Affinage

EREG

Proepiregulin · UniProt O14944

Length
169 aa
Mass
19.0 kDa
Annotated
2026-06-09
52 papers in source corpus 25 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Epiregulin (EREG) is a low-affinity EGF-family ligand that activates EGFR (and other ErbB receptors) to drive proliferative, migratory, and stem-cell programs across both normal tissue homeostasis and cancer (PMID:32929368, PMID:39373858). Receptor engagement is direct and requires EGFR domains I and III together with the N57 residue of EREG, and sustained EREG-EGFR-ERK signaling can mimic the effect of activating EGFR mutations, in part by inducing C-Myc (PMID:32929368). EREG protein stability and membrane localization depend on N-glycosylation at N47 by the glycosyltransferase STT3B; loss of this modification destabilizes the protein (PMID:38945975). Downstream of receptor binding EREG engages the ERK/p38 MAPK and PI3K/AKT cascades to promote cell proliferation, epithelial-mesenchymal transition, glycolytic metabolism, and stemness in multiple cancer contexts including PDAC, glioma, gallbladder, head and neck, and oral squamous cell carcinoma (PMID:38250159, PMID:38972433, PMID:40970086, PMID:39373858). In normal physiology EREG acts downstream of a RHOA-YAP axis to maintain intestinal stem cells (PMID:29129684) and serves as a paracrine signal from THBS1+ tissue monocytes that drives hepatocyte proliferation during liver regeneration (PMID:41983196), and it shapes spatial ERK activation wave propagation during epithelial wound repair. EREG expression is tightly controlled at multiple layers: by promoter CpG methylation (driven by DNMT3b) and histone marks (PMID:22508389, PMID:27270421), by transcription factors MRTF-A/SRF and ELF3 (PMID:33520984, PMID:37345534), by m6A-dependent mRNA stability through FTO (PMID:40970086), and by microRNAs including miR-186-3p and miR-192-5p (PMID:30967627, PMID:34715618). Its broad activation of EGFR signaling makes EREG a determinant of EGFR-inhibitor and cetuximab sensitivity, and its silencing can trigger ferroptosis in head and neck cancer cells (PMID:27270421, PMID:36899869).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2011 Medium

    Established that EREG is an inducible inflammatory gene, linking innate immune receptor signaling to its expression and placing it within host-pathogen response circuits.

    Evidence Gene expression profiling of M. tuberculosis- and TLR-ligand-stimulated macrophages with MyD88/TLR2 knockout validation

    PMID:22170233

    Open questions at the time
    • Does not identify the downstream consequence of EREG induction in infection
    • No demonstration of EREG protein secretion or receptor engagement in this context
  2. 2012 High

    Resolved how EREG is epigenetically silenced in cancer, showing promoter CpG methylation by DNMT3b and associated histone marks gate its transcription.

    Evidence 5-aza-CdR treatment, DNMT isoform-specific siRNA, bisulfite sequencing, and histone-mark ChIP in gastric cancer cells

    PMID:22508389

    Open questions at the time
    • Does not connect methylation state to downstream EGFR signaling output
    • Histone marks correlated but not causally manipulated
  3. 2016 Medium

    Demonstrated that demethylation-driven EREG upregulation during adenoma-carcinoma transition increases EGFR phosphorylation and shapes EGFR-inhibitor sensitivity, giving EREG a predictive-biomarker role.

    Evidence Integrative genomics with laser-capture microdissection and demethylation experiments in CRC cell lines

    PMID:27270421

    Open questions at the time
    • Specific demethylated sites not mechanistically tied to a transcription factor
    • Causality of EGFR-inhibitor sensitization rests on cell-line correlations
  4. 2017 High

    Placed EREG genetically downstream of the RHOA-YAP axis in intestinal stem cell maintenance, establishing a normal-physiology developmental role beyond cancer.

    Evidence Inducible RHOA-knockout mice with active-YAP, EREG-treatment, and active-beta-catenin rescue of ISC markers

    PMID:29129684

    Open questions at the time
    • Direct transcriptional link from YAP to the EREG promoter not shown
    • Receptor on ISCs mediating EREG rescue not defined
  5. 2017 Medium

    Showed EREG sits within an autocrine inflammatory feedback loop, induced by IL-1beta and sustained by EGFR activity in epithelial cells.

