Affinage

ESM1

Endothelial cell-specific molecule 1 · UniProt Q9NQ30

Length
184 aa
Mass
20.1 kDa
Annotated
2026-06-09
90 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    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

    PMID:8702785

    Open questions at the time
    • No receptor or downstream signaling identified
    • Functional consequences of secretion not yet tested
  2. 2005 High

    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

    PMID:16168566

    Open questions at the time
    • Function of the GAG chain not yet assigned
    • Binding partners unknown
  3. 2006 High

    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

    PMID:16764824

    Open questions at the time
    • Upstream signals controlling Hhex activity at ESM1 not defined
    • No activating factors identified at this stage
  4. 2014 High

    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

    PMID:25057127

    Open questions at the time
    • VEGF-A165 specificity mechanism (vs A121) not structurally resolved
    • Role of the GAG chain in fibronectin binding unclear
  5. 2012 Medium

    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)

    PMID:20821239 PMID:22735811

    Open questions at the time
    • Direct ESM1–NF-κB interaction lacks structural validation
    • Whether secreted or intracellular ESM1 mediates the effect not resolved
    • Single lab
  6. 2020 High

    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

    PMID:33347625

    Open questions at the time
    • Mechanism routing a secreted proteoglycan to the nucleus incompletely defined
    • Whether the GAG chain is present on nuclear ESM1 unknown
  7. 2023 Medium

    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

    PMID:38201620

    Open questions at the time
    • Binding site on c-Met not mapped
    • Single lab
  8. 2024 Medium

    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

    PMID:38212795 PMID:38720298 PMID:39309430

    Open questions at the time
    • Receptor selectivity across cancer types not unified
    • Direct vs indirect nature of some interactions (e.g. PKM2–UBA2 bridging) needs reconstitution
    • Single labs
  9. 2024 Medium

    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

    PMID:38956432 PMID:41930148

    Open questions at the time
    • Whether immune effects are cell-autonomous or stromal not fully resolved
    • Single labs
  10. 2025 Medium

    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)

    PMID:39507292 PMID:40332339 PMID:41223251 PMID:41984276

    Open questions at the time
    • Combinatorial logic among activators and repressors not integrated
    • Tissue-specificity of each regulator unclear
  11. 2025 High

    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)

    PMID:40998858

    Open questions at the time
    • Whether ESM1 protein function (vs marker expression) is required for arterial fate not separated
    • Generality beyond intestinal/mesenteric beds unknown
  12. 2026 High

    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

    PMID:41517829

    Open questions at the time
    • Relationship between anticoagulant and angiogenic functions of the same GAG chain not integrated
    • Physiological contexts requiring this activity in humans not defined
  13. 2026 Medium

    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

    PMID:41649926 PMID:42231975

    Open questions at the time
    • SUMO acceptor sites on ESM1 not mapped
    • Single labs

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2 R-HSA-109582 Hemostasis 1
Partners
ANGPTL4CTNNB1EGFRERBB2ERBB3FN1METPKM

