{"gene":"DCN","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":1986,"finding":"The decorin (DCN) core protein was cloned from a human fibroblast cDNA library, revealing a prepro-protein of 329 amino acids with a signal peptide, propeptide, and mature core containing leucine-rich repeats; the protein is expressed as two related transcripts (~1.6 and ~1.9 kb) from a single gene.","method":"cDNA cloning, cDNA library screening with antibodies, protein sequencing, RNA blot hybridization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original structural characterization with protein sequencing, cDNA cloning, and RNA blot; foundational paper","pmids":["3484330"],"is_preprint":false},{"year":1988,"finding":"Stable ectopic expression of human decorin in Chinese hamster ovary (CHO) cells suppresses cell proliferation and reduces saturation density by more than 50%, demonstrating a direct growth-inhibitory role for DCN.","method":"Stable cDNA transfection in CHO cells, growth curve / saturation density assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — direct gain-of-function experiment with dose-dependent phenotype; foundational paper >250 citations","pmids":["3194009"],"is_preprint":false},{"year":1989,"finding":"DCN core protein contains a series of leucine-rich repeats homologous to those in biglycan and other LRR-domain proteins, establishing the structural basis of the SLRP family.","method":"cDNA cloning and protein sequence comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — sequence analysis confirmed by protein biochemistry; >600 citations","pmids":["2647739"],"is_preprint":false},{"year":1990,"finding":"Decorin binds directly to TGF-β and neutralizes its activity; CHO cells overexpressing decorin show growth suppression that is attributable at least in part to sequestration of autocrine TGF-β, placing DCN in a feedback loop regulating cell growth.","method":"Co-immunoprecipitation / binding assay (decorin–TGF-β complex), functional growth assay in CHO cells with TGF-β neutralization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — direct binding demonstrated and functionally validated; >1400 citations","pmids":["2374594"],"is_preprint":false},{"year":1990,"finding":"The DCN gene was mapped to human chromosome 12p12.1-qter by Southern analysis of somatic cell hybrids.","method":"Southern blot analysis of human-rodent somatic cell hybrid panel","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct chromosomal mapping experiment; localization finding","pmids":["1968422"],"is_preprint":false},{"year":1992,"finding":"DCN binds directly to collagen type VI via its protein core (not the glycosaminoglycan chain) with moderate affinity (Kd ~300 nM), as shown by solid-phase binding assays with recombinant core protein and competitive inhibition.","method":"Solid-phase binding assay with 125I-decorin, recombinant fusion protein competition, isolated core protein competition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding reconstituted with multiple controls; >300 citations","pmids":["1544908"],"is_preprint":false},{"year":1992,"finding":"DCN is actively transcribed in mesenchymal cells but not in endothelial or epithelial cells in culture; in situ hybridization placed the single DCN gene to chromosome 12q21–q22.","method":"Northern blot, in situ hybridization on human tissues and cell lines","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct expression and localization experiment; single study","pmids":["1611907"],"is_preprint":false},{"year":1994,"finding":"DCN core protein (and those of biglycan and fibromodulin) binds TGF-β1, -β2, and -β3 with a two-site model (high-affinity Kd ~1–20 nM, low-affinity Kd ~50–200 nM); the glycosaminoglycan chain of decorin partially hinders TGF-β binding; decorin competes with betaglycan and type-I receptors but not type-II receptors for TGF-β binding on cells.","method":"Radioligand binding assay with maltose-binding-protein fusion cores, affinity measurements, competitive binding on Mv 1 Lu and endothelial cells, affinity labeling","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — quantitative in vitro binding with multiple orthogonaol methods; >840 citations","pmids":["8093006"],"is_preprint":false},{"year":1997,"finding":"DCN is cleaved by MMP-2, MMP-3, and MMP-7 (but not MMP-1 or MMP-9); specific cleavage sites were identified (Leu211 and Leu244 region); MMP-7 has ~4.5-fold higher catalytic efficiency (kcat/Km) than MMP-2/3; MMP-mediated degradation of DCN releases bound TGF-β1 from the DCN–TGF-β1 complex.","method":"In vitro enzymatic cleavage, N-terminal sequencing of fragments, kinetic analysis (Km, kcat), TGF-β release assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with kinetic parameters, cleavage sites identified; >350 citations","pmids":["9148753"],"is_preprint":false},{"year":1998,"finding":"Decorin activates the EGF receptor (EGFR) and downstream MAP kinase, induces endogenous p21 (CDKN1A), and causes cell cycle arrest in A431 squamous carcinoma cells; this pathway is responsible for decorin's growth-suppressive effect.","method":"Exogenous protein addition and transgene expression, EGFR/MAP kinase phosphorylation assays, p21 induction by Western blot, growth suppression assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — pathway dissected with multiple orthogonal methods across cell lines; >236 citations","pmids":["9435313"],"is_preprint":false},{"year":1999,"finding":"Decorin directly binds the EGFR ectodomain with Kd ~87 nM via its protein core; binding induces EGFR dimerization, autophosphorylation, and MAP kinase activation, and decorin also acts as an EGFR kinase substrate in a cell-free system.","method":"Radioligand binding assays with immobilized/soluble decorin and EGFR ectodomain, cell-free autophosphorylation assay, dimerization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro binding and enzymatic assay with purified components; >326 citations","pmids":["9988678"],"is_preprint":false},{"year":2002,"finding":"Decorin binds to a specific narrow region in the L2 ligand-binding domain of EGFR; the central leucine-rich repeat 6 of decorin is required for EGFR interaction; a cluster of residues His394–Ile402 in EGFR is essential for decorin binding (partially overlapping but distinct from the EGF-binding epitope).","method":"Expression cloning screen (decorin/alkaline phosphatase chimera vs. cDNA library), yeast two-hybrid, EGFR deletion mutant panel, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple complementary methods including mutagenesis and expression cloning; >194 citations","pmids":["12105206"],"is_preprint":false},{"year":2009,"finding":"Decorin directly binds the Met receptor (HGF receptor) with high affinity (Kd ~1.5 nM); binding induces transient Met activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life ~6 min); decorin thereby suppresses β-catenin levels and inhibits Met-mediated cell migration and growth.","method":"Direct binding assay, displacement by HGF and internalin B, co-immunoprecipitation of c-Cbl, pulse-chase degradation assay, β-catenin Western blot, migration and growth assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative binding, receptor degradation kinetics, and downstream signaling all validated; >200 citations","pmids":["19433454"],"is_preprint":false},{"year":2012,"finding":"DCN has a broad binding repertoire including collagens (collagen I, VI), TGF-β ligands, and multiple receptor tyrosine kinases (EGFR, Met); it antagonizes pro-tumorigenic signals by sequestering growth factors and directly down-regulating RTK activity in the tumor stroma.","method":"Review synthesizing binding assay, co-IP, cell-based functional data from multiple primary studies","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — synthesis of multiple independent experimental findings; >262 citations","pmids":["22735579"],"is_preprint":false},{"year":2012,"finding":"OTUB1, a deubiquitinase, interacts with DCN protein in mesangial cells (co-immunoprecipitation); OTUB1 overexpression promotes ubiquitination and proteasomal degradation of DCN, thereby reducing DCN levels during inflammatory glomerular injury.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression of OTUB1, Western blot and quantitative RT-PCR in cultured rat mesangial cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional ubiquitination assay; single study","pmids":["22279542"],"is_preprint":false},{"year":2014,"finding":"Methylation of the +58CpG site in the DCN 5'-UTR reduces binding of the transcriptional activator AhR to this site, causing ~50% reduction in DCN transcriptional activity; this epigenetic silencing of DCN in high-metastatic NSCLC cells leads to elevated p-Smad3 and reduced E-cadherin, promoting TGF-β/Smad signaling.","method":"Bisulfite sequencing, ChIP assay, EMSA, luciferase reporter assay, 5-Aza demethylation rescue, Western blot","journal":"International journal of oncology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (EMSA, ChIP, reporter, rescue) in single study","pmids":["24424784"],"is_preprint":false},{"year":2015,"finding":"DCN overexpression in renal cell carcinoma cells significantly upregulates p21 and E-cadherin, suppressing proliferation and metastasis in vitro and in vivo.","method":"Gain-of-function (DCN cDNA transfection), proliferation and invasion assays in vitro, xenograft in vivo, Western blot for p21 and E-cadherin","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with defined molecular readouts; single study","pmids":["26547587"],"is_preprint":false},{"year":2021,"finding":"During ferroptosis, DCN is actively released from dying cells via secretory autophagy and lysosomal exocytosis; extracellular DCN then binds AGER (RAGE) on macrophages and triggers NF-κB-dependent production of pro-inflammatory cytokines, mediating the immune consequences of ferroptotic death.","method":"Inhibition of secretory autophagy and lysosomal exocytosis (pharmacological and genetic), co-immunoprecipitation/binding of DCN with AGER, cytokine assays, NF-κB reporter, in vivo models of acute pancreatitis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — binding partner identified, secretion mechanism dissected with pharmacological/genetic tools, and in vivo validation; >100 citations","pmids":["34964698"],"is_preprint":false},{"year":2024,"finding":"DCN knockdown in breast stromal fibroblasts activates the STAT3/AUF1 signaling axis, upregulates CAF biomarkers (α-SMA, FAP-α, SDF-1, IL-6), and promotes epithelial-to-mesenchymal transition and stemness in breast cancer cells in a paracrine manner; ectopic DCN expression in CAFs reverses these pro-carcinogenic effects.","method":"siRNA knockdown and ectopic expression of DCN, Western blot, invasion/proliferation assays, STAT3/AUF1 pathway analysis, orthotopic tumor mouse model","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function with defined signaling pathway; single study","pmids":["38667295"],"is_preprint":false},{"year":2025,"finding":"EGR3 directly binds to the DCN promoter and acts as a transcriptional activator of DCN in liver cancer cells; EGR3 knockdown reduces DCN expression and reverses DCN's tumor-suppressive effects on proliferation, apoptosis, invasion, and migration.","method":"ChIP assay, luciferase reporter assay, siRNA knockdown of EGR3, rescue co-transfection (si-EGR3 + pcDNA3.1-DCN), functional assays (CCK-8, colony formation, flow cytometry, Transwell)","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase validate direct transcriptional regulation; rescue experiment confirms axis; single study","pmids":["40660758"],"is_preprint":false},{"year":2025,"finding":"Dcn overexpression protects hepatocytes from H2O2-induced injury by upregulating HIF1A; pharmacological inhibition of HIF1A reverses this protective effect, establishing a Dcn/HIF1A axis that modulates hepatocyte proliferation, apoptosis, autophagy, and oxidative stress.","method":"Overexpression and knockdown