    Evidence CFTR knockdown, IL-1beta and IL-1R-antagonist treatment, plus JNK and EGFR inhibitor dissection in Caco-2 cells

    PMID:29091309

    Open questions at the time
    • Direct transcription factor downstream of IL-1beta/JNK on EREG not identified
    • Findings limited to a single epithelial cell model
  6. 2019 Medium

    Identified post-transcriptional control of EREG by miR-186-3p and linked EREG-EGFR signaling to aerobic glycolysis and tamoxifen resistance.

    Evidence miRNA target validation, miR-186-3p gain/loss, EREG knockdown/overexpression, glycolysis assays, in vivo agomiR delivery in breast cancer

    PMID:30967627

    Open questions at the time
    • Which glycolytic genes are direct EGFR targets not delineated
    • Single tumor type
  7. 2021 Medium

    Defined the molecular basis of EREG-EGFR engagement (EGFR domains I/III and EREG N57) and showed EREG can mimic EGFR-activating mutations through sustained ERK and C-Myc induction.

    Evidence Direct binding assays, domain and N57 mutagenesis, C-Myc inhibition rescue, in vitro and in vivo assays

    PMID:32929368

    Open questions at the time
    • No structural model of the EREG-EGFR interface
    • Selectivity for EGFR versus other ErbB receptors not quantified here
  8. 2021 High

    Revealed a feedforward transcriptional loop in which MRTF-A/SRF directly activate the EREG promoter and EREG signaling reinforces MRTF-A nuclear translocation, driving hepatic stellate cell activation and fibrosis.

    Evidence ChIP for MRTF-A/SRF promoter binding, in vivo and in vitro MRTF-A loss-of-function, EREG-treatment rescue

    PMID:33520984

    Open questions at the time
    • Receptor mediating EREG feedback onto MRTF-A not specified
    • Loop generality outside HSCs untested
  9. 2022 Medium

    Showed EREG/EGFR expression can be suppressed indirectly via the MIAC micropeptide-AQP2 axis, expanding upstream regulatory inputs in renal cell carcinoma.

    Evidence Co-IP, molecular docking, streptavidin pulldown, and pathway Western blots with xenograft validation

    PMID:36117171

    Open questions at the time
    • Mechanism by which AQP2 controls EREG transcription not established
    • EREG role inferred from pathway readouts rather than direct manipulation
  10. 2023 High

    Established ELF3 as a direct transcriptional repressor of EREG whose loss activates EGFR/mTORC1 and mesenchymal phenotypes, validated by genetic deletion.

    Evidence ChIP on ELF3-overexpressing organoids, CRISPR/Cas9 EREG deletion, RNA-seq, and allograft models in gallbladder cancer

    PMID:37345534

    Open questions at the time
    • Whether ELF3 acts as direct repressor versus competing factor not fully resolved
    • Restricted to gallbladder cancer context
  11. 2023 Medium

    Connected metabolic lactylation of MeCP2 to EREG repression and downstream MAPK-driven endothelial adhesion programs, implicating EREG in vascular disease.

    Evidence RNA-seq, ChIP-qPCR for Mecp2k271la chromatin binding, in vivo lactate administration in a high-fat-diet mouse model

    PMID:37245426

    Open questions at the time
    • Direct demonstration that EREG mediates adhesion-molecule changes is correlative
    • Causality of atherosclerosis outcome not isolated to EREG
  12. 2024 High

    Identified STT3B-mediated N47 N-glycosylation as essential for EREG protein stability and membrane localization, defining a post-translational requirement for its function and a druggable node via PD-L1 regulation.

    Evidence N47 mutagenesis, STT3B knockdown, NGI-1 inhibition, immunofluorescence, and in vivo combination therapy in HNSCC

    PMID:38945975

    Open questions at the time
    • How glycosylation governs trafficking mechanistically not detailed
    • Link from glycosylated EREG to PD-L1 via c-Myc inferred from pathway readouts
  13. 2024 Medium

    Showed EREG silencing sensitizes head and neck cancer to cetuximab and triggers ferroptosis, connecting EREG to metabolic vulnerability and therapy response.

    Evidence EREG silencing, metabolic and ferroptosis marker assays (lipid peroxidation, iron, GPX4), patient-derived tumoroids

    PMID:36899869

    Open questions at the time
    • Molecular link between EREG loss and ferroptosis initiation not defined
    • Single tumor type
  14. 2024 Medium

    Placed EREG downstream of IGF2BP2-FAK/Src signaling as a driver of EMT, adding an upstream RNA-binding-protein regulator and a mesenchymal-program readout.

