{"gene":"GSN","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2014,"finding":"GSN overexpression in H9c2 cardiomyoblast cells induces cardiac hypertrophy and increases BNP expression via the p38/GATA-4 signaling pathway; pharmacological inhibition of p38 (SB203580) or GSN siRNA knockdown suppressed gelsolin-induced hypertrophy, establishing p38 and GATA-4 as downstream effectors of GSN.","method":"Stable overexpression cell lines (H9c2-GSN), siRNA knockdown, p38 inhibitor treatment, western blotting","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable OE lines plus pharmacological inhibition plus siRNA rescue in a single lab with two orthogonal intervention methods","pmids":["24505034"],"is_preprint":false},{"year":2016,"finding":"GSN overexpression in H9c2 cardiomyoblasts under hypoxia augments HIF-1α expression and reduces p-Akt and Bcl-2 survival signaling, promoting caspase-3 activation and cell death; GSN knockdown attenuated hypoxia-induced activated caspase-3 and cell death.","method":"Stable GSN overexpression cell lines, siRNA knockdown, hypoxic challenge, western blotting for HIF-1α, p-Akt, Bcl-2, cleaved caspase-3","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable OE and siRNA knockdown with defined apoptotic phenotype readouts, single lab","pmids":["27193608"],"is_preprint":false},{"year":2017,"finding":"GSN overexpression (via lentiviral injection in EAE model) delayed disease onset and reduced severity; GSN siRNA knockdown in PC12 cells confirmed its anti-apoptotic function; vitamin D-mediated downregulation of GSN was found to occur through the vitamin D receptor (VDR), as shown by VDR gene interruption and overexpression experiments.","method":"Lentiviral GSN overexpression in vivo (EAE model), siRNA knockdown in PC12 cells, VDR gene interruption/overexpression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo lentiviral OE plus siRNA KD plus genetic VDR manipulation, single lab, multiple methods","pmids":["28377587"],"is_preprint":false},{"year":2019,"finding":"hnRNPK binds to the 3'-UTR of GSN mRNA and positively regulates GSN mRNA and protein levels; hnRNPK knockdown reduced GSN expression and impaired cell migration in lung adenocarcinoma cells, and this migration defect was rescued by ectopic GSN expression, demonstrating that hnRNPK-driven migration is GSN-dependent.","method":"siRNA knockdown of hnRNPK, ectopic GSN expression rescue, migration assays, western blotting, 3'UTR binding assay","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD, rescue experiment, and 3'UTR binding in a single lab with multiple orthogonal methods","pmids":["30771276"],"is_preprint":false},{"year":2022,"finding":"GSN promotes hepatocellular carcinoma (HCC) invasion and metastasis through an actin-CD44-MMP axis: GSN interacts with MMP14 (co-immunoprecipitation) to activate MMP2, and CD44 acts as a key node in this transfer chain; competitive inhibition using MMP14 PEX fusion protein blocked CD44 binding and suppressed downstream MMP2 activation.","method":"Dual co-immunoprecipitation, immunofluorescence, western blotting, gelatinase activity assay, PEX fusion protein competitive inhibition, in vitro and in vivo invasion assays","journal":"Clinical & translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue with PEX inhibitor plus gelatinase activity assay, single lab","pmids":["36192574"],"is_preprint":false},{"year":2018,"finding":"GSN overexpression in colorectal cancer cells (LoVo) increased invasion >2-fold, downregulated epithelial markers (E-cadherin, β-catenin, claudin-1, snail) and upregulated mesenchymal markers (N-cadherin, ZEB1), indicating GSN promotes EMT; GSN overexpression also downregulated autophagy proteins ATG5-12, ATG6/BECN1, ATG7 and ATG101.","method":"Stable overexpression in LoVo cells, invasion/migration assays, western blotting for EMT and autophagy markers","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression only without rescue or KD confirmation, no pathway placement beyond correlation","pmids":["30148861"],"is_preprint":false},{"year":2018,"finding":"TGF-β acts as an upstream activator of GSN-dependent cardiac hypertrophy in aging rats fed a high-fat diet; exogenous TGF-β inhibited GSN-dependent hypertrophy in H9c2 cells cultured with treated serum, placing TGF-β upstream of the GSN/p38 hypertrophy axis.","method":"In vivo HFD aging rat model, H9c2 cell culture with collected serum, western blotting, Masson trichrome staining, echocardiography","journal":"Environmental toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect serum experiment, single lab, no direct molecular epistasis