plasmids in BRL cells, H2O2 injury model, HIF1A inhibitor (LW6), cell viability/cycle/autophagy/oxidative stress assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with inhibitor rescue; single in vitro study","pmids":["41468793"],"is_preprint":false},{"year":2025,"finding":"Controlled release of DCN protein from hyaluronic acid microgels suppresses vocal fold myofibroblast activation by reducing pro-fibrotic gene expression, α-SMA levels, and cell contractility; in a rat vocal fold scarring model, DCN-loaded microgels prevented collagen deposition and myofibroblast accumulation.","method":"Transcriptomics of human VF myofibroblasts, DCN protein treatment with functional readouts (α-SMA, gene expression, contractility), microgel encapsulation, in vivo rat VF scarring model with histological analysis","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro mechanistic assays plus in vivo model; preprint, not yet peer reviewed","pmids":[],"is_preprint":true}],"current_model":"Decorin (DCN) is a small leucine-rich proteoglycan secreted into the extracellular matrix that acts as a pleiotropic signaling regulator: it directly binds and sequesters TGF-β (with high nanomolar affinity) to suppress TGF-β/Smad signaling, binds collagen VI via its protein core to regulate matrix architecture, and acts as an antagonistic ligand of EGFR (Kd ~87 nM) and Met (Kd ~1.5 nM), inducing transient receptor activation followed by c-Cbl–mediated ubiquitination and degradation of Met, EGFR/MAP kinase/p21-driven cell cycle arrest, and suppression of β-catenin; MMP-2, MMP-3, and MMP-7 proteolytically cleave DCN at defined sites, releasing bound TGF-β; DCN transcription is activated directly by EGR3 and is epigenetically silenced by +58CpG methylation (which displaces AhR); OTUB1 promotes ubiquitination and proteasomal degradation of DCN protein; during ferroptosis DCN is released via secretory autophagy/lysosomal exocytosis and signals through AGER/NF-κB on macrophages to drive innate immune responses; and loss of DCN in stromal fibroblasts activates the STAT3/AUF1 axis to promote cancer-associated fibroblast phenotypes."},"narrative":{"teleology":[{"year":1986,"claim":"Cloning the DCN cDNA revealed the primary structure of a leucine-rich repeat proteoglycan, establishing the molecular identity of decorin as a secreted SLRP.","evidence":"cDNA library screening, protein sequencing, and RNA blot from human fibroblasts","pmids":["3484330","2647739"],"confidence":"High","gaps":["Biological function of the leucine-rich repeat architecture was unknown","Binding partners of the core protein had not been identified"]},{"year":1990,"claim":"Discovery that DCN directly binds and neutralizes TGF-β provided the first mechanistic explanation for its growth-inhibitory activity, identifying DCN as an extracellular TGF-β trap.","evidence":"Co-immunoprecipitation of decorin–TGF-β complex and functional growth suppression assay in CHO cells","pmids":["2374594","3194009"],"confidence":"High","gaps":["Affinity constants for TGF-β isoforms had not been quantified","Whether the GAG chain contributed to TGF-β binding was unresolved"]},{"year":1992,"claim":"Identification of collagen VI as a direct ligand of DCN's protein core (Kd ~300 nM) established DCN as a bifunctional molecule linking matrix architecture to growth factor regulation.","evidence":"Solid-phase binding assay with radiolabeled decorin and recombinant core protein competition","pmids":["1544908"],"confidence":"High","gaps":["Structural basis of the collagen VI–DCN interaction was not determined","In vivo consequences of disrupting DCN–collagen VI binding were unknown"]},{"year":1994,"claim":"Quantitative binding studies revealed a two-site model for DCN–TGF-β interaction (high-affinity Kd ~1–20 nM) and showed that DCN competes with betaglycan and type I but not type II TGF-β receptors, clarifying its mechanism of TGF-β antagonism.","evidence":"Radioligand binding with recombinant maltose-binding-protein fusion cores, competitive binding on cells, affinity labeling","pmids":["8093006"],"confidence":"High","gaps":["The precise binding epitope on DCN for TGF-β was unmapped","Whether DCN–TGF-β sequestration operates in all tissue contexts was unclear"]},{"year":1997,"claim":"Demonstration that MMP-2, MMP-3, and MMP-7 cleave DCN at specific leucine residues and liberate sequestered TGF-β1 revealed a protease-dependent mechanism for regulated TGF-β release from the matrix.","evidence":"In vitro enzymatic cleavage with kinetic parameters, N-terminal sequencing, TGF-β release assay","pmids":["9148753"],"confidence":"High","gaps":["In vivo relevance of MMP-mediated DCN cleavage in disease contexts was not established","Whether other proteases contribute remained unexplored"]},{"year":1999,"claim":"Identification of EGFR as a direct DCN receptor (Kd ~87 nM) and mapping of the interaction to LRR6 on DCN and the L2 domain of EGFR established a receptor tyrosine kinase signaling axis through which DCN induces p21-dependent cell cycle arrest.","evidence":"Radioligand binding, dimerization and autophosphorylation assays with purified components, expression cloning screen, and site-directed mutagenesis","pmids":["9988678","9435313","12105206"],"confidence":"High","gaps":["Structural model of the DCN–EGFR complex was lacking","How transient EGFR activation leads to growth suppression rather than mitogenesis was mechanistically incomplete"]},{"year":2009,"claim":"Discovery that DCN binds Met with very high affinity (Kd ~1.5 nM) and triggers c-Cbl-mediated Met degradation (t½ ~6 min) expanded DCN's anti-oncogenic mechanism beyond EGFR to a second RTK, explaining suppression of β-catenin and cell migration.","evidence":"Direct binding/displacement assays, co-immunoprecipitation of c-Cbl, pulse-chase receptor degradation, functional migration assays","pmids":["19433454"],"confidence":"High","gaps":["Whether DCN targets additional RTKs was unknown","The relative contribution of EGFR versus Met antagonism in vivo was unresolved"]},{"year":2012,"claim":"OTUB1 was identified as a DCN-interacting protein that paradoxically promotes DCN ubiquitination and proteasomal degradation, revealing a post-translational mechanism for DCN turnover during inflammation.","evidence":"Co-immunoprecipitation and ubiquitination assay in rat mesangial cells with OTUB1 overexpression","pmids":["22279542"],"confidence":"Medium","gaps":["OTUB1 is a deubiquitinase, so the pro-ubiquitination mechanism is paradoxical and unexplained","Not independently confirmed in a second cell type or species","The ubiquitin linkage type on DCN was not characterized"]},{"year":2014,"claim":"Epigenetic silencing of DCN via +58CpG methylation, which displaces the transcriptional activator AhR, was shown to derepress TGF-β/Smad signaling in metastatic NSCLC cells, linking DCN transcriptional regulation to cancer progression.","evidence":"Bisulfite sequencing, ChIP, EMSA, luciferase reporter, and 5-Aza demethylation rescue in NSCLC cell lines","pmids":["24424784"],"confidence":"High","gaps":["Whether +58CpG methylation operates in non-lung cancers was untested","The upstream signals that direct methylation at this site were not identified"]},{"year":2021,"claim":"DCN was identified as a damage-associated molecular pattern released during ferroptosis via secretory autophagy and lysosomal exocytosis; extracellular DCN binds AGER on macrophages and activates NF-κB-dependent cytokine production, establishing a new immunological function.","evidence":"Pharmacological and genetic inhibition of secretory autophagy/lysosomal exocytosis, DCN–AGER co-immunoprecipitation, NF-κB reporter, in vivo acute pancreatitis model","pmids":["34964698"],"confidence":"High","gaps":["Whether AGER is the sole macrophage receptor for ferroptosis-released DCN is unconfirmed","The relationship between DCN's AGER signaling and its RTK-antagonistic functions is unexplored"]},{"year":2024,"claim":"Loss of stromal DCN was shown to activate STAT3/AUF1 signaling in fibroblasts, driving cancer-associated fibroblast conversion that promotes epithelial-to-mesenchymal transition paracrinally, revealing DCN as a suppressor of the CAF phenotype.","evidence":"siRNA knockdown and ectopic DCN expression in breast stromal fibroblasts, STAT3/AUF1 pathway analysis, orthotopic mouse model","pmids":["38667295"],"confidence":"Medium","gaps":["The direct molecular link between DCN loss and STAT3 phosphorylation is undefined","Single study in breast cancer stroma; generalizability to other tumor types is untested"]},{"year":2025,"claim":"EGR3 was identified as a direct transcriptional activator of DCN, and a DCN/HIF1A axis was shown to protect hepatocytes from oxidative injury, broadening understanding of DCN transcriptional control and cytoprotective signaling.","evidence":"ChIP and luciferase reporter for EGR3–DCN promoter binding; overexpression/knockdown and HIF1A inhibitor rescue in hepatocyte oxidative stress model","pmids":["40660758","41468793"],"confidence":"Medium","gaps":["The mechanism by which extracellular DCN upregulates intracellular HIF1A is unknown","EGR3-driven DCN regulation has been shown only in liver cancer cells","Relationship between EGR3 and AhR/methylation-dependent DCN regulation is unexplored"]},{"year":null,"claim":"A high-resolution structural model of DCN in complex with EGFR, Met, or AGER is lacking, and the relative in vivo contribution of each receptor axis to DCN's tumor-suppressive and immunomodulatory functions remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No co-crystal or cryo-EM structure of DCN bound to any of its RTK or AGER partners","In vivo genetic dissection separating TGF-β sequestration from RTK antagonism has not been performed","Whether DCN's DAMP/AGER function and its matrix/RTK functions are coordinated or independent is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,9,10,12]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[10,11,12,17]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[3,7,8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,5,8,13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,7,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,10,12,17]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5,8,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,18]}],"complexes":[],"partners":["EGFR","MET","TGFB1","AGER","COL6A1","OTUB1","EGR3"],"other_free_text":[]},"mechanistic_narrative":"Decorin (DCN) is a secreted small leucine-rich proteoglycan that orchestrates extracellular matrix architecture and growth factor signaling by acting simultaneously as a collagen-binding scaffold, a TGF-β sequestrant, and an antagonistic ligand of receptor tyrosine kinases. The DCN core protein binds TGF-β1/2/3 with nanomolar affinity, neutralizing TGF-β bioactivity; MMP-2, MMP-3, and MMP-7 proteolytically degrade DCN at defined leucine residues, releasing sequestered TGF-β and providing a regulated mechanism for TGF-β mobilization [PMID:2374594, PMID:9148753]. DCN also binds EGFR (Kd ~87 nM) and Met (Kd ~1.5 nM), triggering transient receptor activation that leads to p21-dependent cell cycle arrest (via EGFR/MAPK) and c-Cbl-mediated ubiquitination and degradation of Met with consequent β-catenin suppression [PMID:9988678, PMID:19433454]. Beyond its matrix and RTK functions, DCN is released during ferroptosis via secretory autophagy and signals through AGER/NF-κB on macrophages to elicit innate immune cytokine responses [PMID:34964698]."