    Evidence IGF2BP2 and EREG gain/loss with FAK/Src inhibition and EMT/migration assays in oral squamous cell carcinoma

    PMID:38250159

    Open questions at the time
    • Whether IGF2BP2 stabilizes EREG mRNA directly not shown
    • Receptor mediating EREG-driven EMT not specified
  15. 2024 Medium

    Defined the ERK/p38 MAPK axis as the effector route for EREG in pancreatic cancer tumorigenesis.

    Evidence EREG silencing/overexpression with transcriptome sequencing and pathway Western blots plus in vivo tumor growth

    PMID:38972433

    Open questions at the time
    • Receptor specificity upstream of ERK/p38 not addressed
    • Transcriptional targets driving phenotype not enumerated
  16. 2024 Medium

    Showed EREG ErbB-ERK signaling drives cancer stemness with TGFbeta/Hedgehog downstream, and that its protein stability is controlled by K48-linked polyubiquitination.

    Evidence K48 ubiquitination assays, siRNA, ASIV small-molecule treatment, RNA-seq, and xenograft

    PMID:39373858

    Open questions at the time
    • E3 ligase mediating EREG ubiquitination not identified
    • Direct versus indirect control of TGFbeta/Hedgehog unresolved
  17. 2024 Medium

    Extended EREG-EGFR-ERK signaling into the nervous system, linking it via a Runx1-HDAC2/MeCP2/Sin3A corepressor complex to potassium channel repression and bone cancer pain.

    Evidence In vivo rat bone cancer pain model with pathway inhibition, corepressor complex characterization, and electrophysiology

    PMID:39192337

    Open questions at the time
    • Source of EREG acting on DRG neurons not defined
    • Direct recruitment of the corepressor complex to kcnq loci not shown by ChIP here
  18. 2025 Medium

    Identified FTO-mediated m6A demethylation as a destabilizer of EREG mRNA, with FTO loss enhancing EREG stability and PI3K/AKT-driven glioma proliferation.

    Evidence FTO gain/loss, mRNA stability and m6A assays, PI3K/AKT Western blots, and xenograft

    PMID:40970086

    Open questions at the time
    • m6A reader translating the mark into stability change not identified
    • Single tumor type
  19. 2025 Medium

    Demonstrated a paracrine EREG circuit in which THBS1+ tissue monocytes, recruited by hepatocyte-derived C5a, secrete EREG to drive hepatocyte proliferation during liver regeneration.

    Evidence CyTOF, scRNA-seq, bulk RNA-seq with in vitro and in vivo validation of EREG-EGFR and C5a/C5aR1 axes

    PMID:41983196

    Open questions at the time
    • Quantitative contribution of EREG versus other ligands in regeneration not isolated
    • Trigger for monocyte EREG production not defined
  20. 2025 Medium

    Implicated EREG in intestinal fibrosis in Crohn's disease through EMT and PPARgamma signaling, induced in adipocytes by TNF-alpha and IL-17A.

    Evidence Adipocyte-epithelial co-culture, EREG gain/loss, TNBS rat model with histology and pathway readouts

    PMID:41167459

    Open questions at the time
    • Direct transcriptional control of EREG by TNF-alpha/IL-17A not mapped
    • Receptor mediating epithelial EMT response not specified
  21. 2025 Low

    Provided post-transcriptional and physiological regulation evidence: FXR activation and HDAC2-dependent histone acetylation each modulate EREG expression in colorectal cancer and granulosa cells respectively.

    Evidence FXR/HDCA activation with pathway Western blots in CRC, and HDAC2 inhibitor CAY10683 with H4K12ac and EREG readouts in granulosa cells

    PMID:39834394 PMID:41679019

    Open questions at the time
    • No direct ChIP linking FXR or H4K12ac to the EREG promoter
    • Mechanisms inferred from pharmacological inhibitors in single labs
  22. 2025 Medium

    Resolved a spatial signaling property of EREG as a shed low-affinity ligand generating faster, broader ERK activation waves dependent on epithelial junction integrity, with a wound-repair phenotype in knockout mice.

