{"gene":"PTX3","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1993,"finding":"TSG-14/PTX3 encodes a secreted 42-kDa glycoprotein with a cleavable signal peptide sequence that is glycosylated, and its expression is induced at the transcriptional level by TNF and IL-1 in fibroblasts and endothelial cells, with de novo protein synthesis not required for mRNA induction.","method":"Cell-free transcription/translation, in vitro translation with microsomes, nuclear run-on analysis, Northern blot","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in cell-free system, direct transcriptional run-on analysis, glycosylation and signal peptide cleavage confirmed biochemically in a founding paper replicated by subsequent studies","pmids":["7679696"],"is_preprint":false},{"year":1994,"finding":"PTX3 is expressed and released by monocytes/macrophages and myeloid cell lines in response to LPS or IL-1β at the transcriptional level; induction in monocytes requires de novo protein synthesis, is inhibited by IL-4, and is not mediated by secondary TNF or IL-1 signals.","method":"Northern blot, nuclear run-on analysis, actinomycin D and cycloheximide treatment, antibody neutralization, PTX3-specific antiserum for protein detection","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (run-on, inhibitors, antibody neutralization) in a focused mechanistic study replicated across subsequent literature","pmids":["7949102"],"is_preprint":false},{"year":1994,"finding":"TSG-14/PTX3 protein is produced by fibroblasts and hepatoma cells in response to TNF, IL-1, IL-6, or dexamethasone, but hepatocytes are not the major site of TSG-14 synthesis in vivo after LPS injection in mice.","method":"Immunoprecipitation, Northern blot, LPS injection in mice with tissue analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation, in vivo tissue analysis, single lab with two orthogonal methods","pmids":["7523502"],"is_preprint":false},{"year":1995,"finding":"The TSG-14/PTX3 promoter lacks TATA and CCAAT boxes, uses an initiator element for transcription initiation, and contains NF-IL6, AP-1, NF-κB, Sp1, GAS, and Ets binding sites; TNF-inducible promoter activity was demonstrated by reporter gene transfection.","method":"Primer extension, S1 nuclease protection, luciferase reporter transfection, sequence analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct promoter dissection by reporter assay and transcription start site mapping with multiple orthogonal methods","pmids":["7592730"],"is_preprint":false},{"year":1998,"finding":"IFN-γ inhibits PTX3 gene expression in human monocytes by reducing PTX3 mRNA stability and transcription, and suppresses PTX3 protein secretion; this inhibition is monocyte-specific and does not occur in fibroblasts or endothelial cells.","method":"Northern blot, actinomycin D mRNA stability assay, ELISA for protein, cell-type comparison experiments","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability and transcription assessed by orthogonal approaches, cell-type specificity confirmed, single lab","pmids":["9521058"],"is_preprint":false},{"year":2000,"finding":"LPS-induced TSG-14/PTX3 expression in macrophages (but not fibroblasts) requires de novo protein synthesis, is delayed compared to fibroblasts, is inhibited by IFN-γ through an unconventional STAT1-independent mechanism not involving NF-κB inhibition, and is blocked by the antioxidant PDTC (which inhibits NF-κB).","method":"Northern blot, cycloheximide treatment, NF-κB EMSA, IκB degradation assay, STAT1 null mouse macrophages","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical methods including knockout cells, single lab but comprehensive mechanistic dissection","pmids":["10733100"],"is_preprint":false},{"year":2001,"finding":"TSG-14/PTX3 transgenic mice overexpressing the murine gene are more resistant to LPS-induced endotoxic shock and CLP-induced sepsis; macrophages from transgenic mice produce higher nitric oxide in response to IFN-γ, TNF-α, and LPS due to increased IFN-γ responsiveness.","method":"Transgenic mouse generation, LPS endotoxemia model, CLP sepsis model, NO assay in macrophage cultures","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic gain-of-function with defined survival phenotype, replicated in two transgenic lines, macrophage mechanism identified","pmids":["11404378"],"is_preprint":false},{"year":2004,"finding":"Recombinant PTX3 binds to zymosan particles and Paracoccidioides brasiliensis yeast cells and acts as an opsonin to promote macrophage phagocytosis; this opsonic activity is dependent on dectin-1 receptor signaling.","method":"Recombinant