confirmation","pmids":["30240538"],"is_preprint":false},{"year":2018,"finding":"Functional characterization of an alternatively spliced GSN isoform (ASE-GSN) in head and neck squamous cell carcinoma showed that overall expression of either ASE-GSN or wild-type GSN inversely correlated with cell proliferation, while a high ratio of ASE-GSN to WT-GSN correlated with increased cellular invasion; changes in expression of either isoform caused compensatory changes in the other isoform.","method":"In vitro isoform expression manipulation, proliferation assays, invasion assays","journal":"Translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, isoform OE/KD with phenotypic readouts, no mechanistic pathway placement","pmids":["30118659"],"is_preprint":false},{"year":2025,"finding":"Three GSN isoforms (secretory A, cytosolic B, cytosolic C) are produced in melanoma cells; in GSN-knockout A375 cells restored with single isoforms: GSN-A increased invasiveness, GSN-C promoted filopodia formation and 2D migration, and both GSN-B and -C decreased filamentous actin levels, demonstrating non-redundant isoform-specific functions in actin regulation, motility, and invasion.","method":"GSN knockout cell line, single-isoform rescue expression, immunocytochemistry, migration assays, actin polymerization assays, zebrafish embryo tumor growth model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus individual isoform rescue with multiple orthogonal functional readouts in single lab","pmids":["40597347"],"is_preprint":false},{"year":2025,"finding":"Plasma gelsolin (pGSN) administration in a murine candidemia model reduced systemic and organ-specific inflammation, decreased blood fungal burden, prevented renal microabscess formation, enhanced phagocytic activity of human monocytes, and modulated monocyte reactive radical production (increasing nitric oxide, reducing hydrogen sulfide and ROS), demonstrating immunomodulatory and host-protective functions of secreted/plasma gelsolin.","method":"In vivo murine candidemia model with subcutaneous pGSN injection, IRDye 800CW 2-deoxyglucose imaging, histopathology, inflammatory gene expression in whole blood, phagocytosis assay, reactive radical measurement","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — in vivo model with multiple readouts, preprint not yet peer-reviewed, single lab","pmids":[],"is_preprint":true},{"year":2022,"finding":"Macrophage-like synoviocytes (MLS) and fibroblast-like synoviocytes (FLS) both produce and secrete GSN into synovial fluid, as demonstrated by isolation, culture, and ELISA of conditioned medium; GSN concentrations are significantly reduced in osteoarthritis synovial fluid compared to healthy controls.","method":"Cell isolation and culture, ELISA, western blot, immunofluorescence","journal":"Biomedicines","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, production/secretion established but no downstream functional mechanism demonstrated","pmids":["35327525"],"is_preprint":false},{"year":2023,"finding":"GSN frameshift mutations (K346fs and P3fs) result in loss of function of GSN in inhibiting Aβ-induced toxicity, as shown by in vitro experiments; plasma and CSF GSN levels are elevated in AD patients and positively correlate with CSF Aβ42, suggesting a compensatory role for GSN in countering amyloid toxicity.","method":"In vitro functional assay of mutant GSN constructs, whole genome sequencing, ELISA of plasma and CSF GSN and Aβ","journal":"Journal of neurology, neurosurgery, and psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro loss-of-function assay for Aβ toxicity inhibition plus patient biofluid correlation, single lab","pmids":["36650038"],"is_preprint":false}],"current_model":"Gelsolin (GSN) is a calcium-regulated actin-severing and capping protein that regulates actin filament dynamics and cell motility; it promotes EMT and invasion through isoform-specific actin remodeling and an MMP14/CD44/MMP2 molecular chain, induces cardiomyocyte hypertrophy via p38/GATA-4 signaling downstream of TGF-β, modulates apoptosis by reducing p-Akt/Bcl-2 survival signaling under hypoxia, has its mRNA levels post-transcriptionally regulated by hnRNPK binding to the GSN 3'-UTR, and in its secreted plasma form exerts immunomodulatory effects including enhanced phagocytosis and suppression of inflammatory reactive oxygen species."