    Evidence Shedding probes, optogenetic ectodomain shedding, ERK biosensors in MDCK cells and in vivo, EREG-knockout mice, junction disruption (preprint)

    Open questions at the time
    • Preprint, not yet peer reviewed
    • Molecular basis of wave-speed difference versus high-affinity ligands not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how EREG receptor selectivity between EGFR and other ErbB receptors and the structural basis of its low-affinity binding integrate with its diverse upstream regulators to produce context-specific outputs.
  • No structure of the EREG-EGFR complex
  • No unified model relating ligand affinity to differential pathway and phenotypic outcomes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3
Partners
EGFR

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 EREG binds directly to EGFR; this binding requires EGFR domains I and III and the N57 residue of EREG. EREG overexpression promotes oncogenesis by inducing C-Myc expression, and EREG sustains EGFR-Erk pathway activation in a manner that mimics EGFR mutations. Immunoblotting, direct binding assays, domain mutagenesis (N57 residue), pharmacological C-Myc inhibition rescue experiments, in vitro and in vivo functional assays Theranostics Medium 32929368
2024 EREG is N-glycosylated at residue N47 by the glycosyltransferase STT3B; this modification is essential for EREG protein stability, membrane localization, and biological function. Mutation at N47 abrogates glycosylation and destabilizes EREG. Glycosylated EREG upregulates PDL1 via the c-Myc pathway in HNSCC cells. Site-directed mutagenesis (N47), STT3B knockdown, NGI-1 (STT3B inhibitor) treatment, Western blotting, immunofluorescence, in vivo combination therapy International journal of oral science High 38945975
2017 RHOA GTPase controls YAP signaling in intestinal stem cells (ISCs), and YAP acts upstream of EREG expression in intestinal crypts. Expression of active YAP (S112A) rescues ISC marker expression after RhoA knockout, but EREG treatment alone also rescues RhoA KO ISC phenotypes, placing EREG downstream of the RHOA-YAP axis in ISC maintenance. Inducible RHOA knockout mice, active YAP mutant rescue, EREG treatment rescue, active β-catenin rescue, ISC marker analysis Stem cell reports High 29129684
2021 MRTF-A interacts with serum response factor (SRF) to bind directly to the EREG promoter and activate EREG transcription in hepatic stellate cells (HSCs). EREG treatment then stimulates nuclear translocation of MRTF-A, creating a feedforward loop that promotes HSC activation and liver fibrosis. ChIP assay (MRTF-A/SRF binding to EREG promoter), MRTF-A knockout/knockdown in vivo and in vitro, EREG treatment with MRTF-A depletion/inhibition rescue Frontiers in cell and developmental biology High 33520984
2012 EREG gene silencing in gastric cancer cells is mediated by aberrant CpG methylation of its promoter, primarily driven by DNMT3b (not DNMT1). Histone modifications also contribute: active marks H3K4me3 and AcH3 and repressive mark H3K27me2 at the EREG promoter correlate with its transcriptional state. Treatment with 5-aza-CdR demethylates the promoter and restores EREG expression. 5-aza-CdR treatment, siRNA knockdown of DNMT1 and DNMT3b, bisulfite sequencing, chromatin immunoprecipitation (ChIP) for histone marks Laboratory investigation High 22508389
2016 EREG upregulation during colorectal cancer adenoma-carcinoma transition is associated with demethylation of two key sites within its promoter, leading to increased EGFR phosphorylation. In CRC cell lines, EREG demethylation caused transcriptional upregulation, higher EGFR phosphorylation levels, and sensitization to EGFR inhibitors. Integrative genomics (laser capture microdissection + gene expression profiling), in situ hybridization, reverse-phase protein analysis (EGFR phosphorylation), CRC cell line demethylation experiments Oncogene Medium 27270421
2019 EREG is a direct target of miR-186-3p. Downregulation of miR-186-3p by tamoxifen leads to EREG upregulation in tamoxifen-resistant breast cancer cells. EREG activates EGFR signaling and its downstream glycolytic genes to enhance aerobic glycolysis, mediating tamoxifen resistance. miRNA target validation, miR-186-3p overexpression/inhibition, EREG knockdown/overexpression, glycolysis assays, in vivo cholesterol-modified agomiR-186-3p delivery Oncogene Medium 30967627
2023 Exercise-induced lactylation of Mecp2 at K271 (Mecp2k271la) represses EREG expression by binding to its chromatin. EREG in turn regulates MAPK signaling through modulating EGFR phosphorylation, thereby affecting expression of adhesion molecules (Vcam-1, Icam-1, Mcp-1) and Enos in endothelial cells and influencing atherosclerosis progression. RNA-sequencing of mouse aortic endothelial cells, ChIP-qPCR (Mecp2k271la binding to Ereg chromatin), exogenous lactate administration in vivo, high-fat diet mouse model Atherosclerosis Medium 37245426