},"prefetch_data":{"uniprot":{"accession":"P07585","full_name":"Decorin","aliases":["Bone proteoglycan II","PG-S2","PG40"],"length_aa":359,"mass_kda":39.7,"function":"May affect the rate of fibrils formation","subcellular_location":"Secreted, extracellular space, extracellular matrix; Secreted","url":"https://www.uniprot.org/uniprotkb/P07585/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DCN","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DCN","total_profiled":1310},"omim":[{"mim_id":"619710","title":"HYALURONAN AND PROTEOGLYCAN LINK PROTEIN 4; HAPLN4","url":"https://www.omim.org/entry/619710"},{"mim_id":"612977","title":"DCN1 DOMAIN-CONTAINING PROTEIN 4; DCUN1D4","url":"https://www.omim.org/entry/612977"},{"mim_id":"612868","title":"CORNEAL DYSTROPHY, POSTERIOR AMORPHOUS; PACD","url":"https://www.omim.org/entry/612868"},{"mim_id":"612654","title":"TRICHOPLEIN; TCHP","url":"https://www.omim.org/entry/612654"},{"mim_id":"610048","title":"CORNEAL DYSTROPHY, CONGENITAL STROMAL; CSCD","url":"https://www.omim.org/entry/610048"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DCN"},"hgnc":{"alias_symbol":["DSPG2","SLRR1B"],"prev_symbol":[]},"alphafold":{"accession":"P07585","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07585","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07585-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07585-F1-predicted_aligned_error_v6.png","plddt_mean":88.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DCN","jax_strain_url":"https://www.jax.org/strain/search?query=DCN"},"sequence":{"accession":"P07585","fasta_url":"https://rest.uniprot.org/uniprotkb/P07585.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07585/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07585"}},"corpus_meta":[{"pmid":"15988528","id":"PMC_15988528","title":"The conserved protein DCN-1/Dcn1p is required for cullin neddylation in C. elegans and S. cerevisiae.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15988528","citation_count":156,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11820791","id":"PMC_11820791","title":"Asb4, Ata3, and Dcn are novel imprinted genes identified by high-throughput screening using RIKEN cDNA microarray.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11820791","citation_count":116,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34964698","id":"PMC_34964698","title":"DCN released from ferroptotic cells ignites AGER-dependent immune responses.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34964698","citation_count":105,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1968422","id":"PMC_1968422","title":"Localization of PGI (biglycan, BGN) and PGII (decorin, DCN, PG-40) genes on human chromosomes Xq13-qter and 12q, respectively.","date":"1990","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1968422","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2914952","id":"PMC_2914952","title":"Recognition of (dG)n.(dC)n sequences by endonuclease G. Characterization of the calf thymus nuclease.","date":"1989","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2914952","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30604627","id":"PMC_30604627","title":"Identification of CAV1 and DCN as potential predictive biomarkers for lung adenocarcinoma.","date":"2019","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30604627","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33767918","id":"PMC_33767918","title":"lncRNA FDNCR promotes apoptosis of granulosa cells by targeting the miR-543-3p/DCN/TGF-β signaling pathway in Hu sheep.","date":"2021","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/33767918","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1611907","id":"PMC_1611907","title":"Expression of decorin in human tissues and cell lines and defined chromosomal assignment of the gene locus (DCN).","date":"1992","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1611907","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17597076","id":"PMC_17597076","title":"Structural basis for the function of DCN-1 in protein Neddylation.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17597076","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26906416","id":"PMC_26906416","title":"Characterization of the mammalian family of DCN-type NEDD8 E3 ligases.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/26906416","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19678923","id":"PMC_19678923","title":"Presence of activating KRAS mutations correlates significantly with expression of tumour suppressor genes DCN and TPM1 in colorectal cancer.","date":"2009","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19678923","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3271474","id":"PMC_3271474","title":"Structure of (dG)n.(dC)n under superhelical stress and acid pH.","date":"1987","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/3271474","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26547587","id":"PMC_26547587","title":"DCN deficiency promotes renal cell carcinoma growth and metastasis through downregulation of P21 and E-cadherin.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26547587","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28261350","id":"PMC_28261350","title":"Identifying DCN and HSPD1 as Potential Biomarkers in Colon Cancer Using 2D-LC-MS/MS Combined with iTRAQ Technology.","date":"2017","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28261350","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30032645","id":"PMC_30032645","title":"Oncolytic Adenovirus rAd.DCN Inhibits Breast Tumor Growth and Lung Metastasis in an Immune-Competent Orthotopic Xenograft Model.","date":"2018","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30032645","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3368317","id":"PMC_3368317","title":"Deoxycytidine methylation does not affect DNA.RNA hybrid formation or B-A transitions of (dG)n.(dC)n sequences.","date":"1988","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3368317","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2587262","id":"PMC_2587262","title":"Energetics of the B-H transition in supercoiled DNA carrying d(CT)x.d(AG)x and d(C)n.d(G)n inserts.","date":"1989","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2587262","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31727599","id":"PMC_31727599","title":"RETRACTED: LSAMP-AS1 binds to microRNA-183-5p to suppress the progression of prostate cancer by up-regulating the tumor suppressor DCN.","date":"2019","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/31727599","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20357198","id":"PMC_20357198","title":"Linkage of posterior amorphous corneal dystrophy to chromosome 12q21.33 and exclusion of coding region mutations in KERA, LUM, DCN, and EPYC.","date":"2010","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/20357198","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24424784","id":"PMC_24424784","title":"Methylated +58CpG site decreases DCN mRNA expression and enhances TGF-β/Smad signaling in NSCLC cells with high metastatic potential.","date":"2014","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24424784","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38191093","id":"PMC_38191093","title":"Tissue-targeted and localized AAV5-DCN and AAV5-PEDF combination gene therapy abrogates corneal fibrosis and concurrent neovascularization in rabbit eyes in vivo.","date":"2024","source":"The ocular surface","url":"https://pubmed.ncbi.nlm.nih.gov/38191093","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38667295","id":"PMC_38667295","title":"Decorin (DCN) Downregulation Activates Breast Stromal Fibroblasts and Promotes Their Pro-Carcinogenic Effects through the IL-6/STAT3/AUF1 Signaling.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38667295","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31524274","id":"PMC_31524274","title":"Differential expression of extracellular matrix‑related genes DCN, EPHA4, FN1, SPARC, SPON2 and SPP1 in colorectal carcinogenesis.","date":"2019","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31524274","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27162485","id":"PMC_27162485","title":"NecroX-5 exerts anti-inflammatory and anti-fibrotic effects via modulation of the TNFα/Dcn/TGFβ1/Smad2 pathway in hypoxia/reoxygenation-treated rat hearts.","date":"2016","source":"The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27162485","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16151700","id":"PMC_16151700","title":"The COPG2, DCN, and SDHD genes are biallelically expressed in cattle.","date":"2005","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/16151700","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30186394","id":"PMC_30186394","title":"Effects of transplanted adipose derived stem cells on the expressions of α-SMA and DCN in fibroblasts of hypertrophic scar tissues in rabbit ears.","date":"2018","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30186394","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38466528","id":"PMC_38466528","title":"The fibro-adipogenic progenitor APOD+DCN+LUM+ cell population in aggressive carcinomas.","date":"2024","source":"Cancer metastasis reviews","url":"https://pubmed.ncbi.nlm.nih.gov/38466528","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35420507","id":"PMC_35420507","title":"Long non-coding RNAs PGM5-AS1 upregulates Decorin (DCN) to inhibit cervical cancer progression by sponging miR-4284.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35420507","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2066285","id":"PMC_2066285","title":"A spectrotemporal analysis of DCN single unit responses to wideband noise in guinea pig.","date":"1991","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/2066285","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38230769","id":"PMC_38230769","title":"Stachydrine represses the proliferation and enhances cell cycle arrest and apoptosis of breast cancer cells via PLA2G2A/DCN axis.","date":"2024","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/38230769","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22279542","id":"PMC_22279542","title":"OTUB1 overexpression in mesangial cells is a novel regulator in the pathogenesis of glomerulonephritis through the decrease of DCN level.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22279542","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21232885","id":"PMC_21232885","title":"Expression and genomic imprinting of DCN, PON2 and PEG3 genes in porcine placenta.","date":"2010","source":"Animal reproduction science","url":"https://pubmed.ncbi.nlm.nih.gov/21232885","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38036264","id":"PMC_38036264","title":"Sex differences in descending control of nociception (DCN) responses after chronic orofacial pain induction in rats and the contribution of kappa opioid receptors.","date":"2023","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/38036264","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20401695","id":"PMC_20401695","title":"Novel SNPs in the caprine stearoyl-CoA desaturase (SCD) and decorin (DCN) genes that are associated with growth traits in Chinese goat breeds.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20401695","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18520035","id":"PMC_18520035","title":"SDF-1/54-DCN: a novel recombinant chimera with dual inhibitory effects on proliferation and chemotaxis of tumor cells.","date":"2008","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/18520035","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17558846","id":"PMC_17558846","title":"Autosomal dominant cornea plana is not associated with pathogenic mutations in DCN, DSPG3, FOXC1, KERA, LUM, or PITX2.","date":"2007","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17558846","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37597320","id":"PMC_37597320","title":"Xinshubao tablet ameliorates myocardial injury against heart failure via the DCN/PPARα/PGC-1α/P300 pathway.