{"gene":"SRGN","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2020,"finding":"Secreted SRGN triggers ITGA5/FAK/CREB signaling to enhance YAP transcription; reciprocally, YAP promotes SRGN transcription in a TEAD1-dependent manner, forming a feed-forward circuit. The YAP/RUNX1 complex then promotes HDAC2 transcription to induce chemoresistance and stemness in breast cancer cells. Ectopic YAP expression restored effects of SRGN knockdown, and YAP knockdown rescued SRGN overexpression effects, establishing epistatic pathway order.","method":"Co-immunoprecipitation, luciferase reporter assay, ChIP-qPCR, shRNA knockdown, flow cytometry, mammosphere assay, in vivo xenograft, immunofluorescence","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, reporter assay, genetic rescue epistasis) in single study with in vivo validation","pmids":["32292495"],"is_preprint":false},{"year":2017,"finding":"Secreted SRGN protein activates CD44/CREB1 signaling to increase TGFβ2 expression and secretion, promoting epithelial-to-mesenchymal transition and invasion in triple-negative breast cancer cells. Conversely, TGFβ2 activates Smad3, which binds the SRGN promoter to upregulate SRGN transcription, establishing an autocrine/paracrine feed-forward regulatory loop.","method":"shRNA knockdown, recombinant protein treatment, ChIP assay, transwell invasion assay, in vivo metastasis model, Western blot, qPCR","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 — ChIP confirmed direct Smad3-SRGN promoter binding; reciprocal functional rescue and in vivo validation","pmids":["28692037"],"is_preprint":false},{"year":2024,"finding":"SRGN signals through its receptor CD44 on microglia to activate NF-κB signaling and increase glycolysis, amplifying proinflammatory microglial activation following ischemic stroke. Genetic deletion of Cd44 partially rescued rSRGN-induced excess neuroinflammation and ischemic brain injury in mice.","method":"Srgn and Cd44 knockout mice, middle cerebral artery occlusion model, stereotactic injection of recombinant SRGN, Iba1 immunostaining, cytokine measurement, TTC staining, LPS stimulation in vitro","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (Cd44 KO rescue of Srgn KO phenotype) with multiple orthogonal in vivo and in vitro readouts","pmids":["38287411"],"is_preprint":false},{"year":2018,"finding":"HIF-1α directly binds a hypoxia response element in the SRGN promoter to transcriptionally upregulate SRGN, and SRGN overexpression promotes colorectal cancer cell migration and invasion, placing SRGN as a direct downstream effector of hypoxia signaling in colorectal cancer metastasis.","method":"Chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, transwell migration/invasion assay, shRNA knockdown","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrated direct HIF-1α binding to SRGN promoter; single lab study","pmids":["30121667"],"is_preprint":false},{"year":2022,"finding":"STAT3 regulates SRGN expression in nasopharyngeal carcinoma through a FoxO1-miR-148a-5p-CREB1 axis: FoxO1 binds and activates miR-148a-5p transcription; miR-148a-5p suppresses CREB1; CREB1 directly binds the SRGN promoter to drive SRGN expression. SRGN knockdown suppressed NPC tumor progression in vitro and in vivo.","method":"EMSA, ChIP, dual-luciferase reporter assay, RIP assay, qRT-PCR, Western blot, xenograft tumor model, Transwell assay","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1–2 — EMSA and ChIP validated direct transcription factor-promoter interactions; multiple orthogonal methods and in vivo validation","pmids":["35562411"],"is_preprint":false},{"year":2022,"finding":"SRGN regulates PD-L1 expression as well as proinflammatory cytokines (IL-6, IL-8, CXCL1) in lung adenocarcinoma cells, and increases migratory and invasive properties of LUAD cells and fibroblasts and enhances angiogenesis. SRGN expression is induced by DNA demethylation resulting from NNMT-mediated impairment of methionine metabolism.","method":"siRNA knockdown, syngeneic mouse model, cytokine measurement, migration/invasion assays, proteomic and metabolomic analyses, immunohistochemistry","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotypes and in vivo syngeneic model; single lab","pmids":["34524427"],"is_preprint":false},{"year":2020,"finding":"Low shear stress enhances SRGN expression in human umbilical vein endothelial cells via the PKA/CREB-dependent signaling pathway, and SRGN high-expression cells show increased Ki67+ cell proportion and higher nitric oxide concentration, implicating SRGN in endothelial cell proliferation in response to shear stress.","method":"In vitro shear stress loading in HUVECs, in vivo partial carotid artery ligation in mice, PKA/CREB inhibitor experiments, Ki67 staining, NO concentration measurement, bioinformatics analysis of zebrafish high-throughput data","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic pathway (PKA/CREB) identified by