2023 ELF3 transcription factor directly regulates EREG expression by binding to the Ereg locus, as shown by ChIP assay. Loss of ELF3 upregulates EREG, which activates EGFR/mTORC1 signaling in gallbladder cancer organoids. CRISPR/Cas9 deletion of Ereg in ELF3-deficient organoids suppresses EGFR/mTORC1 and mesenchymal phenotypes. ChIP assay on Elf3-overexpressing organoids, CRISPR/Cas9 Ereg deletion, Western blotting, RNA sequencing, allograft mouse models The Journal of pathology High 37345534
2024 EREG silencing in HNSCC sensitizes cells to cetuximab by reducing cell survival, altering cell metabolism (mitochondrial dysfunction), and initiating ferroptosis characterized by lipid peroxidation, iron accumulation, and loss of GPX4. EREG silencing in HNSCC cell lines, cell survival assays, metabolic assays, ferroptosis markers (lipid peroxidation, iron accumulation, GPX4 Western blot), patient-derived tumoroids Cells Medium 36899869
2024 IGF2BP2 promotes EREG expression through activation of the FAK/Src signaling pathway in oral squamous cell carcinoma. EREG downstream of IGF2BP2 drives epithelial-mesenchymal transition (EMT); knockdown of EREG weakens IGF2BP2-mediated EMT induction, and EREG re-expression rescues EMT in IGF2BP2-depleted cells. IGF2BP2 knockdown/overexpression, EREG knockdown/rescue experiments, FAK/Src pathway inhibition, EMT marker analysis, in vitro migration/invasion assays International journal of biological sciences Medium 38250159
2022 The micropeptide MIAC directly binds to AQP2 protein and inhibits EREG/EGFR expression, thereby suppressing downstream PI3K/AKT and MAPK pathway activation in renal cell carcinoma. This was demonstrated by immunoprecipitation, molecular docking, affinity experiments, and Streptavidin pulldown. Immunoprecipitation, molecular docking, affinity experiments, Streptavidin pulldown, western blotting, in vivo xenograft Molecular cancer Medium 36117171
2024 EREG activates the EREG/EGFR-ERK-Runx1 signaling axis in dorsal root ganglion (DRG) neurons, leading to HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes encoding Kv7/M potassium channels. HDAC2 requires formation of a corepressor complex with MeCP2 and Sin3A to execute this transcriptional repression, causing neuronal hyperexcitability and bone cancer pain. In vivo rat bone cancer pain model, signaling pathway inhibition, HDAC2/MeCP2/Sin3A corepressor complex characterization, electrophysiology, kcnq2/kcnq3 expression analysis Cell communication and signaling Medium 39192337
2021 miR-192-5p directly targets EREG mRNA (validated by luciferase reporter assay). Overexpression of miR-192-5p reduces EREG expression and suppresses M1 macrophage polarization, reducing inflammatory cytokines TNF-α and IL-1β and iNOS. EREG overexpression partially reverses the inhibitory effect of miR-192-5p on M1 polarization. Luciferase reporter system, miR-192-5p agomir in vivo, RAW264.7 macrophage M1 polarization assay, cytokine ELISA, rescue experiments with EREG overexpression Tissue & cell Medium 34715618
2017 EREG expression is upregulated through an IL-1β autocrine loop in CFTR-impaired Caco-2 epithelial cells. IL-1β stimulates EREG mRNA and protein, blocked by the IL-1R antagonist IL1RN. JNK inhibitor SP600125 and EGFR inhibitors (AG1478, PD168393) also suppress EREG expression, indicating EGFR activated in these cells feeds back to sustain EREG upregulation. shRNA knockdown of CFTR, exogenous IL-1β treatment, IL1RN (IL-1R antagonist) treatment, JNK inhibitor, EGFR inhibitors, Western blot and qRT-PCR Journal of cellular biochemistry Medium 29091309
2024 EREG mediates PDAC tumorigenesis through the ERK/p38 MAPK signaling pathway, as established by transcriptome sequencing combined with experimental verification after EREG silencing or overexpression. EREG silencing/overexpression, transcriptome sequencing, ERK/p38 MAPK pathway Western blotting, cell proliferation/migration assays, in vivo tumor growth Biochimica et biophysica acta. Molecular basis of disease Medium 38972433
2025 FTO (m6A demethylase) suppresses EREG mRNA stability in an m6A-dependent manner; loss of FTO increases global m6A levels and enhances EREG mRNA stability, leading to EREG upregulation, which activates the PI3K/Akt signaling pathway (increased PI3K/Akt phosphorylation, decreased p53/p21) and promotes glioma cell proliferation. FTO overexpression/knockdown, mRNA stability assays, m6A level assessment, Western blotting for PI3K/Akt pathway, in vivo xenograft model Frontiers in cell and developmental biology Medium 40970086