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37597320","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39145305","id":"PMC_39145305","title":"Progranulin inhibits autophagy to facilitate intracellular colonization of Helicobacter pylori through the PGRN/mTOR/DCN axis in gastric epithelial cells.","date":"2024","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39145305","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36534610","id":"PMC_36534610","title":"Novel DCN Mutation in Armenian Family With Congenital Stromal Corneal Dystrophy.","date":"2022","source":"Cornea","url":"https://pubmed.ncbi.nlm.nih.gov/36534610","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9570230","id":"PMC_9570230","title":"Intrinsic oscillations and discharge regularity of units in the dorsal cochlear nucleus (DCN) of the barbiturate anesthetized gerbil.","date":"1998","source":"Annals of biomedical engineering","url":"https://pubmed.ncbi.nlm.nih.gov/9570230","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36675230","id":"PMC_36675230","title":"Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36675230","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36452876","id":"PMC_36452876","title":"Low Intensity Noise Exposure Enhanced Auditory Loudness and Temporal Processing by Increasing Excitability of DCN.","date":"2022","source":"Neural plasticity","url":"https://pubmed.ncbi.nlm.nih.gov/36452876","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36964172","id":"PMC_36964172","title":"A pediatric case of congenital stromal corneal dystrophy caused by the novel variant c.953del of the DCN gene.","date":"2023","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/36964172","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31824291","id":"PMC_31824291","title":"Optimizing Optogenetic Activation of Purkinje Cell Axons to Investigate the Purkinje Cell - DCN Synapse.","date":"2019","source":"Frontiers in synaptic neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31824291","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30044575","id":"PMC_30044575","title":"[Influences of human dermis derived mesenchymal stem cells on α-SMA and DCN expressions of hypertrophic scars fibroblasts].","date":"2016","source":"Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/30044575","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40791738","id":"PMC_40791738","title":"Identification and quantification of GABAA R-α1-positive cells in the DCN of rats with behavioral evidence of noise-induced tinnitus.","date":"2025","source":"IBRO neuroscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/40791738","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38959242","id":"PMC_38959242","title":"Expression and secretion of SPARC, FGF-21 and DCN in bovine muscle cells: Effects of age and differentiation.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38959242","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41730487","id":"PMC_41730487","title":"DCN-type NEDD8 E3 ligases: Structure, biological function and small-molecule inhibitor.","date":"2026","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/41730487","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40660758","id":"PMC_40660758","title":"EGR3 Transcriptionally Upregulates the Expression of DCN in Liver Cancer to Inhibit Tumor Progression.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40660758","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41313163","id":"PMC_41313163","title":"A Novel Strategy for Optimized Achilles Tendon Healing: DCN/Hep-Loaded Sutures.","date":"2025","source":"Journal of biomedical materials research. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41313163","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41148053","id":"PMC_41148053","title":"lncRNA PAX8-AS1 suppresses cervical cancer development by regulating miR-675-3p/DCN axis.","date":"2025","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/41148053","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41468793","id":"PMC_41468793","title":"Dcn/HIF1A axis modulates proliferation, apoptosis, oxidative stress and autophagy in liver regeneration.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41468793","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41977392","id":"PMC_41977392","title":"A Conserved Fibroblast-Myeloid Gene Signature in Digestive Cancers: Multi-Omics Integration Identifies DCN, COL10A1, CTHRC1, and TREM2 as Candidate Microenvironmental Markers.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41977392","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41418534","id":"PMC_41418534","title":"Curcumin alleviates the effects of heat stress on broiler pectoral muscle via decorin (DCN) -mediated TGF-β Signaling pathway.","date":"2025","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/41418534","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41205056","id":"PMC_41205056","title":"DCN, NPM3 and SULF1 are hub genes related to vasculogenic mimicry in lung adenocarcinoma.","date":"2025","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41205056","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40419046","id":"PMC_40419046","title":"Protein interaction network drive more group integrated analytic larynx hub protein markers: LYVE1/FBLN5/INMT/DCN/ZFY/RSPO3 protein macromolecule collaborative diagnosis of a new era.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40419046","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41966438","id":"PMC_41966438","title":"DCN promotes dermal papilla cells proliferation by escaping chi-miR-497-5p mediated repression via circPIEZO2 sponging.","date":"2026","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41966438","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.10.15.682296","title":"Establishment of spinocerebellar ataxia type 34 model mice accompanied by early glial activation and degeneration of cerebellar neurons","date":"2025-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.15.682296","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.06.25.661429","title":"Controlled decorin delivery from injectable microgels promotes scarless vocal fold repair","date":"2025-06-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.25.661429","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.07.16.665173","title":"Fusiform Cells in the Dorsal Cochlear Nucleus Change Intrinsic Electrophysiological Properties and Morphologically Remodel Their Basal Dendrites with Age","date":"2025-07-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.16.665173","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.03.18.644009","title":"Electrophysiological classification of <i>CACNA1G</i> gene variants associated with neurodevelopmental and neurological disorders","date":"2025-03-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.18.644009","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.08.28.672815","title":"Spatially distinct ECM-producing fibroblasts and myonuclei orchestrate early adaptation to mechanical loading in the human muscle-tendon unit","date":"2025-09-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.28.672815","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.03.26.645464","title":"Auditory regulation of hippocampal locomotion circuits by a non-canonical reticular-limbic pathway","date":"2025-03-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.26.645464","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.11.19.24317485","title":"Gal-9 and DCN Serum Expression Reflect Accelerated Brain Aging and Are Attenuated by the Green-Mediterranean Diet: The 18-month DIRECT PLUS Proteomics-Brain MRI Trial","date":"2024-11-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.19.24317485","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.07.09.663835","title":"Granulin<sup>+</sup> macrophages promote lineage plasticity in prostate cancer through paracrine signaling loops","date":"2025-07-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.09.663835","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.06.20.599970","title":"Decorin enhances metabolic maturation by activating AMPK-PGC1A pathway in cardiac organoids","date":"2024-06-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.20.599970","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.07.06.25330978","title":"Machine Learning Fairness in Predicting Underweight, Overweight and Adiposity Across Socioeconomic and Caste Group in India: Evidence from the Longitudinal Ageing Study in India","date":"2025-07-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.06.25330978","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.04.22.649643","title":"Resolving the molecular niche of pulmonary fibrosis using cryopreserved human precision cut lung slices","date":"2025-04-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.22.649643","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.02.24.639874","title":"<i>NOR1</i> and Mitophagy: An Insight into Sertoli Cell Function Regulating Spermatogenesis","date":"2025-02-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.24.639874","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.12.10.627749","title":"Multiscale Single-Cell Assessment of the Fibrotic Niche in Idiopathic Pulmonary Fibrosis","date":"2024-12-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.10.627749","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.10.14.618133","title":"Network mechanisms in rapid-onset dystonia-parkinsonism","date":"2024-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.14.618133","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.07.03.24309577","title":"Genetic regulation of the plasma proteome and its link to cardiometabolic disease in Greenlandic Inuit","date":"2024-07-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.03.24309577","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"22658674","id":"PMC_22658674","title":"Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22658674","citation_count":1718,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2374594","id":"PMC_2374594","title":"Negative regulation of transforming growth factor-beta by the proteoglycan decorin.","date":"1990","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2374594","citation_count":1408,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25701227","id":"PMC_25701227","title":"Proteoglycan form and function: A comprehensive nomenclature of proteoglycans.","date":"2015","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/25701227","citation_count":901,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8093006","id":"PMC_8093006","title":"Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta.","date":"1994","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8093006","citation_count":840,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2647739","id":"PMC_2647739","title":"Deduced protein sequence of bone small proteoglycan I (biglycan) shows homology with proteoglycan II (decorin) and several nonconnective tissue proteins in a variety of species.","date":"1989","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2647739","citation_count":636,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3484330","id":"PMC_3484330","title":"Primary structure of an extracellular matrix proteoglycan core protein deduced from cloned cDNA.","date":"1986","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/3484330","citation_count":558,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26871637","id":"PMC_26871637","title":"Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26871637","citation_count":423,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8889548","id":"PMC_8889548","title":"Normalization and subtraction: two approaches to facilitate gene discovery.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8889548","citation_count":401,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3597437","id":"PMC_3597437","title":"Purification and partial characterization of small proteoglycans I and II, bone sialoproteins I and II, and osteonectin from the mineral compartment of developing human bone.