pharmacological inhibition; in vivo and in vitro corroboration; single lab","pmids":["32712749"],"is_preprint":false},{"year":2019,"finding":"SNHG3 (lncRNA) modulates SRGN expression by competitively sponging miR-758-3p; miR-758-3p targets SRGN mRNA; knockdown of SNHG3 decreased SRGN and inhibited AML cell proliferation while inducing apoptosis, and these effects were rescued by miR-758-3p suppression or SRGN overexpression.","method":"siRNA knockdown, luciferase reporter assay (implied), qRT-PCR, Western blot, flow cytometry for apoptosis, CCK-8 proliferation assay, miRNA target validation","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — genetic rescue epistasis established pathway order; single lab with multiple functional readouts","pmids":["31452272"],"is_preprint":false},{"year":2025,"finding":"SRGN activates YAP nuclear translocation in hepatocellular carcinoma cells, and YAP/TEAD1 complex directly targets the CRISPLD2 promoter to upregulate CRISPLD2, establishing a SRGN/YAP/CRISPLD2 axis that promotes HCC metastasis and stemness maintenance in an autocrine manner.","method":"In vitro migration assays, in vivo experiments, reporter assays, knockdown and overexpression of SRGN/YAP/CRISPLD2, nuclear/cytoplasmic fractionation for YAP localization","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway order established by genetic manipulation; single lab; YAP/TEAD1-CRISPLD2 link validated by reporter assay","pmids":["40384866"],"is_preprint":false},{"year":2024,"finding":"SRGN in chondrocytes promotes recruitment of THP-1-derived macrophages by upregulating CCL3 expression and secretion; siRNA-mediated SRGN knockdown reduced CCL3 and impaired macrophage migration in a transwell co-culture model.","method":"siRNA knockdown, plasmid overexpression, conditioned media co-culture, transwell macrophage migration assay, qPCR, Western blot, ELISA for CCL3","journal":"Connective tissue research","confidence":"Medium","confidence_rationale":"Tier 3 — clean mechanistic link (SRGN→CCL3→macrophage migration) with multiple concordant methods; single lab in vitro only","pmids":["39067006"],"is_preprint":false},{"year":2026,"finding":"ALKBH5-mediated m6A demethylation of Srgn mRNA enhances its stability, leading to increased SRGN protein in Sertoli cells exposed to palmitic acid. Elevated SRGN then activates NF-κB and MAPK pathways, upregulating Ccl2 and TNF-α, thereby disrupting blood-testis barrier integrity. Suppressing Alkbh5 alleviated this BTB disruption.","method":"siRNA knockdown of Alkbh5, Srgn overexpression and knockdown, m6A methylation assay, RNA stability assay, NF-κB and MAPK pathway analysis, Western blot, tight junction integrity assays in TM4 and primary Sertoli cells","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — RNA m6A modification mechanism with writer (ALKBH5) identified; multiple pathway validations; single lab","pmids":["41910735"],"is_preprint":false}],"current_model":"SRGN (Serglycin) is a secreted chondroitin sulfate proteoglycan that signals through CD44 and integrin receptors to activate downstream kinase cascades (FAK/CREB, PKA/CREB, NF-κB, MAPK), transcriptional coactivators (YAP/TEAD1), and epigenetic regulators (HDAC2), thereby promoting tumor invasion, immune modulation, and inflammatory responses; its expression is transcriptionally controlled by HIF-1α (via hypoxia response elements), CREB1, STAT3/FoxO1/miR-148a-5p axis, and TGFβ2/Smad3, and post-transcriptionally stabilized by ALKBH5-mediated m6A demethylation."},"narrative":{"teleology":[{"year":2017,"claim":"Establishing that secreted SRGN is not merely a structural proteoglycan but an autocrine/paracrine signaling molecule that engages CD44 to activate CREB1 and TGFβ2, forming a feed-forward loop with Smad3-driven SRGN transcription to promote EMT and invasion.","evidence":"ChIP for Smad3 on SRGN promoter, shRNA knockdown, recombinant protein treatment, and in vivo metastasis model in TNBC cells","pmids":["28692037"],"confidence":"High","gaps":["CD44-CREB1 signaling intermediates not fully mapped","Glycosaminoglycan chain requirement for CD44 engagement not tested","Feed-forward loop dynamics not quantified"]},{"year":2018,"claim":"Identifying HIF-1α as a direct transcriptional activator of SRGN through a hypoxia response element, linking SRGN upregulation to the tumor hypoxic microenvironment.","evidence":"ChIP showing HIF-1α binding to SRGN promoter, shRNA knockdown, and transwell assays in colorectal cancer cells","pmids":["30121667"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Contribution of hypoxia-induced SRGN relative to other HIF-1α targets not dissected","No in vivo hypoxia validation"]},{"year":2019,"claim":"Demonstrating post-transcriptional regulation of SRGN via a ceRNA mechanism (SNHG3/miR-758-3p/SRGN axis), showing that SRGN levels can be modulated by non-coding RNA networks in AML.","evidence":"miRNA target validation, genetic rescue epistasis with SNHG3 knockdown