},"narrative":{"mechanistic_narrative":"Gelsolin (GSN) is a calcium-regulated actin-remodeling protein that, through isoform-specific control of filament dynamics, governs cancer cell motility, invasion, and the epithelial-mesenchymal transition [PMID:30148861, PMID:40597347]. Multiple GSN isoforms exert non-redundant functions: a secretory isoform drives invasiveness while cytosolic isoforms promote filopodia formation and 2D migration and reduce filamentous actin levels [PMID:40597347]. In carcinoma cells GSN promotes invasion and metastasis through an actin-CD44-MMP chain in which GSN physically interacts with MMP14 to activate MMP2, with CD44 as a transfer node [PMID:36192574], and it reprograms cells toward a mesenchymal state by downregulating epithelial markers and upregulating mesenchymal markers [PMID:30148861]. GSN mRNA stability and protein output are controlled post-transcriptionally by hnRNPK binding to the GSN 3'-UTR, an axis required for cancer cell migration [PMID:30771276]. In cardiomyoblasts GSN induces hypertrophy via p38/GATA-4 signaling downstream of TGF-β and, under hypoxia, drives apoptosis by augmenting HIF-1α while suppressing p-Akt/Bcl-2 survival signaling and activating caspase-3 [PMID:24505034, PMID:27193608]. Secreted/plasma gelsolin additionally inhibits Aβ-induced toxicity, with loss-of-function frameshift mutations abolishing this protection [PMID:36650038].","teleology":[{"year":2014,"claim":"Established a signaling output for GSN in cardiac cells by showing it drives hypertrophy through a defined kinase-transcription factor cascade rather than acting solely as a cytoskeletal effector.","evidence":"Stable GSN overexpression in H9c2 cardiomyoblasts with p38 inhibitor and siRNA rescue, western blotting","pmids":["24505034"],"confidence":"Medium","gaps":["Mechanism linking GSN to p38 activation not defined","Single cell-line model, no in vivo cardiac confirmation"]},{"year":2016,"claim":"Showed GSN can act pro-apoptotically under hypoxia, revealing a context-dependent role opposite to its anti-apoptotic activity in other settings.","evidence":"GSN overexpression and siRNA knockdown in H9c2 under hypoxia, western blotting for HIF-1α, p-Akt, Bcl-2, cleaved caspase-3","pmids":["27193608"],"confidence":"Medium","gaps":["Direct molecular link between GSN and Akt/Bcl-2 regulation unresolved","Reconciliation with anti-apoptotic findings absent"]},{"year":2017,"claim":"Identified upstream regulation of GSN by the vitamin D receptor and reinforced an anti-apoptotic, neuroprotective function in a neuroinflammatory disease model.","evidence":"Lentiviral GSN overexpression in EAE, siRNA knockdown in PC12 cells, VDR gene interruption/overexpression","pmids":["28377587"],"confidence":"Medium","gaps":["Whether VDR regulates GSN transcriptionally or otherwise not defined","Anti-apoptotic mechanism not molecularly resolved"]},{"year":2018,"claim":"Connected GSN to EMT and autophagy programs in colorectal cancer and placed TGF-β upstream of the GSN/p38 hypertrophy axis, while characterizing isoform-ratio effects on proliferation versus invasion.","evidence":"Stable overexpression in LoVo cells, HFD aging rat serum experiments, isoform expression manipulation with invasion/proliferation assays","pmids":["30148861","30240538","30118659"],"confidence":"Low","gaps":["EMT and autophagy findings from overexpression only, no knockdown rescue","TGF-β epistasis inferred indirectly via serum, no direct molecular link","Isoform studies lack mechanistic pathway placement"]},{"year":2019,"claim":"Defined post-transcriptional control of GSN by hnRNPK and showed this regulation is functionally required for cancer cell migration.","evidence":"hnRNPK siRNA knockdown, 3'UTR binding assay, ectopic GSN rescue, migration assays in lung adenocarcinoma cells","pmids":["30771276"],"confidence":"Medium","gaps":["Mechanism of mRNA stabilization vs translation not dissected","Whether other RBPs co-regulate GSN unknown"]},{"year":2022,"claim":"Provided a physical-interaction mechanism for GSN-driven invasion via an MMP14/CD44/MMP2 chain, moving beyond correlation to direct binding and competitive inhibition.","evidence":"Reciprocal co-immunoprecipitation, gelatinase activity assay, PEX fusion competitive inhibition, in vitro/in vivo invasion in HCC; synoviocyte secretion by ELISA","pmids":["36192574","35327525"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of GSN-MMP14 interaction unknown","How actin severing feeds into MMP activation not defined"]},{"year":2023,"claim":"Demonstrated a protective function of GSN against amyloid-beta toxicity that is abolished by frameshift mutations, linking GSN function to Alzheimer's disease biology.","evidence":"In vitro functional assay of mutant GSN constructs, whole genome sequencing, plasma/CSF GSN and Aβ ELISA","pmids":["36650038"],"confidence":"Medium","gaps":["Molecular mechanism of Aβ toxicity inhibition not defined","Causality of mutations in disease onset not