II, with loss of esm1 causing venous occlusion in zebrafish and altered coagulation in mice that is rescued by recombinant ESM1 [#15]. In the vasculature, ESM1 binds fibronectin to displace and increase the bioavailability of VEGF-A165, enhancing VEGF/Erk signaling, filopodia extension, leukocyte transmigration, and vascular permeability [#2], and Esm1-expressing endothelial tip cells act as progenitors of intestinal and mesenteric arterial endothelium in an integrin \\u03b21- and VEGF-C/VEGFR3-dependent manner [#24]. As a secreted ligand, ESM1 engages multiple receptor tyrosine kinases\\u2014c-Met to activate MAPK/ERK and upregulate VEGFA, HIF1\\u03b1, and MMP9 [#12], EGFR/HER3 to activate the Akt pathway and drive EMT [#10], and ERBB2 to induce HSPB1 and suppress ferroptosis [#27]\\u2014while also forming positive feedback loops with ANGPTL4 that reprogram lipid metabolism and sustain angiogenesis [#23, #26]. ESM1 expression is controlled by a broad regulatory network: it is directly repressed by the homeodomain protein Hhex [#3] and by PRC2/H3K27me3 (relieved when SNORD3 disrupts EZH2\\u2013RBBP4) [#13], and is directly activated by pSTAT1::pSTAT2 dimers [#14], SOX4 [#22], and LSD1-mediated H3K9me2 demethylation [#21]; it is further regulated post-transcriptionally via mRNA stability (G3BP1, IGF2BP3, miR-181a1) [#18, #19, #32] and stabilized post-translationally by TRIM28-mediated SUMOylation [#20]. In cancer, nuclear-localized ESM1 stabilizes the \\u03b2-catenin\\u2013TCF4 complex to drive Wnt signaling and stemness [#6], and ESM1 broadly activates Akt-dependent NF-\\u03baB signaling to promote proliferation and survival [#4, #5]; it also suppresses anti-tumor immunity by inactivating cGAS-STING and limiting CD8+ T cell infiltration [#29].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that ESM1 is a novel endothelial-specific secreted protein whose expression is cytokine-regulated defined it as a candidate mediator of vascular inflammation.\",\n      \"evidence\": \"Northern blot, immunoprecipitation, COS-cell transfection, and cytokine treatment of HUVECs\",\n      \"pmids\": [\"8702785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No receptor or downstream signaling identified\", \"Functional consequences of secretion not yet tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Biochemical characterization resolved that endocan is a soluble dermatan sulphate proteoglycan with a single GAG chain on Ser137, distinguishing the functional glycoform from the core polypeptide.\",\n      \"evidence\": \"Biochemical characterization, ELISA, and cell-based expression assays\",\n      \"pmids\": [\"16168566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the GAG chain not yet assigned\", \"Binding partners unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying Hhex as a direct repressor binding a conserved promoter element established the first transcriptional control point for ESM1.\",\n      \"evidence\": \"EMSA, ChIP, site-directed mutagenesis, reporter assay, and Hhex-null mouse embryos\",\n      \"pmids\": [\"16764824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling Hhex activity at ESM1 not defined\", \"No activating factors identified at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that Esm1 binds fibronectin to displace VEGF-A165 and that Esm1-KO mice have vascular defects established a direct molecular mechanism linking ESM1 to angiogenesis and permeability.\",\n      \"evidence\": \"Esm1 knockout mice, retinal vascular outgrowth, VEGF permeability and leukocyte transmigration assays, direct Esm1\\u2013fibronectin binding, stroke model\",\n      \"pmids\": [\"25057127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"VEGF-A165 specificity mechanism (vs A121) not structurally resolved\", \"Role of the GAG chain in fibronectin binding unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking ESM-1 to Akt-dependent NF-\\u03baB activation and PTEN/cyclin D1 control in carcinoma cells extended its role from vasculature to direct regulation of tumor cell proliferation and invasion.\",\n      \"evidence\": \"siRNA/overexpression, phospho-MAPK array, cell cycle analysis, migration/invasion assays, NF-\\u03baB reporter and Co-IP in colorectal cancer cells (consistent HCC findings 2010)\",\n      \"pmids\": [\"22735811\", \"20821239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ESM1\\u2013NF-\\u03baB interaction lacks structural validation\", \"Whether secreted or intracellular ESM1 mediates the effect not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that nuclear ESM1 directly binds the \\u03b2-catenin ARM domain to stabilize the \\u03b2-catenin\\u2013TCF4 complex revealed a non-secretory, intracellular mode of action driving Wnt-dependent cancer stemness.\",\n      \"evidence\": \"Reciprocal Co-IP, subcellular fractionation, reporter assay, and stem cell assays in prostate cancer cells\",\n      \"pmids\": [\"33347625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism routing a secreted proteoglycan to the nucleus incompletely defined\", \"Whether the GAG chain is present on nuclear ESM1 unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of c-Met as a direct ESM1 receptor on endothelial cells placed MAPK/ERK-driven angiogenesis and metastasis downstream of secreted ESM1.