PTX3 binding assay, transgenic mouse macrophage phagocytosis assay, dectin-1 blockade, FACS, RT-PCR","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding assay with recombinant protein, receptor blockade identifying dectin-1 dependency, orthogonal methods in one study","pmids":["14726497"],"is_preprint":false},{"year":2005,"finding":"TNF-α induces PTX3 expression in human lung epithelial cells via the JNK signaling pathway; blockade of JNK1 or JNK2 by pharmacological inhibitor SP600125 or siRNA knockdown significantly reduced PTX3 expression, while NF-κB, ERK, and p38 MAPK inhibitors had no effect. Expression requires both transcriptional and translational regulation.","method":"Pharmacological inhibitors, siRNA knockdown, actinomycin D, cycloheximide, in vivo LPS injection in rats","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — pathway dissection using specific inhibitors and siRNA knockdown of JNK1/JNK2 individually, orthogonal verification in vivo","pmids":["16339571"],"is_preprint":false},{"year":2007,"finding":"PTX3 is stored in specific (lactoferrin-positive) granules of neutrophils and undergoes rapid release in response to microbial recognition and inflammatory signals; released PTX3 partially localizes in neutrophil extracellular traps (NETs). PTX3-deficient neutrophils have defective microbial recognition and phagocytosis of Aspergillus fumigatus.","method":"Immunofluorescence, subcellular fractionation, PTX3-deficient mouse neutrophils, phagocytosis assay, NET visualization","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct subcellular localization by fractionation and imaging, loss-of-function with specific phenotypic readout, replicated in subsequent papers","pmids":["17389238"],"is_preprint":false},{"year":2008,"finding":"Human recombinant PTX3 is predominantly composed of covalently linked octamers; Cys47, Cys49, and Cys103 in the N-terminal domain form three interchain disulfide bonds stabilizing a tetrameric unit, and Cys317 and Cys318 in the C-terminal domain link two tetramers into an octamer. PTX3 tetramers (but not predominantly dimeric mutants) are the functional units required for cumulus extracellular matrix organization.","method":"Native and denaturing PAGE, mass spectrometry, Cys-to-Ser site-directed mutagenesis, ex vivo cumulus matrix rescue assay in PTX3-deficient mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with recombinant mutants, mass spectrometry-based disulfide mapping, functional validation in ex vivo biological assay, multiple orthogonal methods","pmids":["18223257"],"is_preprint":false},{"year":2008,"finding":"Glucocorticoids have divergent cell-type-specific effects on PTX3 production: in myeloid dendritic cells and macrophages (hematopoietic cells), GR represses PTX3 transcription in a dimerization-independent manner via interference with NF-κB/AP-1; in fibroblasts and endothelial cells (non-hematopoietic), GR acts as a dimerization-dependent transcription factor to induce PTX3 expression. GC administration in vivo increases blood PTX3 levels.","method":"Cell-specific PTX3 production assays, GR dimerization-deficient mouse cells, in vivo GC administration in mice and humans (Cushing syndrome patients)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — dimerization-deficient mouse cells distinguish GR mechanisms, orthogonal in vivo and clinical validation, multiple cell types tested","pmids":["18703503"],"is_preprint":false},{"year":2009,"finding":"PTX3 and TSG-6 are co-regulated in monocytes, macrophages, and myeloid dendritic cells; both proteins are stored in neutrophil granules; IL-10 synergizes with TLR-mediated PTX3 induction but inhibits TSG-6, while IL-4 suppresses both. TSG-6 co-localizes with PTX3 in inflammatory infiltrates.","method":"RT-PCR, ELISA, immunohistochemistry, cell stimulation assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple cell types and cytokine conditions tested, single lab, no in vitro reconstitution","pmids":["19389798"],"is_preprint":false},{"year":2010,"finding":"CEBPD (C/EBPδ) transcriptionally activates PTX3 expression in astrocytes, and astrocyte-derived PTX3 attenuates macrophage-mediated phagocytosis of damaged neuron cells, contributing to accumulation of damaged neurons as a hallmark of Alzheimer's disease pathogenesis.","method":"Global gene expression profiling, reporter assay, PTX3 knockdown/overexpression, phagocytosis assay","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation confirmed by reporter assay, functional phagocytosis assay, single lab with two orthogonal