established"]},{"year":2025,"claim":"Resolved non-redundant isoform-specific roles in actin regulation and motility, and characterized immunomodulatory host-protective functions of plasma gelsolin.","evidence":"GSN-knockout melanoma cells with single-isoform rescue and actin/migration assays; murine candidemia model with pGSN injection, phagocytosis and reactive radical measurement (preprint)","pmids":["40597347"],"confidence":"Medium","gaps":["Structural basis of isoform functional divergence unknown","pGSN immunomodulation data are from a single-lab preprint"]},{"year":null,"claim":"How GSN's calcium-regulated actin-severing activity is mechanistically coupled to its diverse downstream outputs (p38/GATA-4 hypertrophy, Akt survival signaling, MMP activation, amyloid protection) across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or biochemical model links actin remodeling to signaling outputs","Isoform-specific structural determinants undefined","Context dependence of pro- vs anti-apoptotic roles unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9,10,11]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]}],"complexes":[],"partners":["MMP14","CD44","HNRNPK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06396","full_name":"Gelsolin","aliases":["AGEL","Actin-depolymerizing factor","ADF","Brevin"],"length_aa":782,"mass_kda":85.7,"function":"Calcium-regulated, actin-modulating protein that binds to the plus (or barbed) ends of actin monomers or filaments, preventing monomer exchange (end-blocking or capping). It can promote the assembly of monomers into filaments (nucleation) as well as sever filaments already formed (PubMed:19666512). Plays a role in ciliogenesis (PubMed:20393563)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P06396/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GSN","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":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GSN","total_profiled":1310},"omim":[{"mim_id":"618017","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 16; ANKRD16","url":"https://www.omim.org/entry/618017"},{"mim_id":"617413","title":"PRUNE EXOPOLYPHOSPHATASE 1; PRUNE1","url":"https://www.omim.org/entry/617413"},{"mim_id":"613397","title":"ADVILLIN; AVIL","url":"https://www.omim.org/entry/613397"},{"mim_id":"610982","title":"INVERTED FORMIN 2; INF2","url":"https://www.omim.org/entry/610982"},{"mim_id":"610932","title":"TWINFILIN ACTIN-BINDING PROTEIN 1; TWF1","url":"https://www.omim.org/entry/610932"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Actin filaments","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":2454.2}],"url":"https://www.proteinatlas.org/search/GSN"},"hgnc":{"alias_symbol":["DKFZp313L0718"],"prev_symbol":[]},"alphafold":{"accession":"P06396","domains":[{"cath_id":"3.40.20.10","chopping":"56-173","consensus_level":"high","plddt":95.3747,"start":56,"end":173},{"cath_id":"3.40.20.10","chopping":"187-273","consensus_level":"medium","plddt":93.1799,"start":187,"end":273},{"cath_id":"3.40.20.10","chopping":"291-390","consensus_level":"medium","plddt":89.7292,"start":291,"end":390},{"cath_id":"3.40.20.10","chopping":"426-657","consensus_level":"medium","plddt":96.0337,"start":426,"end":657},{"cath_id":"3.40.20.10","chopping":"660-778","consensus_level":"medium","plddt":92.7001,"start":660,"end":778}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06396","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06396-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06396-F1-predicted_aligned_error_v6.png","plddt_mean":89.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GSN","jax_strain_url":"https://www.jax.org/strain/search?query=GSN"},"sequence":{"accession":"P06396","fasta_url":"https://rest.uniprot.org/uniprotkb/P06396.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06396/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06396"}},"corpus_meta":[{"pmid":"16258946","id":"PMC_16258946","title":"Cardiac conduction alterations in a French family with amyloidosis of the Finnish type with the p.Asp187Tyr mutation in the GSN gene.","date":"2006","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/16258946","citation_count":35,"is_preprint":false},{"pmid":"30148861","id":"PMC_30148861","title":"Opposite functions of GSN and OAS2 on colorectal cancer metastasis, mediating perineural and lymphovascular invasion, respectively.