and miR-758-3p inhibition in AML cells","pmids":["31452272"],"confidence":"Medium","gaps":["In vitro only with no in vivo validation","Direct miR-758-3p binding site on SRGN 3′UTR not confirmed by mutation","Physiological relevance to AML progression unclear"]},{"year":2020,"claim":"Deciphering the SRGN/ITGA5/FAK/CREB/YAP/HDAC2 signaling cascade that establishes a feed-forward transcriptional circuit driving chemoresistance and stemness in breast cancer, and separately showing that PKA/CREB mediates shear-stress-induced SRGN expression in endothelial cells.","evidence":"Co-IP, ChIP-qPCR, luciferase reporters, epistasis via YAP knockdown/overexpression, xenograft models (breast cancer); PKA/CREB inhibitors and carotid ligation model (endothelial cells)","pmids":["32292495","32712749"],"confidence":"High","gaps":["ITGA5 as direct SRGN receptor not validated by binding assay","Relative contribution of FAK vs other integrin-proximal kinases unknown","PKA/CREB-SRGN link in endothelial cells relies on pharmacological inhibition"]},{"year":2022,"claim":"Mapping a STAT3/FoxO1/miR-148a-5p/CREB1 regulatory cascade converging on SRGN promoter activation, and confirming SRGN's role in immune evasion through PD-L1 upregulation and proinflammatory cytokine induction in lung adenocarcinoma.","evidence":"EMSA, ChIP, dual-luciferase reporter, and xenograft models (NPC); siRNA knockdown with cytokine profiling and syngeneic models (LUAD)","pmids":["35562411","34524427"],"confidence":"High","gaps":["SRGN-to-PD-L1 signaling intermediates not identified","NNMT-DNA methylation-SRGN link is correlative without direct demethylation rescue","Whether STAT3 axis and HIF-1α axis converge on SRGN promoter simultaneously is unknown"]},{"year":2024,"claim":"Establishing CD44 as a genetically validated SRGN receptor in vivo through Cd44-knockout rescue of SRGN-driven neuroinflammation, and identifying SRGN-dependent CCL3 secretion as a macrophage chemoattractant mechanism in chondrocytes.","evidence":"Srgn-KO and Cd44-KO mice with MCAO stroke model and recombinant SRGN injection; siRNA knockdown with transwell macrophage migration in chondrocyte co-culture","pmids":["38287411","39067006"],"confidence":"High","gaps":["Glycosaminoglycan chain versus core protein requirement for CD44 binding not dissected","CCL3 induction mechanism downstream of SRGN not identified","Chondrocyte findings are in vitro only"]},{"year":2025,"claim":"Extending the SRGN/YAP axis to hepatocellular carcinoma and identifying CRISPLD2 as a direct YAP/TEAD1 transcriptional target mediating SRGN-driven HCC metastasis and stemness.","evidence":"Reporter assays for YAP/TEAD1 on CRISPLD2 promoter, nuclear fractionation, knockdown/overexpression epistasis, and in vivo HCC models","pmids":["40384866"],"confidence":"Medium","gaps":["Single lab; receptor mediating SRGN-to-YAP in HCC not identified","Whether CRISPLD2 is the principal YAP effector or one of many targets is unclear","No structural data on SRGN-receptor interaction"]},{"year":2026,"claim":"Revealing epitranscriptomic regulation of SRGN through ALKBH5-mediated m6A demethylation that stabilizes Srgn mRNA, connecting lipotoxic stress to NF-κB/MAPK activation and blood-testis barrier disruption.","evidence":"m6A methylation assay, RNA stability assay, ALKBH5 knockdown rescue, tight junction integrity assays in Sertoli cells","pmids":["41910735"],"confidence":"Medium","gaps":["Specific m6A sites on Srgn mRNA not mapped","In vivo fertility consequences not assessed","Whether ALKBH5 regulation of SRGN operates in other cell types is unknown"]},{"year":null,"claim":"The identity and structural basis of SRGN's interaction with its receptors (CD44, ITGA5) — including whether the glycosaminoglycan chains or core protein mediate binding — remain unresolved, and no structural model of SRGN-receptor complexes exists.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of SRGN or SRGN-receptor complex","GAG chain versus core protein contribution to signaling not dissected","Unified model integrating multiple receptor inputs (CD44, ITGA5) is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2,5,8,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,6,8,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,3,4,5,8]}],"complexes":[],"partners":["CD44","ITGA5","YAP1","TEAD1","CREB1","SMAD3","ALKBH5","HDAC2"],"other_free_text":[]},"mechanistic_narrative":"SRGN (serglycin) is a secreted proteoglycan that functions as an extracellular signaling molecule activating multiple receptor-mediated pathways to drive inflammation, tumor invasion, stemness, and chemoresistance. Secreted SRGN engages CD44 to activate NF-κB signaling in microglia and CREB1-dependent TGFβ2 transcription in breast cancer, and signals through ITGA5/FAK to promote YAP nuclear translocation and YAP/TEAD1-dependent transcriptional programs including HDAC2 and CRISPLD2, establishing feed-forward circuits that sustain tumor stemness and metastasis [PMID:32292495, PMID:28692037, PMID:38287411, PMID:40384866]. SRGN also activates NF-κB and MAPK cascades to induce proinflammatory cytokines (CCL2, TNF-α, IL-6, CCL3) in diverse cell types including Sertoli cells, endothelial cells, and chondrocytes [PMID:41910735, PMID:34524427, PMID:39067006]. SRGN transcription is directly regulated by HIF-1α, Smad3, and CREB1 binding to its promoter, and its mRNA is post-transcriptionally stabilized by ALKBH5-mediated m6A demethylation [PMID:30121667, PMID:35562411, PMID:41910735]."