2025 PP2A-B56α activation increases expression and processing of EREG (alongside amphiregulin and HB-EGF), leading to increased EGFR signaling and PDAC proliferative phenotypes. Pharmacological PP2A activation combined with EGFR inhibitors mitigates this increased EGFR signaling. Genetic and pharmacological PP2A-B56α activation, EGFR ligand expression analysis, EGFR inhibitor combination treatment, in vivo mouse models bioRxivpreprint Low
2024 EREG, as a low-affinity EGFR ligand shed by ADAM17 sheddase, mediates faster and broader ERK activation waves than high-affinity EGFR ligands in confluent epithelial cells. The integrity of tight/adherens junctions is essential for ERK wave propagation. EREG-deficient mice show impaired ERK wave propagation and cell migration during skin wound repair. Fluorescent probes for EGFRL shedding, optogenetic tool for ectodomain shedding, ERK biosensor in MDCK cells and in vivo, EREG-knockout mice, tight junction disruption experiments bioRxivpreprint Medium
2022 EREG knockdown in cardiac cells mitigates isoproterenol-induced upregulation of Nppb and Fn1 and reduces cardiomyocyte size enlargement. Syringic acid alleviates cardiac hypertrophy and fibrosis mechanistically by downregulating Ereg, and Ereg knockdown also suppresses Myc and Ngfr upregulation. RNA sequencing, si-Ereg transfection, isoproterenol mouse model, qRT-PCR, Western blotting, Picrosirius red staining Journal of cellular and molecular medicine Low 35719043
2025 EREG secreted by THBS1+ tissue monocytes promotes hepatocyte proliferation via EREG-EGFR interactions during liver regeneration. C5a secreted by hepatocytes recruits THBS1+ tissue monocytes via C5a/C5aR1 interaction. These functions were verified in vitro and in vivo. CyTOF, scRNA-seq, bulk RNA-seq, in vitro and in vivo functional validation of EREG-EGFR interaction and C5a/C5aR1 recruitment Hepatobiliary surgery and nutrition Medium 41983196
2025 HDAC2 inhibition in granulosa cells specifically promotes EREG secretion and expression at both mRNA and protein levels, and HDAC2 inhibition increases H4K12 acetylation (H4K12ac), suggesting that HDAC2 represses EREG expression through H4K12 deacetylation in the context of oocyte maturation. HDAC2-specific inhibitor CAY10683, H4K12ac immunofluorescence, EREG RT-qPCR and Western blot, ELISA for EREG secretion, FSH/LH stimulation Reproductive biology Low 41679019
2025 EREG promotes intestinal fibrosis and inflammation in Crohn's disease via epithelial-mesenchymal transition (EMT) and PPARγ signaling pathways in intestinal epithelial cells. TNF-α and IL-17A induce EREG expression in adipocytes. EREG knockdown in vivo alleviates CD symptoms and fibrosis in TNBS-induced rats. In vitro co-culture of primary adipocytes and intestinal epithelial cells, EREG overexpression/knockdown, in vivo TNBS rat model, Western blot, qRT-PCR, IHC, IF Translational research Medium 41167459
2025 FXR activation by hyodeoxycholic acid (HDCA) suppresses EREG expression and thereby inhibits the EREG/EGFR signaling pathway in colorectal cancer cells, reducing proliferation. A negative correlation between FXR and EREG was demonstrated in CRC tissue samples. FXR activation (HDCA treatment), EREG/EGFR pathway Western blotting, flow cytometry, CCK-8, EdU assay, colony formation, in vivo animal experiments Frontiers in cell and developmental biology Low 39834394
2024 EREG promotes K48-linked polyubiquitination-resistant stability when cells are treated with taxol, and ASIV (Astragaloside IV) promotes K48-linked polyubiquitination of EREG leading to its degradation. EREG binds to ErbB receptors and activates ERK signaling to regulate stemness-associated genes, with TGFβ and Hedgehog signaling acting downstream of EREG/ErbB/ERK. Ubiquitination assays (K48-linked), siRNA knockdown, small molecule inhibitors, RNA-seq, immunohistochemistry, xenograft assay Cellular oncology Medium 39373858
2011 EREG expression is induced in monocytes and PBMCs stimulated with M. tuberculosis as well as TLR4 and TLR2/1/6 ligands. In murine macrophages, EREG induction by M. tuberculosis is MYD88- and TLR2-dependent. Gene expression profiling of M. tuberculosis-stimulated macrophages, TLR ligand stimulation assays, MyD88 and TLR2 genetic deficiency experiments in murine macrophages Genes and immunity Medium 22170233
2021 EREG depletion in dental pulp stem cells (DPSCs) enhances osteo/dentinogenic differentiation by activating p38 MAPK and Erk signaling pathways. Under inflammatory conditions (TNF-α), EREG expression is increased and impairs differentiation; EREG knockdown rescues this impairment by restoring p-p38 MAPK and p-Erk levels. shRNA-mediated EREG knockdown, recombinant EREG protein treatment, ALP staining, Alizarin red staining, calcium quantification, qRT-PCR for differentiation markers and signaling pathway components BMC oral health Low 34154572