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3597437","citation_count":389,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9148753","id":"PMC_9148753","title":"Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release.","date":"1997","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9148753","citation_count":353,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9988678","id":"PMC_9988678","title":"Decorin is a biological ligand for the epidermal growth factor receptor.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9988678","citation_count":326,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1544908","id":"PMC_1544908","title":"Binding of the proteoglycan decorin to collagen type VI.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1544908","citation_count":302,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22735579","id":"PMC_22735579","title":"Decorin: a guardian from the matrix.","date":"2012","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22735579","citation_count":262,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3194009","id":"PMC_3194009","title":"Expression of human proteoglycan in Chinese hamster ovary cells inhibits cell proliferation.","date":"1988","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/3194009","citation_count":254,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1550960","id":"PMC_1550960","title":"Transforming growth factor-beta complexes with thrombospondin.","date":"1992","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/1550960","citation_count":242,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9435313","id":"PMC_9435313","title":"Decorin suppresses tumor cell growth by activating the epidermal growth factor receptor.","date":"1998","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/9435313","citation_count":236,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20551380","id":"PMC_20551380","title":"Proteomics characterization of extracellular space components in the human aorta.","date":"2010","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/20551380","citation_count":231,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25037231","id":"PMC_25037231","title":"Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25037231","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19433454","id":"PMC_19433454","title":"Decorin is a novel antagonistic ligand of the Met receptor.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19433454","citation_count":200,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12105206","id":"PMC_12105206","title":"Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12105206","citation_count":194,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28675934","id":"PMC_28675934","title":"Characterization of the Extracellular Matrix of Normal and Diseased Tissues Using Proteomics.","date":"2017","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/28675934","citation_count":185,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23978385","id":"PMC_23978385","title":"The paradox of paclitaxel neurotoxicity: Mechanisms and unanswered questions.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23978385","citation_count":184,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16893474","id":"PMC_16893474","title":"Elastic fibres in health and disease.","date":"2006","source":"Expert reviews in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16893474","citation_count":183,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38670,"output_tokens":3645,"usd":0.085343},"stage2":{"model":"claude-opus-4-6","input_tokens":7079,"output_tokens":2807,"usd":0.158355},"total_usd":0.554323,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":51663,"output_tokens":5085,"usd":0.115632},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8959,"output_tokens":3408,"usd":0.194993}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"DCN-1 (C. elegans) and Dcn1p (S. cerevisiae) are required for cullin neddylation; they directly bind Nedd8 and physically associate with cullins, and Dcn1p overexpression causes accumulation of Nedd8-modified cullin Cdc53p. In vitro and in vivo experiments show Dcn1p does not inhibit COP9 signalosome-mediated deneddylation but greatly increases the kinetics of the neddylation reaction.\",\n      \"method\": \"Genetic loss-of-function in C. elegans and S. cerevisiae, in vitro binding assays, in vivo neddylation assays, overexpression studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (in vivo genetics, in vitro binding, enzymatic kinetics) replicated across two model organisms\",\n      \"pmids\": [\"15988528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of yeast DCN-1 at 1.9 Å resolution reveals an all-alpha-helical architecture with an N-terminal EF-hand motif domain (similar to c-Cbl ubiquitin E3 ligase) and a C-terminal domain. DCN-1 directly binds Rbx-1, a factor important for neddylation, consistent with DCN-1 functioning as a scaffold protein in a multisubunit neddylation E3 ligase complex.\",\n      \"method\": \"X-ray crystallography (1.9 Å), biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with biochemical validation of Rbx-1 binding\",\n      \"pmids\": [\"17597076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mammalian DCN-like (DCNL) proteins form stable stoichiometric complexes with CAND1 and cullins that can only be neddylated in the presence of a substrate adaptor, suggesting these CAND-cullin-DCNL complexes represent 'reserve' CRLs. All five DCNLs interact with most cullin subtypes but neddylate different subpopulations of any given cullin, with specificity determined by subcellular localization and tissue-specific expression.\",\n      \"method\": \"Biochemical co-immunoprecipitation, stoichiometric complex analysis, subcellular localization studies, tissue expression profiling\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal co-IP and localization studies in mammalian cells, single lab\",\n      \"pmids\": [\"26906416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The proteoglycan decorin (DCN) is released by ferroptotic cells via secretory autophagy and lysosomal exocytosis, and extracellular DCN binds to the receptor AGER on macrophages to trigger NFKB-dependent pro-inflammatory cytokine production. Pharmacological and genetic inhibition of the DCN-AGER axis protects against ferroptotic death-related acute pancreatitis.\",\n      \"method\": \"Genetic and pharmacological inhibition, receptor binding assays, cytokine production assays, mouse models of acute pancreatitis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic KO, pharmacological inhibition, receptor binding, in vivo models) with strong evidence\",\n      \"pmids\": [\"34964698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"OTUB1 (a deubiquitinating enzyme) interacts with DCN in mesangial cells as shown by co-immunoprecipitation; OTUB1 overexpression enhances ubiquitination and degradation of DCN, suggesting DCN stability is regulated via ubiquitin-dependent proteasomal degradation with OTUB1 as a key regulator.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, overexpression studies in cultured rat mesangial cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/pulldown with functional follow-up, single lab\",\n      \"pmids\": [\"22279542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Methylation of the +58CpG site in the DCN 5'-UTR reduces recruitment of the transcriptional activator AhR to the DCN promoter region, causing ~50% reduction in DCN transcriptional activity and consequent enhancement of TGF-β/Smad3 signaling and downregulation of E-cadherin in NSCLC cells with high metastatic potential.\",\n      \"method\": \"Bisulfite sequencing, ChIP assay, EMSA, luciferase reporter assay, demethylation with 5-Aza treatment\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, EMSA, luciferase, bisulfite sequencing) in a single lab\",\n      \"pmids\": [\"24424784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NecroX-5 treatment in hypoxia/reoxygenation-injured rat hearts increases decorin (Dcn) expression while attenuating TGFβ1 expression and Smad2 phosphorylation, placing DCN upstream of TGFβ1/Smad2 signaling in a TNFα/Dcn/TGFβ1/Smad2 pathway regulating cardiac inflammation and fibrosis.\",\n      \"method\": \"In vivo rat heart hypoxia/reoxygenation model, LPS-stimulated H9C2 cells, Western blot for pathway components\",\n      \"journal\": \"The Korean journal of physiology & pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pharmacological approach with pathway inference, no direct mechanistic reconstitution\",\n      \"pmids\": [\"27162485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DCN knockdown in breast stromal fibroblasts activates STAT3/AUF1 signaling, modulates CAF biomarkers (α-SMA, FAP-α, SDF-1, IL-6), and promotes epithelial-to-mesenchymal transition and stemness in breast cancer cells in a paracrine manner; ectopic DCN expression in CAFs suppresses their pro-carcinogenic effects.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, paracrine co-culture assays, orthotopic mouse tumor model, Western blot for signaling pathway components\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with defined signaling pathway readouts, in vitro and in vivo\",\n      \"pmids\": [\"38667295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EGR3 acts as a transcriptional activator of DCN in liver cancer cells, directly binding to the DCN promoter as validated by ChIP and luciferase reporter assays; DCN overexpression suppresses proliferation, invasion, and migration while promoting apoptosis, and EGR3 knockdown reverses these tumor-suppressive effects.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA knockdown, overexpression (pcDNA3.1-DCN), rescue co-transfection experiments\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, luciferase, rescue experiments) in single lab\",\n      \"pmids\": [\"40660758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Progranulin (PGRN) suppresses H. pylori-induced autophagy by downregulating DCN expression through the mTOR pathway; DCN acts downstream of PGRN/mTOR signaling to regulate autophagic responses that otherwise restrict intracellular H. pylori colonization in gastric epithelial cells.\",\n      \"method\": \"In vitro and in vivo H. pylori infection models, overexpression/knockdown of PGRN and DCN, mTOR pathway inhibitor experiments\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pharmacological and genetic approaches but limited mechanistic reconstitution of DCN-specific role\",\n      \"pmids\": [\"39145305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DCN1-5 (mammalian DCNL proteins) are E3 ligases of the neddylation pathway that selectively catalyze cullin neddylation, thereby mediating activation of Cullin-RING Ligases (CRLs) and modulating downstream target protein activity; DCN1 inhibitors have been developed targeting this catalytic function.\",\n      \"method\": \"Review synthesizing biochemical, structural and medicinal chemistry data on DCN1-5\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — review corroborating established mechanistic findings from multiple labs including structural and enzymatic data\",\n      \"pmids\": [\"41730487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DCN overexpression in hepatocytes alleviates H2O2-induced injury by upregulating HIF1A; HIF1A inhibition with LW6 reverses the protective effect of DCN on hepatocyte proliferation, apoptosis, autophagy, and oxidative stress, establishing a DCN/HIF1A axis in liver regeneration.\",\n      \"method\": \"Overexpression and knockdown plasmids, H2O2-induced hepatocyte injury model, HIF1A inhibitor (LW6), in vitro cell functional assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pharmacological and genetic approach but mechanistic link is indirect\",\n      \"pmids\": [\"41468793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DCN frameshift mutation (p.His317Thrfs*11) in congenital stromal corneal dystrophy results in a truncated decorin protein that accumulates predominantly in widened interlamellar spaces, associated with disorganized collagen fibril formation and irregular lamellar collagen spacing, demonstrating DCN's structural role in regulating collagen fibril organization in the corneal stroma.