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Northern blot, RT-PCR, Southern blot, immunoprecipitation, immunoblotting, COS cell transfection, cytokine treatment of HUVECs The Journal of biological chemistry High 8702785
2005 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. Biochemical characterization, ELISA, cell-based expression assays Biochimica et biophysica acta High 16168566
2014 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. 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 Circulation research High 25057127
2006 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. Transient co-transfection assay, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis, chromatin immunoprecipitation (ChIP), Hhex-null mouse embryos Biochemical and biophysical research communications High 16764824
2012 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. siRNA knockdown, overexpression, phospho-MAPK array, cell cycle analysis, migration/invasion assays, NF-κB promoter reporter assay, co-immunoprecipitation (ESM-1/NF-κB interaction) Cellular signalling Medium 22735811
2010 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. siRNA knockdown, cell viability assay, cell cycle analysis, migration/invasion assays, Western blot Amino acids Medium 20821239
2020 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. 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 The EMBO journal High 33347625
2018 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. IH cell culture model, HIF-1α shRNA knockdown, VEGFR inhibitor treatment, ESM-1 siRNA/recombinant protein, adhesion assay, Western blot, ELISA Journal of cellular physiology Medium 30144067
2016 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. Gene expression array, NGF stimulation, ESM1 overexpression, shRNA knockdown, migration/invasion assays, in vivo metastasis model Oncotarget Medium 27683113
2024 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. 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 Molecular cancer High 38720298
2024 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. Signal-peptide deletion mutant, patient-derived organoids, xenograft models, EGFR/HER3 co-immunoprecipitation/association assay, Western blot, therapeutic peptide inhibition International journal of biological sciences Medium 39309430
2024 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. Co-immunoprecipitation, molecular docking, RNA sequencing, MTT, EdU, wound healing, transwell, xenograft, CAM assay, zebrafish model, Western blot Journal of translational medicine Medium 38212795
2023 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. Co-immunoprecipitation (ESM1–c-Met binding), in vitro angiogenesis assays, MAPK/ERK pathway Western blot, xenograft/peritoneal metastasis models, clinical tissue validation Cancers Medium 38201620
2025 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. 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 Science translational medicine High 41223251
2025 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. scRNA-seq, IRF5 knockdown, luciferase reporter assay, ChIP-qPCR, Western blot for nuclear pSTAT1/pSTAT2, DOCA-salt mouse model International journal of molecular sciences Medium 40332339
2026 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. Zebrafish esm1 knockout/overexpression (time-to-occlusion assay), mouse Esm1 knockout, recombinant human ESM1 rescue, in vitro thrombin inhibitor activation assays (HCII), ELISA Advanced science High 41517829
2021 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. 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 Stem cells Medium 30372556
2021 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. RNA sequencing of transplanted ADSCs, recombinant Esm1 tube formation assay, PKH-labeled cell tracking, echocardiography, histology Circulation journal Medium 33716265
2023 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. Phosphoproteomics (LIMK2 targets), RNA-seq (G3BP1 KD), mRNA stability assay, ESM1 rescue (ectopic expression), melanoma cell culture and mouse models Oncogene Medium 36922679
2025 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. mRNA sequencing, Co-IP, dual-luciferase reporter assay, actinomycin D treatment (mRNA stability), autophagy inhibitor (chloroquine), xenograft model, microarray analysis Cell death & disease Medium 40240362
2026 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. Co-immunoprecipitation (TRIM28–ESM1, SUMOylation), proteasome inhibitor assay, ITGB1/FAK pathway Western blot, in vivo OC mouse models, conditioned medium angiogenesis assays Cell reports Medium 41649926
2025 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. 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 of assisted reproduction and genetics Medium 41984276
2025 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. RNA-seq, ChIP (SOX4 binding to ESM1 promoter), cell proliferation/migration/angiogenesis assays, 3D microtumor model, animal experiments Precision clinical medicine Medium 39507292
2025 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. 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 Scientific reports Medium 40320451
2025 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. Genetic lineage tracing (Esm1-Cre), immunohistochemistry, single-cell RNA sequencing, genetic epistasis (integrin β1 KO, VEGF-C/VEGFR3 pathway ablation), confocal imaging Nature communications High 40998858
2025 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. 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 Experimental neurology Medium 40992616
2026 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. Co-immunoprecipitation, immunoprecipitation-mass spectrometry (IP-MS), RNA sequencing, metabolomics, tube formation assay, Western blot, xenograft model, tissue microarray Neoplasia Medium 41864037
2026 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. RNA sequencing after ESM1 KD, immunoprecipitation-mass spectrometry (IP-MS), Co-IP (ESM1–ERBB2), electron microscopy (ferroptosis), Western blot, tissue microarray, multiplex immunofluorescence iScience Medium 42231975
2022 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. P2Y2R knockdown, VEGFR2 siRNA, Src inhibitor, Western blot (pSrc, pVEGFR2), RT-PCR, FoxO1 localization assays, extracellular ATP treatment International journal of oncology Medium 37165911
2024 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. 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 Oncology research Medium 41930148
2024 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. Transcription factor analysis, antibody depletion experiment (CD4+ vs CD8+ T cells), ESM1 expression modulation, ICAM-1/LFA-1 pathway analysis, in vivo HCC models NPJ precision oncology Medium 38956432
2024 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. MTT, EdU, wound healing, Oil red O, tubule formation assay, xenograft model, CAM model, Western blot (AKT, SCD1, FASN), ESM1 knockdown/overexpression Heliyon Medium 39281564
2023 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. IH cell culture (HUEhT-1, UV2), real-time RT-PCR, ELISA, promoter activity assay, miR-181a1 mimic transfection Journal of cellular and molecular medicine Medium 37968862
2024 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. TMEM16A siRNA knockdown, ESM1 siRNA knockdown, transcriptome analysis, Western blot, in vitro high-salt VSMC model, in vivo hypertension mouse model Biomedicines Medium 36359280