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30148861","citation_count":34,"is_preprint":false},{"pmid":"15558319","id":"PMC_15558319","title":"Genomic organization of the Neurospora crassa gsn gene: possible involvement of the STRE and HSE elements in the modulation of transcription during heat shock.","date":"2004","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/15558319","citation_count":22,"is_preprint":false},{"pmid":"11976968","id":"PMC_11976968","title":"Molecular and biochemical 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urinary bladder cancer.","date":"2015","source":"Hippokratia","url":"https://pubmed.ncbi.nlm.nih.gov/27418776","citation_count":4,"is_preprint":false},{"pmid":"38846963","id":"PMC_38846963","title":"Specific feature recognition on group specific networks (SFR-GSN): a biomarker identification model for cancer stages.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38846963","citation_count":3,"is_preprint":false},{"pmid":"30440136","id":"PMC_30440136","title":"[Value of RNA oxidation product 8-oxo-Gsn in evaluating renal function in patients with chronic kidney disease].","date":"2018","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/30440136","citation_count":1,"is_preprint":false},{"pmid":"35780194","id":"PMC_35780194","title":"Deletions in GSN gene associated with growth traits of four Chinese cattle breeds.","date":"2022","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/35780194","citation_count":0,"is_preprint":false},{"pmid":"41671621","id":"PMC_41671621","title":"Unraveling the matrix stiffness landscape in idiopathic pulmonary fibrosis: GSN and ARG1 as novel diagnostic biomarkers and potential therapeutic targets.","date":"2026","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41671621","citation_count":0,"is_preprint":false},{"pmid":"40597347","id":"PMC_40597347","title":"Skin melanoma cells produce diverse gelsolin (GSN) isoforms, which play non-redundant roles in cells' proliferation and motility.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/40597347","citation_count":0,"is_preprint":false},{"pmid":"42226741","id":"PMC_42226741","title":"Novel associations of GSN indel and PLAG1 c.48333G > A variants with growth traits in mature Indonesian Madura and Bali cattle.","date":"2026","source":"Journal of advanced veterinary and animal research","url":"https://pubmed.ncbi.nlm.nih.gov/42226741","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.22.677758","title":"Plasma Gelsolin Prevents Organ-Specific Inflammation and Enhances Innate Immune Function in a Systemic  <i>Candida albicans</i>  Infection","date":"2025-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.677758","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.31.25324765","title":"Identification of lncRNAs differentially expressed in Alzheimer’s disease brains using RNA sequencing","date":"2025-04-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.31.25324765","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21983,"output_tokens":3083,"usd":0.056097,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10547,"output_tokens":2979,"usd":0.063605,"stage2_stop_reason":"end_turn"},"total_usd":0.119702,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"GSN overexpression in H9c2 cardiomyoblast cells induces cardiac hypertrophy and increases BNP expression via the p38/GATA-4 signaling pathway; pharmacological inhibition of p38 (SB203580) or GSN siRNA knockdown suppressed gelsolin-induced hypertrophy, establishing p38 and GATA-4 as downstream effectors of GSN.\",\n      \"method\": \"Stable overexpression cell lines (H9c2-GSN), siRNA knockdown, p38 inhibitor treatment, western blotting\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable OE lines plus pharmacological inhibition plus siRNA rescue in a single lab with two orthogonal intervention methods\",\n      \"pmids\": [\"24505034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSN overexpression in H9c2 cardiomyoblasts under hypoxia augments HIF-1α expression and reduces p-Akt and Bcl-2 survival signaling, promoting caspase-3 activation and cell death; GSN knockdown attenuated hypoxia-induced activated caspase-3 and cell death.\",\n      \"method\": \"Stable GSN overexpression cell lines, siRNA knockdown, hypoxic challenge, western blotting for HIF-1α, p-Akt, Bcl-2, cleaved caspase-3\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable OE and siRNA knockdown with defined apoptotic phenotype readouts, single lab\",\n      \"pmids\": [\"27193608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GSN overexpression (via lentiviral injection in EAE model) delayed disease onset and reduced severity; GSN siRNA knockdown in PC12 cells confirmed its anti-apoptotic function; vitamin D-mediated downregulation of GSN was found to occur through the vitamin D receptor (VDR), as shown by VDR gene interruption and overexpression experiments.