},"prefetch_data":{"uniprot":{"accession":"P10124","full_name":"Serglycin","aliases":["Hematopoietic proteoglycan core protein","Platelet proteoglycan core protein","P.PG","Secretory granule proteoglycan core protein"],"length_aa":158,"mass_kda":17.7,"function":"Plays a role in formation of mast cell secretory granules and mediates storage of various compounds in secretory vesicles. Required for storage of some proteases in both connective tissue and mucosal mast cells and for storage of granzyme B in T-lymphocytes. Plays a role in localizing neutrophil elastase in azurophil granules of neutrophils. Mediates processing of MMP2. Plays a role in cytotoxic cell granule-mediated apoptosis by forming a complex with granzyme B which is delivered to cells by perforin to induce apoptosis. Regulates the secretion of TNF and may also regulate protease secretion. Inhibits bone mineralization","subcellular_location":"Cytoplasmic granule; Cytolytic granule; Secreted, extracellular space; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/P10124/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRGN","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRGN","total_profiled":1310},"omim":[{"mim_id":"177040","title":"SERGLYCIN; SRGN","url":"https://www.omim.org/entry/177040"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":7641.5}],"url":"https://www.proteinatlas.org/search/SRGN"},"hgnc":{"alias_symbol":["PPG"],"prev_symbol":["PRG","PRG1"]},"alphafold":{"accession":"P10124","domains":[{"cath_id":"-","chopping":"29-89","consensus_level":"medium","plddt":71.6357,"start":29,"end":89}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10124","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10124-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10124-F1-predicted_aligned_error_v6.png","plddt_mean":59.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRGN","jax_strain_url":"https://www.jax.org/strain/search?query=SRGN"},"sequence":{"accession":"P10124","fasta_url":"https://rest.uniprot.org/uniprotkb/P10124.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10124/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10124"}},"corpus_meta":[{"pmid":"18571452","id":"PMC_18571452","title":"PRG-1 and 21U-RNAs interact to form the piRNA complex required for fertility in C. elegans.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18571452","citation_count":458,"is_preprint":false},{"pmid":"18501605","id":"PMC_18501605","title":"A C. elegans Piwi, PRG-1, regulates 21U-RNAs during spermatogenesis.","date":"2008","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/18501605","citation_count":222,"is_preprint":false},{"pmid":"31178117","id":"PMC_31178117","title":"Piwi/PRG-1 Argonaute and TGF-β Mediate Transgenerational Learned Pathogenic Avoidance.","date":"2019","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/31178117","citation_count":194,"is_preprint":false},{"pmid":"19766573","id":"PMC_19766573","title":"Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19766573","citation_count":122,"is_preprint":false},{"pmid":"12730698","id":"PMC_12730698","title":"A new phospholipid phosphatase, PRG-1, is involved in axon growth and regenerative sprouting.","date":"2003","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12730698","citation_count":110,"is_preprint":false},{"pmid":"26290108","id":"PMC_26290108","title":"PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation.","date":"2015","source":"American journal of physiology. 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Analysis of residual acceleration-induced motion.","date":"2003","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/12657808","citation_count":1,"is_preprint":false},{"pmid":"39200248","id":"PMC_39200248","title":"What Remote PPG Oximetry Tells Us about Pulsatile Volume?","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39200248","citation_count":0,"is_preprint":false},{"pmid":"39915794","id":"PMC_39915794","title":"MiR-18a-LncRNA NONRATG-022419 pairs targeted PRG-1 regulates diabetic induced cognitive impairment by regulating NGF\\BDNF-Trkb signaling pathway.","date":"2025","source":"Proteome science","url":"https://pubmed.ncbi.nlm.nih.gov/39915794","citation_count":0,"is_preprint":false},{"pmid":"40946583","id":"PMC_40946583","title":"Bioactive caries-preventing effects of mineral ions released from surface pre-reacted glass-ionomer (S-PRG) filler