\",\n      \"method\": \"Genetic sequencing, light and electron microscopy, immunofluorescence of excised corneal tissue\",\n      \"journal\": \"Cornea\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetic variant with direct tissue-level structural validation by electron microscopy and immunofluorescence\",\n      \"pmids\": [\"36534610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DCN suppresses myofibroblast activation by reducing pro-fibrotic gene expression, α-SMA levels, and cell contractility in vocal fold fibroblasts; DCN is downregulated during fibrotic wound healing and its delivery via hyaluronic acid microgels prevents collagen deposition and myofibroblast activation in a rat model of vocal fold scarring.\",\n      \"method\": \"Transcriptomics, in vitro myofibroblast activation assays, α-SMA quantification, rat in vivo scarring model with controlled DCN delivery\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic assays plus in vivo validation, but preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DCN treatment of cardiac organoids activates AMPK signaling, which drives mitochondrial biogenesis, enhanced fatty acid oxidation, increased mitophagy, and structural maturation (aligned sarcomeres, t-tubules, vessel formation); AMPK knockdown in DCN-treated organoids reverses these maturation effects.\",\n      \"method\": \"Cardiac organoid culture, DCN protein treatment, transcriptional profiling, AMPK knockdown, functional cardiac assays (Ca2+ transient, contraction-relaxation)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, mechanistic pathway proposed with genetic rescue but not independently replicated\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Decorin (DCN) is a small leucine-rich proteoglycan that functions as a scaffold/E3 ligase component promoting cullin neddylation (via the conserved DCN-1/DCNL family), directly binds Nedd8 and Rbx-1, and in its extracellular proteoglycan form antagonizes TGF-β signaling, regulates collagen fibril organization, acts as a DAMP that signals through AGER upon ferroptotic release to trigger NF-κB-dependent inflammation, and is transcriptionally regulated by AhR (via CpG methylation) and EGR3, with its protein stability controlled by OTUB1-mediated ubiquitination.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1986,\n      \"finding\": \"The decorin (DCN) core protein was cloned from a human fibroblast cDNA library, revealing a prepro-protein of 329 amino acids with a signal peptide, propeptide, and mature core containing leucine-rich repeats; the protein is expressed as two related transcripts (~1.6 and ~1.9 kb) from a single gene.\",\n      \"method\": \"cDNA cloning, cDNA library screening with antibodies, protein sequencing, RNA blot hybridization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original structural characterization with protein sequencing, cDNA cloning, and RNA blot; foundational paper\",\n      \"pmids\": [\"3484330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Stable ectopic expression of human decorin in Chinese hamster ovary (CHO) cells suppresses cell proliferation and reduces saturation density by more than 50%, demonstrating a direct growth-inhibitory role for DCN.\",\n      \"method\": \"Stable cDNA transfection in CHO cells, growth curve / saturation density assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct gain-of-function experiment with dose-dependent phenotype; foundational paper >250 citations\",\n      \"pmids\": [\"3194009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"DCN core protein contains a series of leucine-rich repeats homologous to those in biglycan and other LRR-domain proteins, establishing the structural basis of the SLRP family.\",\n      \"method\": \"cDNA cloning and protein sequence comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — sequence analysis confirmed by protein biochemistry; >600 citations\",\n      \"pmids\": [\"2647739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Decorin binds directly to TGF-β and neutralizes its activity; CHO cells overexpressing decorin show growth suppression that is attributable at least in part to sequestration of autocrine TGF-β, placing DCN in a feedback loop regulating cell growth.\",\n      \"method\": \"Co-immunoprecipitation / binding assay (decorin–TGF-β complex), functional growth assay in CHO cells with TGF-β neutralization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding demonstrated and functionally validated; >1400 citations\",\n      \"pmids\": [\"2374594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The DCN gene was mapped to human chromosome 12p12.1-qter by Southern analysis of somatic cell hybrids.\",\n      \"method\": \"Southern blot analysis of human-rodent somatic cell hybrid panel\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping experiment; localization finding\",\n      \"pmids\": [\"1968422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"DCN binds directly to collagen type VI via its protein core (not the glycosaminoglycan chain) with moderate affinity (Kd ~300 nM), as shown by solid-phase binding assays with recombinant core protein and competitive inhibition.\",\n      \"method\": \"Solid-phase binding assay with 125I-decorin, recombinant fusion protein competition, isolated core protein competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding reconstituted with multiple controls; >300 citations\",\n      \"pmids\": [\"1544908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"DCN is actively transcribed in mesenchymal cells but not in endothelial or epithelial cells in culture; in situ hybridization placed the single DCN gene to chromosome 12q21–q22.\",\n      \"method\": \"Northern blot, in situ hybridization on human tissues and cell lines\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct expression and localization experiment; single study\",\n      \"pmids\": [\"1611907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"DCN core protein (and those of biglycan and fibromodulin) binds TGF-β1, -β2, and -β3 with a two-site model (high-affinity Kd ~1–20 nM, low-affinity Kd ~50–200 nM); the glycosaminoglycan chain of decorin partially hinders TGF-β binding; decorin competes with betaglycan and type-I receptors but not type-II receptors for TGF-β binding on cells.\",\n      \"method\": \"Radioligand binding assay with maltose-binding-protein fusion cores, affinity measurements, competitive binding on Mv 1 Lu and endothelial cells, affinity labeling\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative in vitro binding with multiple orthogonaol methods; >840 citations\",\n      \"pmids\": [\"8093006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"DCN is cleaved by MMP-2, MMP-3, and MMP-7 (but not MMP-1 or MMP-9); specific cleavage sites were identified (Leu211 and Leu244 region); MMP-7 has ~4.5-fold higher catalytic efficiency (kcat/Km) than MMP-2/3; MMP-mediated degradation of DCN releases bound TGF-β1 from the DCN–TGF-β1 complex.\",\n      \"method\": \"In vitro enzymatic cleavage, N-terminal sequencing of fragments, kinetic analysis (Km, kcat), TGF-β release assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with kinetic parameters, cleavage sites identified; >350 citations\",\n      \"pmids\": [\"9148753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Decorin activates the EGF receptor (EGFR) and downstream MAP kinase, induces endogenous p21 (CDKN1A), and causes cell cycle arrest in A431 squamous carcinoma cells; this pathway is responsible for decorin's growth-suppressive effect.\",\n      \"method\": \"Exogenous protein addition and transgene expression, EGFR/MAP kinase phosphorylation assays, p21 induction by Western blot, growth suppression assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissected with multiple orthogonal methods across cell lines; >236 citations\",\n      \"pmids\": [\"9435313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Decorin directly binds the EGFR ectodomain with Kd ~87 nM via its protein core; binding induces EGFR dimerization, autophosphorylation, and MAP kinase activation, and decorin also acts as an EGFR kinase substrate in a cell-free system.\",\n      \"method\": \"Radioligand binding assays with immobilized/soluble decorin and EGFR ectodomain, cell-free autophosphorylation assay, dimerization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding and enzymatic assay with purified components; >326 citations\",\n      \"pmids\": [\"9988678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Decorin binds to a specific narrow region in the L2 ligand-binding domain of EGFR; the central leucine-rich repeat 6 of decorin is required for EGFR interaction; a cluster of residues His394–Ile402 in EGFR is essential for decorin binding (partially overlapping but distinct from the EGF-binding epitope).\",\n      \"method\": \"Expression cloning screen (decorin/alkaline phosphatase chimera vs. cDNA library), yeast two-hybrid, EGFR deletion mutant panel, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple complementary methods including mutagenesis and expression cloning; >194 citations\",\n      \"pmids\": [\"12105206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Decorin directly binds the Met receptor (HGF receptor) with high affinity (Kd ~1.5 nM); binding induces transient Met activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life ~6 min); decorin thereby suppresses β-catenin levels and inhibits Met-mediated cell migration and growth.\",\n      \"method\": \"Direct binding assay, displacement by HGF and internalin B, co-immunoprecipitation of c-Cbl, pulse-chase degradation assay, β-catenin Western blot, migration and growth assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative binding, receptor degradation kinetics, and downstream signaling all validated; >200 citations\",\n      \"pmids\": [\"19433454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DCN has a broad binding repertoire including collagens (collagen I, VI), TGF-β ligands, and multiple receptor tyrosine kinases (EGFR, Met); it antagonizes pro-tumorigenic signals by sequestering growth factors and directly down-regulating RTK activity in the tumor stroma.\",\n      \"method\": \"Review synthesizing binding assay, co-IP, cell-based functional data from multiple primary studies\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — synthesis of multiple independent experimental findings; >262 citations\",\n      \"pmids\": [\"22735579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"OTUB1, a deubiquitinase, interacts with DCN protein in mesangial cells (co-immunoprecipitation); OTUB1 overexpression promotes ubiquitination and proteasomal degradation of DCN, thereby reducing DCN levels during inflammatory glomerular injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression of OTUB1, Western blot and quantitative RT-PCR in cultured rat mesangial cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional ubiquitination assay; single study\",\n      \"pmids\": [\"22279542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Methylation of the +58CpG site in the DCN 5'-UTR reduces binding of the transcriptional activator AhR to this site, causing ~50% reduction in DCN transcriptional activity; this epigenetic silencing of DCN in high-metastatic NSCLC cells leads to elevated p-Smad3 and reduced E-cadherin, promoting TGF-β/Smad signaling.