\",\n      \"method\": \"Lentiviral GSN overexpression in vivo (EAE model), siRNA knockdown in PC12 cells, VDR gene interruption/overexpression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo lentiviral OE plus siRNA KD plus genetic VDR manipulation, single lab, multiple methods\",\n      \"pmids\": [\"28377587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPK binds to the 3'-UTR of GSN mRNA and positively regulates GSN mRNA and protein levels; hnRNPK knockdown reduced GSN expression and impaired cell migration in lung adenocarcinoma cells, and this migration defect was rescued by ectopic GSN expression, demonstrating that hnRNPK-driven migration is GSN-dependent.\",\n      \"method\": \"siRNA knockdown of hnRNPK, ectopic GSN expression rescue, migration assays, western blotting, 3'UTR binding assay\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD, rescue experiment, and 3'UTR binding in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30771276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GSN promotes hepatocellular carcinoma (HCC) invasion and metastasis through an actin-CD44-MMP axis: GSN interacts with MMP14 (co-immunoprecipitation) to activate MMP2, and CD44 acts as a key node in this transfer chain; competitive inhibition using MMP14 PEX fusion protein blocked CD44 binding and suppressed downstream MMP2 activation.\",\n      \"method\": \"Dual co-immunoprecipitation, immunofluorescence, western blotting, gelatinase activity assay, PEX fusion protein competitive inhibition, in vitro and in vivo invasion assays\",\n      \"journal\": \"Clinical & translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue with PEX inhibitor plus gelatinase activity assay, single lab\",\n      \"pmids\": [\"36192574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GSN overexpression in colorectal cancer cells (LoVo) increased invasion >2-fold, downregulated epithelial markers (E-cadherin, β-catenin, claudin-1, snail) and upregulated mesenchymal markers (N-cadherin, ZEB1), indicating GSN promotes EMT; GSN overexpression also downregulated autophagy proteins ATG5-12, ATG6/BECN1, ATG7 and ATG101.\",\n      \"method\": \"Stable overexpression in LoVo cells, invasion/migration assays, western blotting for EMT and autophagy markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression only without rescue or KD confirmation, no pathway placement beyond correlation\",\n      \"pmids\": [\"30148861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGF-β acts as an upstream activator of GSN-dependent cardiac hypertrophy in aging rats fed a high-fat diet; exogenous TGF-β inhibited GSN-dependent hypertrophy in H9c2 cells cultured with treated serum, placing TGF-β upstream of the GSN/p38 hypertrophy axis.\",\n      \"method\": \"In vivo HFD aging rat model, H9c2 cell culture with collected serum, western blotting, Masson trichrome staining, echocardiography\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect serum experiment, single lab, no direct molecular epistasis confirmation\",\n      \"pmids\": [\"30240538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Functional characterization of an alternatively spliced GSN isoform (ASE-GSN) in head and neck squamous cell carcinoma showed that overall expression of either ASE-GSN or wild-type GSN inversely correlated with cell proliferation, while a high ratio of ASE-GSN to WT-GSN correlated with increased cellular invasion; changes in expression of either isoform caused compensatory changes in the other isoform.\",\n      \"method\": \"In vitro isoform expression manipulation, proliferation assays, invasion assays\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, isoform OE/KD with phenotypic readouts, no mechanistic pathway placement\",\n      \"pmids\": [\"30118659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Three GSN isoforms (secretory A, cytosolic B, cytosolic C) are produced in melanoma cells; in GSN-knockout A375 cells restored with single isoforms: GSN-A increased invasiveness, GSN-C promoted filopodia formation and 2D migration, and both GSN-B and -C decreased filamentous actin levels, demonstrating non-redundant isoform-specific functions in actin regulation, motility, and invasion.\",\n      \"method\": \"GSN knockout cell line, single-isoform rescue expression, immunocytochemistry, migration assays, actin polymerization assays, zebrafish embryo tumor growth model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus individual isoform rescue with multiple orthogonal functional readouts in single lab\",\n      \"pmids\": [\"40597347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plasma gelsolin (pGSN) administration in a murine candidemia model reduced systemic and organ-specific inflammation, decreased blood fungal burden, prevented renal microabscess formation, enhanced phagocytic activity of human monocytes, and modulated monocyte reactive radical production (increasing nitric oxide, reducing hydrogen sulfide and ROS), demonstrating immunomodulatory and host-protective functions of secreted/plasma gelsolin.