\",\n      \"evidence\": \"Co-IP for ESM1\\u2013c-Met binding, angiogenesis assays, MAPK/ERK Western blot, and peritoneal metastasis models\",\n      \"pmids\": [\"38201620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on c-Met not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A series of studies established ESM1 as a multi-receptor secreted ligand (EGFR/HER3) and metabolic hub coupling RTK signaling, ANGPTL4/LPL lipid reprogramming, and PKM2 SUMOylation to tumor angiogenesis and the Warburg effect.\",\n      \"evidence\": \"Signal-peptide deletion mutant, EGFR/HER3 association assay, GST pull-down, Co-IP, and metabolic assays in gastric and ovarian cancer with xenografts\",\n      \"pmids\": [\"39309430\", \"38212795\", \"38720298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor selectivity across cancer types not unified\", \"Direct vs indirect nature of some interactions (e.g. PKM2\\u2013UBA2 bridging) needs reconstitution\", \"Single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that ESM1 suppresses CD8+ and CD4+ T cell infiltration via Akt1-MDM2-p53/cGAS-STING and ICAM-1/LFA-1 signaling defined a role in tumor immune evasion.\",\n      \"evidence\": \"ESM1 KO mice, antibody depletion of T cell subsets, comet assay, flow cytometry, and pathway Western blots in tumor models\",\n      \"pmids\": [\"41930148\", \"38956432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether immune effects are cell-autonomous or stromal not fully resolved\", \"Single labs\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple studies delineated the transcriptional and epigenetic activation network for ESM1, identifying pSTAT1::pSTAT2 dimers, SOX4, and LSD1-mediated H3K9me2 demethylation as direct activators and SNORD3-mediated EZH2 disruption as a derepression mechanism.\",\n      \"evidence\": \"ChIP/ChIP-qPCR, luciferase reporters, RIP, and in vivo disease models (hypertension, hemangioma, RA, recurrent abortion)\",\n      \"pmids\": [\"40332339\", \"39507292\", \"41984276\", \"41223251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Combinatorial logic among activators and repressors not integrated\", \"Tissue-specificity of each regulator unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Lineage tracing established that Esm1+ endothelial tip cells are bona fide arterial progenitors during gut and mesenteric vascular development, requiring integrin \\u03b21 and VEGF-C/VEGFR3 signaling.\",\n      \"evidence\": \"Esm1-Cre genetic lineage tracing, scRNA-seq, IHC, and genetic epistasis (integrin \\u03b21 and VEGFR3 ablation)\",\n      \"pmids\": [\"40998858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ESM1 protein function (vs marker expression) is required for arterial fate not separated\", \"Generality beyond intestinal/mesenteric beds unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Establishing that the GAG chain activates heparin cofactor II to inhibit thrombin assigned ESM1 a defined anticoagulant function and an in vivo role in preventing venous thrombosis.\",\n      \"evidence\": \"In vitro HCII activation assay, zebrafish esm1 KO/overexpression time-to-occlusion, mouse KO, and recombinant ESM1 rescue\",\n      \"pmids\": [\"41517829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between anticoagulant and angiogenic functions of the same GAG chain not integrated\", \"Physiological contexts requiring this activity in humans not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of TRIM28-mediated SUMOylation as a stabilizer of ESM1 and ERBB2 as an additional receptor linked post-translational control to therapy resistance and ferroptosis suppression.\",\n      \"evidence\": \"Co-IP for SUMOylation and ESM1\\u2013ERBB2 interaction, proteasome inhibitor assays, IP-MS, and ovarian cancer mouse models\",\n      \"pmids\": [\"41649926\", \"42231975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO acceptor sites on ESM1 not mapped\", \"Single labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the single dermatan sulphate chain mechanistically reconciles ESM1's distinct activities\\u2014anticoagulation, growth-factor displacement, and receptor engagement\\u2014and what governs the switch between secreted and nuclear ESM1 pools remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of ESM1 bound to any receptor or to fibronectin\", \"Determinants of nuclear translocation undefined\", \"Whether glycoform composition dictates partner selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [10, 12, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 31]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 12, 10, 6]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [24, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [29, 30, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 14, 22, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FN1\", \"MET\", \"EGFR\", \"ERBB3\", \"ERBB2\", \"CTNNB1\", \"ANGPTL4\", \"PKM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}