\",\n      \"method\": \"Bisulfite sequencing, ChIP assay, EMSA, luciferase reporter assay, 5-Aza demethylation rescue, Western blot\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (EMSA, ChIP, reporter, rescue) in single study\",\n      \"pmids\": [\"24424784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DCN overexpression in renal cell carcinoma cells significantly upregulates p21 and E-cadherin, suppressing proliferation and metastasis in vitro and in vivo.\",\n      \"method\": \"Gain-of-function (DCN cDNA transfection), proliferation and invasion assays in vitro, xenograft in vivo, Western blot for p21 and E-cadherin\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with defined molecular readouts; single study\",\n      \"pmids\": [\"26547587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During ferroptosis, DCN is actively released from dying cells via secretory autophagy and lysosomal exocytosis; extracellular DCN then binds AGER (RAGE) on macrophages and triggers NF-κB-dependent production of pro-inflammatory cytokines, mediating the immune consequences of ferroptotic death.\",\n      \"method\": \"Inhibition of secretory autophagy and lysosomal exocytosis (pharmacological and genetic), co-immunoprecipitation/binding of DCN with AGER, cytokine assays, NF-κB reporter, in vivo models of acute pancreatitis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — binding partner identified, secretion mechanism dissected with pharmacological/genetic tools, and in vivo validation; >100 citations\",\n      \"pmids\": [\"34964698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DCN knockdown in breast stromal fibroblasts activates the STAT3/AUF1 signaling axis, upregulates CAF biomarkers (α-SMA, FAP-α, SDF-1, IL-6), and promotes epithelial-to-mesenchymal transition and stemness in breast cancer cells in a paracrine manner; ectopic DCN expression in CAFs reverses these pro-carcinogenic effects.\",\n      \"method\": \"siRNA knockdown and ectopic expression of DCN, Western blot, invasion/proliferation assays, STAT3/AUF1 pathway analysis, orthotopic tumor mouse model\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with defined signaling pathway; single study\",\n      \"pmids\": [\"38667295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EGR3 directly binds to the DCN promoter and acts as a transcriptional activator of DCN in liver cancer cells; EGR3 knockdown reduces DCN expression and reverses DCN's tumor-suppressive effects on proliferation, apoptosis, invasion, and migration.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA knockdown of EGR3, rescue co-transfection (si-EGR3 + pcDNA3.1-DCN), functional assays (CCK-8, colony formation, flow cytometry, Transwell)\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase validate direct transcriptional regulation; rescue experiment confirms axis; single study\",\n      \"pmids\": [\"40660758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dcn overexpression protects hepatocytes from H2O2-induced injury by upregulating HIF1A; pharmacological inhibition of HIF1A reverses this protective effect, establishing a Dcn/HIF1A axis that modulates hepatocyte proliferation, apoptosis, autophagy, and oxidative stress.\",\n      \"method\": \"Overexpression and knockdown plasmids in BRL cells, H2O2 injury model, HIF1A inhibitor (LW6), cell viability/cycle/autophagy/oxidative stress assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with inhibitor rescue; single in vitro study\",\n      \"pmids\": [\"41468793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Controlled release of DCN protein from hyaluronic acid microgels suppresses vocal fold myofibroblast activation by reducing pro-fibrotic gene expression, α-SMA levels, and cell contractility; in a rat vocal fold scarring model, DCN-loaded microgels prevented collagen deposition and myofibroblast accumulation.\",\n      \"method\": \"Transcriptomics of human VF myofibroblasts, DCN protein treatment with functional readouts (α-SMA, gene expression, contractility), microgel encapsulation, in vivo rat VF scarring model with histological analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic assays plus in vivo model; preprint, not yet peer reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Decorin (DCN) is a small leucine-rich proteoglycan secreted into the extracellular matrix that acts as a pleiotropic signaling regulator: it directly binds and sequesters TGF-β (with high nanomolar affinity) to suppress TGF-β/Smad signaling, binds collagen VI via its protein core to regulate matrix architecture, and acts as an antagonistic ligand of EGFR (Kd ~87 nM) and Met (Kd ~1.5 nM), inducing transient receptor activation followed by c-Cbl–mediated ubiquitination and degradation of Met, EGFR/MAP kinase/p21-driven cell cycle arrest, and suppression of β-catenin; MMP-2, MMP-3, and MMP-7 proteolytically cleave DCN at defined sites, releasing bound TGF-β; DCN transcription is activated directly by EGR3 and is epigenetically silenced by +58CpG methylation (which displaces AhR); OTUB1 promotes ubiquitination and proteasomal degradation of DCN protein; during ferroptosis DCN is released via secretory autophagy/lysosomal exocytosis and signals through AGER/NF-κB on macrophages to drive innate immune responses; and loss of DCN in stromal fibroblasts activates the STAT3/AUF1 axis to promote cancer-associated fibroblast phenotypes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Decorin (DCN) is a multifunctional small leucine-rich proteoglycan that operates both intracellularly as a neddylation co-E3 ligase component and extracellularly as a regulator of collagen fibrillogenesis, TGF-β signaling, and inflammatory responses. The DCN/DCNL family directly binds Nedd8, Rbx-1, and cullins to catalyze cullin neddylation, thereby activating Cullin-RING Ligases; specificity among the five mammalian DCNLs is determined by subcellular localization and tissue expression, and DCNL–CAND1–cullin complexes serve as substrate-dependent reserve CRLs [PMID:15988528, PMID:17597076, PMID:26906416, PMID:41730487]. As a secreted proteoglycan, DCN is essential for collagen fibril organization—loss-of-function frameshift mutations cause congenital stromal corneal dystrophy with disorganized lamellar collagen [PMID:36534610]—and it antagonizes TGF-β/Smad signaling, suppresses myofibroblast activation, and acts as a tumor-suppressive paracrine factor that restrains epithelial-to-mesenchymal transition via STAT3/AUF1 modulation [PMID:24424784, PMID:38667295]. DCN also functions as a damage-associated molecular pattern released by ferroptotic cells through secretory autophagy, engaging AGER on macrophages to activate NF-κB-dependent inflammation [PMID:34964698].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that DCN-1/Dcn1p is a conserved positive regulator of cullin neddylation resolved how neddylation efficiency is controlled beyond the E1-E2 cascade, showing DCN-1 directly binds Nedd8 and cullins to accelerate neddylation kinetics.\",\n      \"evidence\": \"Genetic loss-of-function in C. elegans and S. cerevisiae combined with in vitro binding and neddylation kinetics assays\",\n      \"pmids\": [\"15988528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DCN-1 accelerates neddylation (E3-like catalysis vs. scaffold) not fully resolved\", \"No structural model at this stage\", \"Mammalian DCNL family members not yet characterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The crystal structure of DCN-1 revealed an all-alpha-helical fold with an EF-hand-like N-terminal domain resembling c-Cbl ubiquitin E3 ligase and demonstrated direct Rbx-1 binding, establishing DCN-1 as a scaffold/E3 component within a multisubunit neddylation ligase.\",\n      \"evidence\": \"X-ray crystallography at 1.9 Å resolution with biochemical binding assays\",\n      \"pmids\": [\"17597076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full reconstitution of the neddylation E3 complex with all subunits not achieved\", \"Structural basis of DCN-1–cullin interface unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of OTUB1 as a DCN-interacting partner that paradoxically enhances DCN ubiquitination and degradation revealed a post-translational mechanism controlling extracellular DCN levels.\",\n      \"evidence\": \"Co-immunoprecipitation and overexpression studies in rat mesangial cells\",\n      \"pmids\": [\"22279542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"OTUB1 normally acts as a deubiquitinase—mechanism of pro-degradation activity on DCN not clarified\", \"Not confirmed in other cell types\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that CpG methylation at +58 in the DCN 5'-UTR reduces AhR recruitment to the DCN promoter, thereby diminishing DCN transcription and unleashing TGF-β/Smad3 signaling, linked epigenetic silencing of DCN to metastatic potential in NSCLC.\",\n      \"evidence\": \"Bisulfite sequencing, ChIP, EMSA, and luciferase reporter assays in NSCLC cell lines\",\n      \"pmids\": [\"24424784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this methylation event is a driver or passenger of metastatic progression not established\", \"AhR–DCN axis not validated in non-lung cancers\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Characterization of mammalian DCNL1-5 showed they form stoichiometric CAND1–cullin–DCNL reserve complexes that are neddylated only upon substrate-adaptor engagement, explaining how cells maintain latent CRL pools and how different DCNLs achieve cullin subtype specificity through localization.\",\n      \"evidence\": \"Biochemical co-immunoprecipitation, stoichiometric complex analysis, subcellular localization and tissue expression profiling\",\n      \"pmids\": [\"26906416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study; independent replication across cell types needed\", \"Structural basis of DCNL–CAND1–cullin ternary complex not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that ferroptotic cells release decorin via secretory autophagy and lysosomal exocytosis, and that extracellular DCN engages AGER on macrophages to trigger NF-κB-dependent cytokine production, established DCN as a DAMP linking ferroptosis to sterile inflammation.\",\n      \"evidence\": \"Genetic and pharmacological inhibition of DCN–AGER axis, receptor binding assays, cytokine readouts, and mouse acute pancreatitis models\",\n      \"pmids\": [\"34964698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DCN–AGER signaling operates in ferroptosis contexts beyond pancreatitis is unknown\", \"Direct structural basis of DCN–AGER interaction not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A DCN frameshift mutation (p.His317Thrfs*11) causing congenital stromal corneal dystrophy, with truncated decorin accumulating in widened interlamellar spaces and disrupting collagen fibril organization, provided direct human genetic proof that DCN is essential for corneal collagen architecture.\",\n      \"evidence\": \"Genetic sequencing combined with electron microscopy and immunofluorescence of excised corneal tissue\",\n      \"pmids\": [\"36534610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether truncated DCN exerts a dominant-negative effect versus haploinsufficiency not resolved\", \"No functional rescue experiment performed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that DCN loss in stromal fibroblasts activates STAT3/AUF1 and promotes cancer-associated fibroblast features and paracrine epithelial-to-mesenchymal transition, while ectopic DCN reverses these effects, established DCN as a stromal tumor suppressor regulating the breast cancer microenvironment.\",\n      \"evidence\": \"siRNA knockdown and ectopic overexpression in stromal fibroblasts, paracrine co-culture, orthotopic mouse tumor model\",\n      \"pmids\": [\"38667295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DCN target mediating STAT3/AUF1 suppression not identified\", \"Applicability beyond breast cancer stroma not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"EGR3 was identified as a direct transcriptional activator of DCN in hepatocellular carcinoma, with DCN mediating EGR3's tumor-suppressive effects on proliferation, invasion, and apoptosis, adding a second transcription factor axis controlling DCN expression.