Source papers

Stage 0 corpus · 90 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 ESM-1 is a novel human endothelial cell-specific molecule expressed in lung and regulated by cytokines. The Journal of biological chemistry 328 8702785
2005 Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy. Biochimica et biophysica acta 294 16168566
2014 Esm1 modulates endothelial tip cell behavior and vascular permeability by enhancing VEGF bioavailability. Circulation research 197 25057127
2002 Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM. Microvascular research 138 11866539
2016 HULC long noncoding RNA silencing suppresses angiogenesis by regulating ESM-1 via the PI3K/Akt/mTOR signaling pathway in human gliomas. Oncotarget 126 26894862
2010 Vascular endocan (ESM-1) is markedly overexpressed in clear cell renal cell carcinoma. Histopathology 109 20102396
2019 Exosomal MicroRNA-9-3p Secreted from BMSCs Downregulates ESM1 to Suppress the Development of Bladder Cancer. Molecular therapy. Nucleic acids 89 31734559
2024 ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment. Molecular cancer 83 38720298
2019 ESM1 as a Marker of Macrotrabecular-Massive Hepatocellular Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 80 31358545
2012 ESM-1 regulates cell growth and metastatic process through activation of NF-κB in colorectal cancer. Cellular signalling 66 22735811
2018 ESM-1 promotes adhesion between monocytes and endothelial cells under intermittent hypoxia. Journal of cellular physiology 54 30144067
2010 Overexpression of endothelial cell specific molecule-1 (ESM-1) in gastric cancer. Annals of surgical oncology 54 20383661
2010 ESM-1 silencing decreased cell survival, migration, and invasion and modulated cell cycle progression in hepatocellular carcinoma. Amino acids 46 20821239
2020 Direct interaction of β-catenin with nuclear ESM1 supports stemness of metastatic prostate cancer. The EMBO journal 40 33347625
2021 Type V collagen alpha 1 chain promotes the malignancy of glioblastoma through PPRC1-ESM1 axis activation and extracellular matrix remodeling. Cell death discovery 39 34702798
2013 ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma. Journal of hepatology 38 23928407
2024 ANGPTL4 accelerates ovarian serous cystadenocarcinoma carcinogenesis and angiogenesis in the tumor microenvironment by activating the JAK2/STAT3 pathway and interacting with ESM1. Journal of translational medicine 37 38212795
2020 ESM1/HIF‑1α pathway modulates chronic intermittent hypoxia‑induced non‑small‑cell lung cancer proliferation, stemness and epithelial‑mesenchymal transition. Oncology reports 35 33650648
2020 Pan-cancer analysis identifies ESM1 as a novel oncogene for esophageal cancer. Esophagus : official journal of the Japan Esophageal Society 33 33175267
2020 ESM-1 Overexpression is Involved in Increased Tumorigenesis of Radiotherapy-Resistant Breast Cancer Cells. Cancers 30 32466580
2016 A comparative analysis of ESM-1 and vascular endothelial cell marker (CD34/CD105) expression on pituitary adenoma invasion. Pituitary 29 26809958
2023 ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis. Cancers 28 38201620
2014 Plasma endothelial cell-specific molecule-1 (ESM-1) in management of community-acquired pneumonia. Clinical chemistry and laboratory medicine 28 24108208
2021 ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway. Annals of translational medicine 27 33987231
2018 Enhanced Function of Induced Pluripotent Stem Cell-Derived Endothelial Cells Through ESM1 Signaling. Stem cells (Dayton, Ohio) 27 30372556
2023 ESM1 promotes angiogenesis in colorectal cancer by activating PI3K/Akt/mTOR pathway, thus accelerating tumor progression. Aging 24 37100467
2024 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. International immunopharmacology 23 38897128
2019 Identification of ESM1 overexpressed in head and neck squamous cell carcinoma. Cancer cell international 22 31073279
2021 Silenced lncRNA SNHG14 restrains the biological behaviors of bladder cancer cells via regulating microRNA-211-3p/ESM1 axis. Cancer cell international 21 33482820
2016 ESM1 mediates NGFR-induced invasion and metastasis in murine oral squamous cell carcinoma. Oncotarget 21 27683113
2006 Hhex is a direct repressor of endothelial cell-specific molecule 1 (ESM-1). Biochemical and biophysical research communications 21 16764824
2021 Esm1 and Stc1 as Angiogenic Factors Responsible for Protective Actions of Adipose-Derived Stem Cell Sheets on Chronic Heart Failure After Rat Myocardial Infarction. Circulation journal : official journal of the Japanese Circulation Society 19 33716265