on oral biofilm.","date":"2025","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/40946583","citation_count":0,"is_preprint":false},{"pmid":"41910735","id":"PMC_41910735","title":"ALKBH5 facilitates Srgn stability via m6A demethylation to disrupt blood-testis barrier integrity in the high-fat diet mice.","date":"2026","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41910735","citation_count":0,"is_preprint":false},{"pmid":"41374551","id":"PMC_41374551","title":"Real-Time Subject-Specific Predictive Modeling of PPG Signals for Artifact-Resilient SpO2 Estimation Under Hypoxia.","date":"2025","source":"Sensors (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41374551","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.10.675458","title":"The Ubiquitin-Proteasome Pathway Mediates Selective Degradation of Unloaded Argonautes in <i>C. elegans</i>","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.10.675458","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.13.682143","title":"Evaluation of a Polarization-Sensitive, Dual-Wavelength Wearable Photoplethysmography Sensor Across a Range of Skin Tones","date":"2025-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.13.682143","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.15.25333751","title":"Heart rate monitoring using wrist photoplethysmography in Parkinson disease: feasibility and relation with autonomic dysfunction","date":"2025-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.15.25333751","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.15.25340310","title":"A photoplethysmography-based aging clock reveals genetic determinants of arterial aging","date":"2025-11-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.15.25340310","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.15.676386","title":"Exploring the Effect of LED-to-Photodetector Spacing on Subcutaneous Photoplethysmography for Continuous Blood Pressure Measurement","date":"2025-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.15.676386","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.30.25339198","title":"RAGCBPNet: An Efficient Feature Fusion Framework for Wearable Cuffless Blood Pressure Monitoring and Long-term Validation in Real-world Settings","date":"2025-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.30.25339198","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.14.25340258","title":"Electrodermal Activity as a Critical Modality for Wearable Sleep Monitoring: A Comprehensive Systematic Review from Fundamental Physiology to Clinical Translation","date":"2025-11-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.25340258","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.12.653514","title":"RG motifs promote piRNA-mediated gene silencing in <i>C. elegans</i>","date":"2025-05-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.12.653514","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52026,"output_tokens":3254,"usd":0.102444},"stage2":{"model":"claude-opus-4-6","input_tokens":6436,"output_tokens":2660,"usd":0.14802},"total_usd":0.250464,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human/mammalian gene SRGN (Serglycin), a chondroitin sulfate proteoglycan. I'll focus on papers where direct experiments established mechanistic findings about SRGN.\n\nMany papers in this corpus are about unrelated genes/topics sharing similar abbreviations (PRG-1 in C. elegans/Piwi, PRG-1 as plasticity-related gene/PLPPR4, PPG neurons, S-PRG dental fillers, PPG photoplethysmography, etc.) — these are symbol collisions and should be excluded.\n\nRelevant SRGN papers: 9, 14, 16, 22, 27, 28, 51, 55, 69, 70, 72, 91.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"Secreted SRGN triggers ITGA5/FAK/CREB signaling to enhance YAP transcription; reciprocally, YAP promotes SRGN transcription in a TEAD1-dependent manner, forming a feed-forward circuit. The YAP/RUNX1 complex then promotes HDAC2 transcription to induce chemoresistance and stemness in breast cancer cells. Ectopic YAP expression restored effects of SRGN knockdown, and YAP knockdown rescued SRGN overexpression effects, establishing epistatic pathway order.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, ChIP-qPCR, shRNA knockdown, flow cytometry, mammosphere assay, in vivo xenograft, immunofluorescence\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, reporter assay, genetic rescue epistasis) in single study with in vivo validation\",\n      \"pmids\": [\"32292495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Secreted SRGN protein activates CD44/CREB1 signaling to increase TGFβ2 expression and secretion, promoting epithelial-to-mesenchymal transition and invasion in triple-negative breast cancer cells. Conversely, TGFβ2 activates Smad3, which binds the SRGN promoter to upregulate SRGN transcription, establishing an autocrine/paracrine feed-forward regulatory loop.