\",\n      \"evidence\": \"ChIP assay, luciferase reporter, siRNA knockdown, and rescue co-transfection in liver cancer cells\",\n      \"pmids\": [\"40660758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EGR3–DCN axis not validated in non-hepatic contexts\", \"Downstream effector pathway of DCN-mediated apoptosis not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DCN's dual identity—as an intracellular neddylation E3 co-factor (DCNL family) and as an extracellular proteoglycan/DAMP—is coordinated remains unresolved, and structural details of DCN–AGER engagement, the mechanism by which OTUB1 promotes DCN degradation, and whether tissue-specific DCN isoforms differentially regulate CRL activation versus extracellular signaling are open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model connecting intracellular neddylation function with extracellular proteoglycan signaling\", \"Structural basis of DCN–AGER interaction undetermined\", \"OTUB1-mediated DCN degradation mechanism not reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 2, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 12, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"complexes\": [\n      \"CAND1-cullin-DCNL reserve complex\",\n      \"Cullin-RING Ligase (CRL) neddylation complex\"\n    ],\n    \"partners\": [\n      \"NEDD8\",\n      \"RBX1\",\n      \"CAND1\",\n      \"CUL1\",\n      \"AGER\",\n      \"OTUB1\",\n      \"AHR\",\n      \"EGR3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Decorin (DCN) is a secreted small leucine-rich proteoglycan that orchestrates extracellular matrix architecture and growth factor signaling by acting simultaneously as a collagen-binding scaffold, a TGF-β sequestrant, and an antagonistic ligand of receptor tyrosine kinases. The DCN core protein binds TGF-β1/2/3 with nanomolar affinity, neutralizing TGF-β bioactivity; MMP-2, MMP-3, and MMP-7 proteolytically degrade DCN at defined leucine residues, releasing sequestered TGF-β and providing a regulated mechanism for TGF-β mobilization [PMID:2374594, PMID:9148753]. DCN also binds EGFR (Kd ~87 nM) and Met (Kd ~1.5 nM), triggering transient receptor activation that leads to p21-dependent cell cycle arrest (via EGFR/MAPK) and c-Cbl-mediated ubiquitination and degradation of Met with consequent β-catenin suppression [PMID:9988678, PMID:19433454]. Beyond its matrix and RTK functions, DCN is released during ferroptosis via secretory autophagy and signals through AGER/NF-κB on macrophages to elicit innate immune cytokine responses [PMID:34964698].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Cloning the DCN cDNA revealed the primary structure of a leucine-rich repeat proteoglycan, establishing the molecular identity of decorin as a secreted SLRP.\",\n      \"evidence\": \"cDNA library screening, protein sequencing, and RNA blot from human fibroblasts\",\n      \"pmids\": [\"3484330\", \"2647739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biological function of the leucine-rich repeat architecture was unknown\",\n        \"Binding partners of the core protein had not been identified\"\n      ]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Discovery that DCN directly binds and neutralizes TGF-β provided the first mechanistic explanation for its growth-inhibitory activity, identifying DCN as an extracellular TGF-β trap.\",\n      \"evidence\": \"Co-immunoprecipitation of decorin–TGF-β complex and functional growth suppression assay in CHO cells\",\n      \"pmids\": [\"2374594\", \"3194009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Affinity constants for TGF-β isoforms had not been quantified\",\n        \"Whether the GAG chain contributed to TGF-β binding was unresolved\"\n      ]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of collagen VI as a direct ligand of DCN's protein core (Kd ~300 nM) established DCN as a bifunctional molecule linking matrix architecture to growth factor regulation.\",\n      \"evidence\": \"Solid-phase binding assay with radiolabeled decorin and recombinant core protein competition\",\n      \"pmids\": [\"1544908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the collagen VI–DCN interaction was not determined\",\n        \"In vivo consequences of disrupting DCN–collagen VI binding were unknown\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Quantitative binding studies revealed a two-site model for DCN–TGF-β interaction (high-affinity Kd ~1–20 nM) and showed that DCN competes with betaglycan and type I but not type II TGF-β receptors, clarifying its mechanism of TGF-β antagonism.\",\n      \"evidence\": \"Radioligand binding with recombinant maltose-binding-protein fusion cores, competitive binding on cells, affinity labeling\",\n      \"pmids\": [\"8093006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The precise binding epitope on DCN for TGF-β was unmapped\",\n        \"Whether DCN–TGF-β sequestration operates in all tissue contexts was unclear\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstration that MMP-2, MMP-3, and MMP-7 cleave DCN at specific leucine residues and liberate sequestered TGF-β1 revealed a protease-dependent mechanism for regulated TGF-β release from the matrix.\",\n      \"evidence\": \"In vitro enzymatic cleavage with kinetic parameters, N-terminal sequencing, TGF-β release assay\",\n      \"pmids\": [\"9148753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of MMP-mediated DCN cleavage in disease contexts was not established\",\n        \"Whether other proteases contribute remained unexplored\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of EGFR as a direct DCN receptor (Kd ~87 nM) and mapping of the interaction to LRR6 on DCN and the L2 domain of EGFR established a receptor tyrosine kinase signaling axis through which DCN induces p21-dependent cell cycle arrest.\",\n      \"evidence\": \"Radioligand binding, dimerization and autophosphorylation assays with purified components, expression cloning screen, and site-directed mutagenesis\",\n      \"pmids\": [\"9988678\", \"9435313\", \"12105206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural model of the DCN–EGFR complex was lacking\",\n        \"How transient EGFR activation leads to growth suppression rather than mitogenesis was mechanistically incomplete\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that DCN binds Met with very high affinity (Kd ~1.5 nM) and triggers c-Cbl-mediated Met degradation (t½ ~6 min) expanded DCN's anti-oncogenic mechanism beyond EGFR to a second RTK, explaining suppression of β-catenin and cell migration.\",\n      \"evidence\": \"Direct binding/displacement assays, co-immunoprecipitation of c-Cbl, pulse-chase receptor degradation, functional migration assays\",\n      \"pmids\": [\"19433454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DCN targets additional RTKs was unknown\",\n        \"The relative contribution of EGFR versus Met antagonism in vivo was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"OTUB1 was identified as a DCN-interacting protein that paradoxically promotes DCN ubiquitination and proteasomal degradation, revealing a post-translational mechanism for DCN turnover during inflammation.\",\n      \"evidence\": \"Co-immunoprecipitation and ubiquitination assay in rat mesangial cells with OTUB1 overexpression\",\n      \"pmids\": [\"22279542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"OTUB1 is a deubiquitinase, so the pro-ubiquitination mechanism is paradoxical and unexplained\",\n        \"Not independently confirmed in a second cell type or species\",\n        \"The ubiquitin linkage type on DCN was not characterized\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Epigenetic silencing of DCN via +58CpG methylation, which displaces the transcriptional activator AhR, was shown to derepress TGF-β/Smad signaling in metastatic NSCLC cells, linking DCN transcriptional regulation to cancer progression.\",\n      \"evidence\": \"Bisulfite sequencing, ChIP, EMSA, luciferase reporter, and 5-Aza demethylation rescue in NSCLC cell lines\",\n      \"pmids\": [\"24424784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether +58CpG methylation operates in non-lung cancers was untested\",\n        \"The upstream signals that direct methylation at this site were not identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"DCN was identified as a damage-associated molecular pattern released during ferroptosis via secretory autophagy and lysosomal exocytosis; extracellular DCN binds AGER on macrophages and activates NF-κB-dependent cytokine production, establishing a new immunological function.\",\n      \"evidence\": \"Pharmacological and genetic inhibition of secretory autophagy/lysosomal exocytosis, DCN–AGER co-immunoprecipitation, NF-κB reporter, in vivo acute pancreatitis model\",\n      \"pmids\": [\"34964698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether AGER is the sole macrophage receptor for ferroptosis-released DCN is unconfirmed\",\n        \"The relationship between DCN's AGER signaling and its RTK-antagonistic functions is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Loss of stromal DCN was shown to activate STAT3/AUF1 signaling in fibroblasts, driving cancer-associated fibroblast conversion that promotes epithelial-to-mesenchymal transition paracrinally, revealing DCN as a suppressor of the CAF phenotype.\",\n      \"evidence\": \"siRNA knockdown and ectopic DCN expression in breast stromal fibroblasts, STAT3/AUF1 pathway analysis, orthotopic mouse model\",\n      \"pmids\": [\"38667295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The direct molecular link between DCN loss and STAT3 phosphorylation is undefined\",\n        \"Single study in breast cancer stroma; generalizability to other tumor types is untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"EGR3 was identified as a direct transcriptional activator of DCN, and a DCN/HIF1A axis was shown to protect hepatocytes from oxidative injury, broadening understanding of DCN transcriptional control and cytoprotective signaling.\",\n      \"evidence\": \"ChIP and luciferase reporter for EGR3–DCN promoter binding; overexpression/knockdown and HIF1A inhibitor rescue in hepatocyte oxidative stress model\",\n      \"pmids\": [\"40660758\", \"41468793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The mechanism by which extracellular DCN upregulates intracellular HIF1A is unknown\",\n        \"EGR3-driven DCN regulation has been shown only in liver cancer cells\",\n        \"Relationship between EGR3 and AhR/methylation-dependent DCN regulation is unexplored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural model of DCN in complex with EGFR, Met, or AGER is lacking, and the relative in vivo contribution of each receptor axis to DCN's tumor-suppressive and immunomodulatory functions remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No co-crystal or cryo-EM structure of DCN bound to any of its RTK or AGER partners\",\n        \"In vivo genetic dissection separating TGF-β sequestration from RTK antagonism has not been performed\",\n        \"Whether DCN's DAMP/AGER function and its matrix/RTK functions are coordinated or independent is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 9, 10, 12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [10, 11, 12, 17]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 5, 8, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 7, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 10, 12, 17]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5, 8, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EGFR\",\n      \"MET\",\n      \"TGFB1\",\n      \"AGER\",\n      \"COL6A1\",\n      \"OTUB1\",\n      \"EGR3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}