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 The Role of EREG/EGFR Pathway in Tumor Progression. International journal of molecular sciences 171 34884633
2011 Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥ 2 line cetuximab-based therapy of colorectal cancer patients. PloS one 100 21283802
2023 Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway. Atherosclerosis 97 37245426
2019 The miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in breast cancer cells. Oncogene 88 30967627
2016 Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer. British journal of cancer 82 27272216
2016 Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter. Oncogene 65 27270421
2022 Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 and inhibiting EREG/EGFR signaling in renal cell carcinoma. Molecular cancer 58 36117171
2019 Inhibition of hydrogen sulfide synthesis reverses acquired resistance to 5-FU through miR-215-5p-EREG/TYMS axis in colon cancer cells. Cancer letters 57 31542354
2012 Gene silencing of EREG mediated by DNA methylation and histone modification in human gastric cancers. Laboratory investigation; a journal of technical methods and pathology 40 22508389
2017 RHOA GTPase Controls YAP-Mediated EREG Signaling in Small Intestinal Stem Cell Maintenance. Stem cell reports 36 29129684
2020 EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy. Theranostics 34 32929368
2024 IGF2BP2 promotes cell invasion and epithelial-mesenchymal transition through Src-mediated upregulation of EREG in oral cancer. International journal of biological sciences 30 38250159
2023 EREG is the core onco-immunological biomarker of cuproptosis and mediates the cross-talk between VEGF and CD99 signaling in glioblastoma. Journal of translational medicine 30 36647156
2023 Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction. Cells 27 36899869
2019 E2F7, EREG, miR-451a and miR-106b-5p are associated with the cervical cancer development. Archives of gynecology and obstetrics 26 30607582
2021 Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation. Frontiers in cell and developmental biology 25 33520984
2021 MiR-192-5p suppresses M1 macrophage polarization via epiregulin (EREG) downregulation in gouty arthritis. Tissue & cell 25 34715618
2017 Epiregulin (EREG) is upregulated through an IL-1β autocrine loop in Caco-2 epithelial cells with reduced CFTR function. Journal of cellular biochemistry 24 29091309
2022 Syringic acid mitigates isoproterenol-induced cardiac hypertrophy and fibrosis by downregulating Ereg. Journal of cellular and molecular medicine 20 35719043
2019 Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction. Cancers 16 31181806
2020 High EREG Expression Is Predictive of Better Outcomes in Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy. Oncology 14 32408308
2011 Epiregulin (EREG) variation is associated with susceptibility to tuberculosis. Genes and immunity 14 22170233
2010 Up-regulation of EGF receptor and its ligands, AREG, EREG, and HB-EGF in oral lichen planus. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 13 20952227
2024 Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma. International journal of oral science 12 38945975
2023 ELF3 suppresses gallbladder cancer development through downregulation of the EREG/EGFR/mTOR complex 1 signalling pathway. The Journal of pathology 12 37345534
2024 Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway. Cellular oncology (Dordrecht, Netherlands) 11 39373858
2021 Cav1/EREG/YAP Axis in the Treatment Resistance of Cav1-Expressing Head and Neck Squamous Cell Carcinoma. Cancers 11 34207120
2015 BMP7 and EREG Contribute to the Inductive Potential of Dental Mesenchyme. Scientific reports 11 25952286
2014 Epiregulin (EREG) and human V-ATPase (TCIRG1): genetic variation, ethnicity and pulmonary tuberculosis susceptibility in Guinea-Bissau and The Gambia. Genes and immunity 10 24898387