\",\n      \"method\": \"shRNA knockdown, recombinant protein treatment, ChIP assay, transwell invasion assay, in vivo metastasis model, Western blot, qPCR\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirmed direct Smad3-SRGN promoter binding; reciprocal functional rescue and in vivo validation\",\n      \"pmids\": [\"28692037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRGN signals through its receptor CD44 on microglia to activate NF-κB signaling and increase glycolysis, amplifying proinflammatory microglial activation following ischemic stroke. Genetic deletion of Cd44 partially rescued rSRGN-induced excess neuroinflammation and ischemic brain injury in mice.\",\n      \"method\": \"Srgn and Cd44 knockout mice, middle cerebral artery occlusion model, stereotactic injection of recombinant SRGN, Iba1 immunostaining, cytokine measurement, TTC staining, LPS stimulation in vitro\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (Cd44 KO rescue of Srgn KO phenotype) with multiple orthogonal in vivo and in vitro readouts\",\n      \"pmids\": [\"38287411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HIF-1α directly binds a hypoxia response element in the SRGN promoter to transcriptionally upregulate SRGN, and SRGN overexpression promotes colorectal cancer cell migration and invasion, placing SRGN as a direct downstream effector of hypoxia signaling in colorectal cancer metastasis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, transwell migration/invasion assay, shRNA knockdown\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrated direct HIF-1α binding to SRGN promoter; single lab study\",\n      \"pmids\": [\"30121667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STAT3 regulates SRGN expression in nasopharyngeal carcinoma through a FoxO1-miR-148a-5p-CREB1 axis: FoxO1 binds and activates miR-148a-5p transcription; miR-148a-5p suppresses CREB1; CREB1 directly binds the SRGN promoter to drive SRGN expression. SRGN knockdown suppressed NPC tumor progression in vitro and in vivo.\",\n      \"method\": \"EMSA, ChIP, dual-luciferase reporter assay, RIP assay, qRT-PCR, Western blot, xenograft tumor model, Transwell assay\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — EMSA and ChIP validated direct transcription factor-promoter interactions; multiple orthogonal methods and in vivo validation\",\n      \"pmids\": [\"35562411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRGN regulates PD-L1 expression as well as proinflammatory cytokines (IL-6, IL-8, CXCL1) in lung adenocarcinoma cells, and increases migratory and invasive properties of LUAD cells and fibroblasts and enhances angiogenesis. SRGN expression is induced by DNA demethylation resulting from NNMT-mediated impairment of methionine metabolism.\",\n      \"method\": \"siRNA knockdown, syngeneic mouse model, cytokine measurement, migration/invasion assays, proteomic and metabolomic analyses, immunohistochemistry\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotypes and in vivo syngeneic model; single lab\",\n      \"pmids\": [\"34524427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Low shear stress enhances SRGN expression in human umbilical vein endothelial cells via the PKA/CREB-dependent signaling pathway, and SRGN high-expression cells show increased Ki67+ cell proportion and higher nitric oxide concentration, implicating SRGN in endothelial cell proliferation in response to shear stress.\",\n      \"method\": \"In vitro shear stress loading in HUVECs, in vivo partial carotid artery ligation in mice, PKA/CREB inhibitor experiments, Ki67 staining, NO concentration measurement, bioinformatics analysis of zebrafish high-throughput data\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic pathway (PKA/CREB) identified by pharmacological inhibition; in vivo and in vitro corroboration; single lab\",\n      \"pmids\": [\"32712749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNHG3 (lncRNA) modulates SRGN expression by competitively sponging miR-758-3p; miR-758-3p targets SRGN mRNA; knockdown of SNHG3 decreased SRGN and inhibited AML cell proliferation while inducing apoptosis, and these effects were rescued by miR-758-3p suppression or SRGN overexpression.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay (implied), qRT-PCR, Western blot, flow cytometry for apoptosis, CCK-8 proliferation assay, miRNA target validation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic rescue epistasis established pathway order; single lab with multiple functional readouts\",\n      \"pmids\": [\"31452272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRGN activates YAP nuclear translocation in hepatocellular carcinoma cells, and YAP/TEAD1 complex directly targets the CRISPLD2 promoter to upregulate CRISPLD2, establishing a SRGN/YAP/CRISPLD2 axis that promotes HCC metastasis and stemness maintenance in an autocrine manner.