2017 ESM-1 siRNA Knockdown Decreased Migration and Expression of CXCL3 in Prostate Cancer Cells. International journal of biomedical science : IJBS 17 28533735
2017 Functional analysis of ESM1 by siRNA knockdown in primary and metastatic head and neck cancer cells. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 17 29024069
2022 Arctigenin Attenuates Vascular Inflammation Induced by High Salt through TMEM16A/ESM1/VCAM-1 Pathway. Biomedicines 15 36359280
2019 ESM-1: A Novel Tumor Biomaker and its Research Advances. Anti-cancer agents in medicinal chemistry 15 31284875
2022 Increasing circulating ESM-1 and adhesion molecules are associated with earlystage atherosclerosis in OSA patients:A cross-sectional study. Sleep medicine 14 35830780
2017 Clinical validation of serum endocan (ESM-1) as a potential biomarker in patients with renal cell carcinoma. Oncotarget 14 29416643
2019 Circulating ESM-1 levels are correlated with the presence of coronary artery disease in patients with obstructive sleep apnea. Respiratory research 13 31429753
2024 B cell lymphoma 6 promotes hepatocellular carcinoma progression by inhibiting tumor infiltrating CD4+T cell cytotoxicity through ESM1. NPJ precision oncology 11 38956432
2024 ESM1 facilitates the EGFR/HER3-triggered epithelial-to-mesenchymal transition and progression of gastric cancer via modulating interplay between Akt and angiopoietin-2 signaling. International journal of biological sciences 11 39309430
2023 LIMK2 promotes melanoma tumor growth and metastasis through G3BP1-ESM1 pathway-mediated apoptosis inhibition. Oncogene 11 36922679
2020 Endocan (ESM-1) levels in gingival crevicular fluid correlate with ICAM-1 and LFA-1 in periodontitis. Brazilian oral research 10 33206778
2023 Targeting ESM1/ VEGFα signaling axis: a promising therapeutic avenue for angiogenesis in cervical squamous cell carcinoma. Journal of Cancer 9 37476182
2025 IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming. Cell death & disease 8 40240362
2025 ESM1 promote proliferation, invasion and angiogenesis via Akt/mTOR and Ras pathway in kidney renal clear cell carcinoma. Scientific reports 7 39929852
2023 Novel specific anti-ESM1 antibodies overcome tumor bevacizumab resistance by suppressing angiogenesis and metastasis. Cancer science 7 37715566
2023 Combination of Maternal Serum ESM-1 and PLGF with Uterine Artery Doppler PI for Predicting Preeclampsia. Journal of clinical medicine 6 36675388
2022 Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer. Open medicine (Warsaw, Poland) 6 36117773
2020 The Relationship Between the Level of Serum ESM-1 and Lp-PLA2 in Patients With Acute ST-Segment Elevation Myocardial Infarction. Clinical and translational science 6 32710501
2016 Levels of endothelial cell-specific molecule-1 (ESM-1) in overt hypothyroidisim. Endocrine research 6 26906498
2013 Detection and mechanism of action of ESM-1 in rat kidney transplantation under various immune states. Cellular immunology 6 23850961
2024 The role of ESM1 in the lipids metabolic reprogramming and angiogenesis of lung adenocarcinoma cells. Heliyon 5 39281564
2024 Targeting ESM1 via SOX4 promotes the progression of infantile hemangioma through the PI3K/AKT signaling pathway. Precision clinical medicine 5 39507292
2023 Intermittent hypoxia increased the expression of ESM1 and ICAM-1 in vascular endothelial cells via the downregulation of microRNA-181a1. Journal of cellular and molecular medicine 5 37968862
2025 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. Discover oncology 4 40089962
2025 Single-cell sequencing uncovers a high ESM1-expression endothelial cell subpopulation associated with bladder cancer progression and the immunosuppressive microenvironment. Scientific reports 4 40159545
2025 Unveiling the protective role of ESM1 in endothelial cell proliferation and lipid reprogramming. Scientific reports 4 40320451
2023 P2Y2R‑mediated transactivation of VEGFR2 through Src phosphorylation is associated with ESM‑1 overexpression in radiotherapy‑resistant‑triple negative breast cancer cells. International journal of oncology 4 37165911
2023 ESM-1 Mediates Cell Progression in Clear Cell Renal Cell Carcinoma by Affecting Wnt/β-Catenin Signalling Pathway. Archivos espanoles de urologia 4 37455528
2025 Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells. Nature communications 3 40998858
2018 Polyphasic characterization of Delftia acidovorans ESM-1, a facultative methylotrophic bacterium isolated from rhizosphere of Eruca sativa. Saudi journal of biological sciences 3 31516356