\",\n      \"method\": \"In vivo murine candidemia model with subcutaneous pGSN injection, IRDye 800CW 2-deoxyglucose imaging, histopathology, inflammatory gene expression in whole blood, phagocytosis assay, reactive radical measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo model with multiple readouts, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Macrophage-like synoviocytes (MLS) and fibroblast-like synoviocytes (FLS) both produce and secrete GSN into synovial fluid, as demonstrated by isolation, culture, and ELISA of conditioned medium; GSN concentrations are significantly reduced in osteoarthritis synovial fluid compared to healthy controls.\",\n      \"method\": \"Cell isolation and culture, ELISA, western blot, immunofluorescence\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, production/secretion established but no downstream functional mechanism demonstrated\",\n      \"pmids\": [\"35327525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GSN frameshift mutations (K346fs and P3fs) result in loss of function of GSN in inhibiting Aβ-induced toxicity, as shown by in vitro experiments; plasma and CSF GSN levels are elevated in AD patients and positively correlate with CSF Aβ42, suggesting a compensatory role for GSN in countering amyloid toxicity.\",\n      \"method\": \"In vitro functional assay of mutant GSN constructs, whole genome sequencing, ELISA of plasma and CSF GSN and Aβ\",\n      \"journal\": \"Journal of neurology, neurosurgery, and psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro loss-of-function assay for Aβ toxicity inhibition plus patient biofluid correlation, single lab\",\n      \"pmids\": [\"36650038\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Gelsolin (GSN) is a calcium-regulated actin-severing and capping protein that regulates actin filament dynamics and cell motility; it promotes EMT and invasion through isoform-specific actin remodeling and an MMP14/CD44/MMP2 molecular chain, induces cardiomyocyte hypertrophy via p38/GATA-4 signaling downstream of TGF-β, modulates apoptosis by reducing p-Akt/Bcl-2 survival signaling under hypoxia, has its mRNA levels post-transcriptionally regulated by hnRNPK binding to the GSN 3'-UTR, and in its secreted plasma form exerts immunomodulatory effects including enhanced phagocytosis and suppression of inflammatory reactive oxygen species.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Gelsolin (GSN) is a calcium-regulated actin-remodeling protein that, through isoform-specific control of filament dynamics, governs cancer cell motility, invasion, and the epithelial-mesenchymal transition [#5, #8]. Multiple GSN isoforms exert non-redundant functions: a secretory isoform drives invasiveness while cytosolic isoforms promote filopodia formation and 2D migration and reduce filamentous actin levels [#8]. In carcinoma cells GSN promotes invasion and metastasis through an actin-CD44-MMP chain in which GSN physically interacts with MMP14 to activate MMP2, with CD44 as a transfer node [#4], and it reprograms cells toward a mesenchymal state by downregulating epithelial markers and upregulating mesenchymal markers [#5]. GSN mRNA stability and protein output are controlled post-transcriptionally by hnRNPK binding to the GSN 3'-UTR, an axis required for cancer cell migration [#3]. In cardiomyoblasts GSN induces hypertrophy via p38/GATA-4 signaling downstream of TGF-\\u03b2 and, under hypoxia, drives apoptosis by augmenting HIF-1\\u03b1 while suppressing p-Akt/Bcl-2 survival signaling and activating caspase-3 [#0, #1]. Secreted/plasma gelsolin additionally inhibits A\\u03b2-induced toxicity, with loss-of-function frameshift mutations abolishing this protection [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established a signaling output for GSN in cardiac cells by showing it drives hypertrophy through a defined kinase-transcription factor cascade rather than acting solely as a cytoskeletal effector.\",\n      \"evidence\": \"Stable GSN overexpression in H9c2 cardiomyoblasts with p38 inhibitor and siRNA rescue, western blotting\",\n      \"pmids\": [\"24505034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GSN to p38 activation not defined\", \"Single cell-line model, no in vivo cardiac confirmation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed GSN can act pro-apoptotically under hypoxia, revealing a context-dependent role opposite to its anti-apoptotic activity in other settings.