\",\n      \"method\": \"In vitro migration assays, in vivo experiments, reporter assays, knockdown and overexpression of SRGN/YAP/CRISPLD2, nuclear/cytoplasmic fractionation for YAP localization\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway order established by genetic manipulation; single lab; YAP/TEAD1-CRISPLD2 link validated by reporter assay\",\n      \"pmids\": [\"40384866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRGN in chondrocytes promotes recruitment of THP-1-derived macrophages by upregulating CCL3 expression and secretion; siRNA-mediated SRGN knockdown reduced CCL3 and impaired macrophage migration in a transwell co-culture model.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, conditioned media co-culture, transwell macrophage migration assay, qPCR, Western blot, ELISA for CCL3\",\n      \"journal\": \"Connective tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — clean mechanistic link (SRGN→CCL3→macrophage migration) with multiple concordant methods; single lab in vitro only\",\n      \"pmids\": [\"39067006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ALKBH5-mediated m6A demethylation of Srgn mRNA enhances its stability, leading to increased SRGN protein in Sertoli cells exposed to palmitic acid. Elevated SRGN then activates NF-κB and MAPK pathways, upregulating Ccl2 and TNF-α, thereby disrupting blood-testis barrier integrity. Suppressing Alkbh5 alleviated this BTB disruption.\",\n      \"method\": \"siRNA knockdown of Alkbh5, Srgn overexpression and knockdown, m6A methylation assay, RNA stability assay, NF-κB and MAPK pathway analysis, Western blot, tight junction integrity assays in TM4 and primary Sertoli cells\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA m6A modification mechanism with writer (ALKBH5) identified; multiple pathway validations; single lab\",\n      \"pmids\": [\"41910735\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRGN (Serglycin) is a secreted chondroitin sulfate proteoglycan that signals through CD44 and integrin receptors to activate downstream kinase cascades (FAK/CREB, PKA/CREB, NF-κB, MAPK), transcriptional coactivators (YAP/TEAD1), and epigenetic regulators (HDAC2), thereby promoting tumor invasion, immune modulation, and inflammatory responses; its expression is transcriptionally controlled by HIF-1α (via hypoxia response elements), CREB1, STAT3/FoxO1/miR-148a-5p axis, and TGFβ2/Smad3, and post-transcriptionally stabilized by ALKBH5-mediated m6A demethylation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SRGN (serglycin) is a secreted proteoglycan that functions as an extracellular signaling molecule activating multiple receptor-mediated pathways to drive inflammation, tumor invasion, stemness, and chemoresistance. Secreted SRGN engages CD44 to activate NF-κB signaling in microglia and CREB1-dependent TGFβ2 transcription in breast cancer, and signals through ITGA5/FAK to promote YAP nuclear translocation and YAP/TEAD1-dependent transcriptional programs including HDAC2 and CRISPLD2, establishing feed-forward circuits that sustain tumor stemness and metastasis [PMID:32292495, PMID:28692037, PMID:38287411, PMID:40384866]. SRGN also activates NF-κB and MAPK cascades to induce proinflammatory cytokines (CCL2, TNF-α, IL-6, CCL3) in diverse cell types including Sertoli cells, endothelial cells, and chondrocytes [PMID:41910735, PMID:34524427, PMID:39067006]. SRGN transcription is directly regulated by HIF-1α, Smad3, and CREB1 binding to its promoter, and its mRNA is post-transcriptionally stabilized by ALKBH5-mediated m6A demethylation [PMID:30121667, PMID:35562411, PMID:41910735].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing that secreted SRGN is not merely a structural proteoglycan but an autocrine/paracrine signaling molecule that engages CD44 to activate CREB1 and TGFβ2, forming a feed-forward loop with Smad3-driven SRGN transcription to promote EMT and invasion.\",\n      \"evidence\": \"ChIP for Smad3 on SRGN promoter, shRNA knockdown, recombinant protein treatment, and in vivo metastasis model in TNBC cells\",\n      \"pmids\": [\"28692037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CD44-CREB1 signaling intermediates not fully mapped\", \"Glycosaminoglycan chain requirement for CD44 engagement not tested\", \"Feed-forward loop dynamics not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying HIF-1α as a direct transcriptional activator of SRGN through a hypoxia response element, linking SRGN upregulation to the tumor hypoxic microenvironment.\",\n      \"evidence\": \"ChIP showing HIF-1α binding to SRGN promoter, shRNA knockdown, and transwell assays in colorectal cancer cells\",\n      \"pmids\": [\"30121667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without independent replication\", \"Contribution of hypoxia-induced SRGN relative to other HIF-1α targets not dissected\", \"No in vivo hypoxia validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating post-transcriptional regulation of SRGN via a ceRNA mechanism (SNHG3/miR-758-3p/SRGN axis), showing that SRGN levels can be modulated by non-coding RNA networks in AML.