2009 [Expression of ESM-1 in hepatocellular carcinoma is associated with angiogenesis and tumor invasion]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 3 19785952
2025 ESM-1 and GBP-1 are associated with endothelial dysfunction: emerging biomarkers or key players in the pathophysiology of preeclampsia? The Journal of physiology 2 40042932
2025 IRF5 Mediates Artery Inflammation in Salt-Sensitive Hypertension by Regulating STAT1 and STAT2 Phosphorylation to Increase ESM1 Transcription: Insights from Bioinformatics and Mechanistic Analysis. International journal of molecular sciences 2 40332339
2025 snoRNA Snord3 promotes rheumatoid arthritis by epigenetic regulation of ESM1 in fibroblast-like synoviocytes in mice. Science translational medicine 2 41223251
2023 Identification of ESM1 as a Potential Biomarker Involving Drug Sensitivity and the Tumor Immune Microenvironment that Promotes Proliferation of Melanoma. Cellular and molecular biology (Noisy-le-Grand, France) 2 37605575
2023 EpCAM, Ki67, and ESM1 Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation. Applied immunohistochemistry & molecular morphology : AIMM 2 37668411
2022 P2Y2R-Mediated PAK1 Activation Is Involved in ESM-1 Overexpression in RT-R-MDA-MB-231 through FoxO1 Regulation. Cancers 2 36077661
2021 Serum Expression of ESM-1, HMWA, and AGEs and Its Relationship with Disease Severity in Patients with Gestational Hypertension. Computational and mathematical methods in medicine 2 34925547
2026 ESM1 SUMOylation mediates bevacizumab resistance in ovarian cancer through ITGB1-FAK-driven angiogenesis. Cell reports 1 41649926
2024 Esm-1 mediates transcriptional polarization associated with diabetic kidney disease. American journal of physiology. Renal physiology 1 38601985
2026 Endothelial Cell-Specific Molecule-1 (ESM1): An Endogenous Anticoagulant and Protective Factor in Venous Thrombosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41517829
2026 PRDM1 Knockdown Promotes Ferroptosis and Sunitinib Sensitivity by Modulating the PI3K/Akt Signaling Through Inhibition of ESM1 Transcription in Renal Cell Carcinoma. The Kaohsiung journal of medical sciences 0 41693648
2026 CuET inhibits Ewing sarcoma of bone progression through modulation of the ESM1-MAPK/ERK signaling axis. International immunopharmacology 0 41791304
2026 ESM1 drives cancer angiogenesis and bevacizumab resistance via trioleate synthesis. Neoplasia (New York, N.Y.) 0 41864037
2026 Lactic Acid Drives ESM1 to Attenuate DNA Damage and CD8+ T Cell Infiltration in Cancer. Oncology research 0 41930148
2026 LSD1-ESM1 regulates extravillous trophoblast function through metabolic reprogramming in recurrent spontaneous abortion. Journal of assisted reproduction and genetics 0 41984276
2026 ESM1 drives cisplatin resistance and ferroptosis resistance via ERBB2/FAK/SRC/HSPB1/NF-κB signaling in ovarian cancer. iScience 0 42231975
2025 ESM-1 Promotes the Process of Diabetic Nephropathy by Promoting the Expression of CXCL3. Current molecular medicine 0 40045860
2025 Changes in Gingival Crevicular Fluid Endocan (ESM-1) Levels as a Potential Biomarker After Non-Surgical Periodontal Treatment in Periodontitis Patients. Biomedicines 0 40426985
2025 Serum expression of ESM-1 and Syndecan-1 and its relationship with disease severity in children with Mycoplasma pneumoniae pneumonia. Italian journal of pediatrics 0 40764585
2025 HOXD4-mediated transcriptional activation of ESM1 drives glioblastoma progression in human tumor cells and mouse models. Neuroscience letters 0 40854419
2025 Elevated ESM1 facilitates peripheral nerve regeneration via enhancing Schwann cell activity and developing a pro-regenerative microenvironment. Experimental neurology 0 40992616
2025 Multi-omics profiling identifies ESM1 as a key mediator of immunoevasion through the SPP1 pathway in bladder cancer. Scientific reports 0 41366275
2025 Assessment of Serum Endothelial Cell-Specific Molecule-1 (ESM-1, Endocan) Levels in Patients with Diabetic Retinopathy. The Eurasian journal of medicine 0 41578817
2024 Functional analysis of ESM1 by shRNA-mediated knockdown of its expression in papillary thyroid cancer cells. PloS one 0 38626010
2024 Erratum to ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway. Annals of translational medicine 0 39507447
2023 Esm-1 mediates transcriptional polarization associated with diabetic kidney disease. bioRxiv : the preprint server for biology 0 36993439
2023 Retracted: Serum Expression of ESM-1, HMWA, and AGEs and Its Relationship with Disease Severity in Patients with Gestational Hypertension. Computational and mathematical methods in medicine 0 38094421

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