2024 Involvement of HDAC2-mediated kcnq2/kcnq3 genes transcription repression activated by EREG/EGFR-ERK-Runx1 signaling in bone cancer pain. Cell communication and signaling : CCS 9 39192337
2019 Polymorphism in the EREG gene confers susceptibility to tuberculosis. BMC medical genetics 8 30634928
2021 Depletion of EREG enhances the osteo/dentinogenic differentiation ability of dental pulp stem cells via the p38 MAPK and Erk pathways in an inflammatory microenvironment. BMC oral health 7 34154572
2025 BRAF-activated ARSI suppressed EREG-mediated ferroptosis to promote BRAFV600E (mutant) papillary thyroid carcinoma progression and sorafenib resistance. International journal of biological sciences 6 39744439
2024 Exosomal SOX21-AS1 Regulates EREG by Sponging miR-451a and Promotes the Malignancy of Pancreatic Ductal Adenocarcinoma. Journal of Cancer 4 38817864
2024 EREG silencing inhibits tumorigenesis via inactivating ERK/p38 MAPK pathway in pancreatic ductal adenocarcinoma. Biochimica et biophysica acta. Molecular basis of disease 4 38972433
2023 MicroRNA-1179 targets Epiregulin (EREG) regulates the proliferation and metastasis of human multiple myeloma cells. Acta biochimica Polonica 4 37329522
2023 LncRNA CYP4A22-AS1 promotes the progression of lung adenocarcinoma through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes. Cancer cell international 4 37670265
2020 miR-215 Targeting Novel Genes EREG, NIPAL1 and PTPRU Regulates the Resistance to E.coli F18 in Piglets. Genes 4 32906628
2025 Polysaccharides of Atractylodes Macrocephala Koidz Alleviate LPS-Induced Bursa of Fabricius Injury in Goslings by Inhibiting EREG Expression. Animals : an open access journal from MDPI 3 39795027
2025 Hyodeoxycholic acid inhibits colorectal cancer proliferation through the FXR/EREG/EGFR axis. Frontiers in cell and developmental biology 3 39834394
2025 Adipose-Derived Mesenchymal Stem Cells Accelerate Diabetic Foot Ulcer Healing by Promoting Macrophage M2 Polarization Through Downregulation of EREG and CSTA. Journal of inflammation research 3 40529896
2023 Hsa_circ_0000078 Regulates miR-205-5p/EREG Pathway to Inhibit Cervical Cancer Progression. Molecular biotechnology 3 36645579
2020 Human papillomavirus-positivity is associated with EREG down-regulation and promoter hypermethylation in head and neck squamous cell carcinoma. Experimental and molecular pathology 2 33007298
2025 AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer. Cancer research 1 40637454
2022 The Role of EREG, PTPN1, and SERPINB7 Genes in the Pathogenesis of Psoriasis: May SERPINB7 Be Protective and a Marker of Severity for Psoriasis? Dermatology practical & conceptual 1 37196256
2026 EREG promotes colorectal cancer progression and immune suppressive microenvironment formation through IL-17A/NF-κB pathway. Discover oncology 0 41559353
2026 HDAC2 regulates oocyte maturation in Tan sheep via its strong association with regulating H4K12 acetylation and EREG secretion. Reproductive biology 0 41679019
2026 Dietary targeting of CNBP to rein in the EREG-EGFR cascade and restore homeostasis in colitis-associated colorectal cancer. International journal of biological sciences 0 41943842
2026 Multi-Transcriptomic Analysis Reveals That EREG-Driven TME Crosstalk Defines Anti-EGFR Response in Colorectal Cancer. Cancer medicine 0 42043480
2025 The m6A demethylase FTO suppresses glioma proliferation by regulating the EREG/PI3K/Akt signaling pathway. Frontiers in cell and developmental biology 0 40970086
2025 Mesenteric adipocytes promote intestinal fibrosis and inflammation in Crohn's disease through epiregulin (EREG). Translational research : the journal of laboratory and clinical medicine 0 41167459
2025 EREG-secreting THBS1+ tissue monocytes are recruited by C5a to promote rapid liver regeneration in patients and mice during the ALPPS procedure. Hepatobiliary surgery and nutrition 0 41983196

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