\",\n      \"evidence\": \"miRNA target validation, genetic rescue epistasis with SNHG3 knockdown and miR-758-3p inhibition in AML cells\",\n      \"pmids\": [\"31452272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro only with no in vivo validation\", \"Direct miR-758-3p binding site on SRGN 3′UTR not confirmed by mutation\", \"Physiological relevance to AML progression unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Deciphering the SRGN/ITGA5/FAK/CREB/YAP/HDAC2 signaling cascade that establishes a feed-forward transcriptional circuit driving chemoresistance and stemness in breast cancer, and separately showing that PKA/CREB mediates shear-stress-induced SRGN expression in endothelial cells.\",\n      \"evidence\": \"Co-IP, ChIP-qPCR, luciferase reporters, epistasis via YAP knockdown/overexpression, xenograft models (breast cancer); PKA/CREB inhibitors and carotid ligation model (endothelial cells)\",\n      \"pmids\": [\"32292495\", \"32712749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ITGA5 as direct SRGN receptor not validated by binding assay\", \"Relative contribution of FAK vs other integrin-proximal kinases unknown\", \"PKA/CREB-SRGN link in endothelial cells relies on pharmacological inhibition\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping a STAT3/FoxO1/miR-148a-5p/CREB1 regulatory cascade converging on SRGN promoter activation, and confirming SRGN's role in immune evasion through PD-L1 upregulation and proinflammatory cytokine induction in lung adenocarcinoma.\",\n      \"evidence\": \"EMSA, ChIP, dual-luciferase reporter, and xenograft models (NPC); siRNA knockdown with cytokine profiling and syngeneic models (LUAD)\",\n      \"pmids\": [\"35562411\", \"34524427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SRGN-to-PD-L1 signaling intermediates not identified\", \"NNMT-DNA methylation-SRGN link is correlative without direct demethylation rescue\", \"Whether STAT3 axis and HIF-1α axis converge on SRGN promoter simultaneously is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing CD44 as a genetically validated SRGN receptor in vivo through Cd44-knockout rescue of SRGN-driven neuroinflammation, and identifying SRGN-dependent CCL3 secretion as a macrophage chemoattractant mechanism in chondrocytes.\",\n      \"evidence\": \"Srgn-KO and Cd44-KO mice with MCAO stroke model and recombinant SRGN injection; siRNA knockdown with transwell macrophage migration in chondrocyte co-culture\",\n      \"pmids\": [\"38287411\", \"39067006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycosaminoglycan chain versus core protein requirement for CD44 binding not dissected\", \"CCL3 induction mechanism downstream of SRGN not identified\", \"Chondrocyte findings are in vitro only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending the SRGN/YAP axis to hepatocellular carcinoma and identifying CRISPLD2 as a direct YAP/TEAD1 transcriptional target mediating SRGN-driven HCC metastasis and stemness.\",\n      \"evidence\": \"Reporter assays for YAP/TEAD1 on CRISPLD2 promoter, nuclear fractionation, knockdown/overexpression epistasis, and in vivo HCC models\",\n      \"pmids\": [\"40384866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; receptor mediating SRGN-to-YAP in HCC not identified\", \"Whether CRISPLD2 is the principal YAP effector or one of many targets is unclear\", \"No structural data on SRGN-receptor interaction\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealing epitranscriptomic regulation of SRGN through ALKBH5-mediated m6A demethylation that stabilizes Srgn mRNA, connecting lipotoxic stress to NF-κB/MAPK activation and blood-testis barrier disruption.\",\n      \"evidence\": \"m6A methylation assay, RNA stability assay, ALKBH5 knockdown rescue, tight junction integrity assays in Sertoli cells\",\n      \"pmids\": [\"41910735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on Srgn mRNA not mapped\", \"In vivo fertility consequences not assessed\", \"Whether ALKBH5 regulation of SRGN operates in other cell types is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity and structural basis of SRGN's interaction with its receptors (CD44, ITGA5) — including whether the glycosaminoglycan chains or core protein mediate binding — remain unresolved, and no structural model of SRGN-receptor complexes exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of SRGN or SRGN-receptor complex\", \"GAG chain versus core protein contribution to signaling not dissected\", \"Unified model integrating multiple receptor inputs (CD44, ITGA5) is lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2, 5, 8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 6, 8, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD44\", \"ITGA5\", \"YAP1\", \"TEAD1\", \"CREB1\", \"SMAD3\", \"ALKBH5\", \"HDAC2\"],\n    \"other_free_text\": []\n  }\n}\n```"}