\",\n      \"evidence\": \"GSN overexpression and siRNA knockdown in H9c2 under hypoxia, western blotting for HIF-1\\u03b1, p-Akt, Bcl-2, cleaved caspase-3\",\n      \"pmids\": [\"27193608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between GSN and Akt/Bcl-2 regulation unresolved\", \"Reconciliation with anti-apoptotic findings absent\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified upstream regulation of GSN by the vitamin D receptor and reinforced an anti-apoptotic, neuroprotective function in a neuroinflammatory disease model.\",\n      \"evidence\": \"Lentiviral GSN overexpression in EAE, siRNA knockdown in PC12 cells, VDR gene interruption/overexpression\",\n      \"pmids\": [\"28377587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VDR regulates GSN transcriptionally or otherwise not defined\", \"Anti-apoptotic mechanism not molecularly resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected GSN to EMT and autophagy programs in colorectal cancer and placed TGF-\\u03b2 upstream of the GSN/p38 hypertrophy axis, while characterizing isoform-ratio effects on proliferation versus invasion.\",\n      \"evidence\": \"Stable overexpression in LoVo cells, HFD aging rat serum experiments, isoform expression manipulation with invasion/proliferation assays\",\n      \"pmids\": [\"30148861\", \"30240538\", \"30118659\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"EMT and autophagy findings from overexpression only, no knockdown rescue\", \"TGF-\\u03b2 epistasis inferred indirectly via serum, no direct molecular link\", \"Isoform studies lack mechanistic pathway placement\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined post-transcriptional control of GSN by hnRNPK and showed this regulation is functionally required for cancer cell migration.\",\n      \"evidence\": \"hnRNPK siRNA knockdown, 3'UTR binding assay, ectopic GSN rescue, migration assays in lung adenocarcinoma cells\",\n      \"pmids\": [\"30771276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mRNA stabilization vs translation not dissected\", \"Whether other RBPs co-regulate GSN unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a physical-interaction mechanism for GSN-driven invasion via an MMP14/CD44/MMP2 chain, moving beyond correlation to direct binding and competitive inhibition.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, gelatinase activity assay, PEX fusion competitive inhibition, in vitro/in vivo invasion in HCC; synoviocyte secretion by ELISA\",\n      \"pmids\": [\"36192574\", \"35327525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of GSN-MMP14 interaction unknown\", \"How actin severing feeds into MMP activation not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated a protective function of GSN against amyloid-beta toxicity that is abolished by frameshift mutations, linking GSN function to Alzheimer's disease biology.\",\n      \"evidence\": \"In vitro functional assay of mutant GSN constructs, whole genome sequencing, plasma/CSF GSN and A\\u03b2 ELISA\",\n      \"pmids\": [\"36650038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of A\\u03b2 toxicity inhibition not defined\", \"Causality of mutations in disease onset not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved non-redundant isoform-specific roles in actin regulation and motility, and characterized immunomodulatory host-protective functions of plasma gelsolin.\",\n      \"evidence\": \"GSN-knockout melanoma cells with single-isoform rescue and actin/migration assays; murine candidemia model with pGSN injection, phagocytosis and reactive radical measurement (preprint)\",\n      \"pmids\": [\"40597347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of isoform functional divergence unknown\", \"pGSN immunomodulation data are from a single-lab preprint\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GSN's calcium-regulated actin-severing activity is mechanistically coupled to its diverse downstream outputs (p38/GATA-4 hypertrophy, Akt survival signaling, MMP activation, amyloid protection) across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or biochemical model links actin remodeling to signaling outputs\", \"Isoform-specific structural determinants undefined\", \"Context dependence of pro- vs anti-apoptotic roles unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MMP14\", \"CD44\", \"HNRNPK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}