approaches","pmids":["21112127"],"is_preprint":false},{"year":2012,"finding":"PTX3 interacts with C1q, ficolin-1, ficolin-2, and mannose-binding lectin (MBL) in the classical and lectin complement pathways, and also interacts with complement regulators C4b-binding protein and factor H; these interactions result in cooperative pathogen recognition and complement activation or regulation.","method":"Binding assays (as reviewed with referenced experimental data), interaction studies","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding partners identified, referenced experimental data, but review paper summarizing prior results; no single novel experiment in this paper","pmids":["22964239"],"is_preprint":false},{"year":2013,"finding":"PTX3 deficiency in mice impairs blood-brain barrier integrity and resolution of brain edema after ischemic injury, associated with impaired glial scar formation and altered scar-associated extracellular matrix production; IL-1 is identified as a key driver of PTX3 expression in the brain after experimental stroke.","method":"PTX3 gene-deleted mice, middle cerebral artery occlusion model, BBB integrity assay, brain edema measurement, immunohistochemistry","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular phenotype and ECM analysis, single lab","pmids":["24346689"],"is_preprint":false},{"year":2013,"finding":"PTX3 attenuates cardiac ischemia-reperfusion injury in a transplantation model by reducing cardiomyocyte apoptosis, neutrophil/macrophage infiltration, and restricting γδ T-cell expansion with decreased IL-23/IL-17A expression; neutralizing PTX3 antibody worsened injury.","method":"Murine heterotopic heart transplant model, neutralizing antibody, exogenous PTX3 administration, troponin T measurement, hemodynamic assessment, flow cytometry for γδ T cells","journal":"Transplant international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function (exogenous PTX3) and loss-of-function (neutralizing antibody) with defined hemodynamic and immune phenotype, single lab","pmids":["24112130"],"is_preprint":false},{"year":2013,"finding":"PTX3 exacerbates pressure overload-induced left ventricular dysfunction; recombinant PTX3 phosphorylates ERK1/2 in cardiac fibroblasts. PTX3-KO mice show attenuated ERK1/2 and NF-κB phosphorylation, reduced IL-6 and CTGF production after TAC; PTX3 transgenic mice show enhanced adverse remodeling and fibrosis.","method":"PTX3 knockout and cardiac-specific transgenic mice, transverse aortic constriction model, echocardiography, Western blot (pERK1/2), in vitro recombinant PTX3 treatment of cardiac fibroblasts","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic approaches (KO and TG) with defined mechanistic signaling readout (ERK1/2 phosphorylation) and in vitro receptor validation","pmids":["23372656"],"is_preprint":false},{"year":2014,"finding":"PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts antifungal protection against Aspergillus fumigatus through TLR4/MD-2-mediated TRIF-dependent signaling, converging on IL-10 production; MD-2-deficient mice phenocopy TLR4-deficient mice in aspergillosis susceptibility and cannot be rescued by PTX3 treatment unless reconstituted with MD-2-competent neutrophils.","method":"In vitro MD-2 binding assay, Md2-/- and Tlr4-/- mouse infection models, adoptive neutrophil transfer, cytokine measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding assay, multiple knockout mouse models, adoptive transfer rescue experiment, defined signaling pathway","pmids":["25049357"],"is_preprint":false},{"year":2014,"finding":"PTX3 acts as an extrinsic oncosuppressor by regulating complement-dependent, macrophage-sustained tumor-promoting inflammation; PTX3 deficiency amplifies complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression is epigenetically silenced by promoter methylation in selected human tumors (leiomyosarcomas, colorectal cancer).","method":"Ptx3-/- mice in carcinogenesis models, pharmacological complement blocking, CCL2 measurement, macrophage depletion, DNA methylation analysis, gene-targeted mouse epistasis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with complement pathway, pharmacological blocking, multiple tumor models, epigenetic mechanism validated","pmids":["25679762"],"is_preprint":false},{"year":2014,"finding":"PTX3 stimulates osteoclastogenesis indirectly by increasing RANKL mRNA expression and protein secretion from precursor osteoblasts, accompanied by increased RUNX2 expression; PTX3 siRNA knockdown in precursor osteoblasts suppresses RANKL production and reduces osteoclastogenesis in co-culture.","method":"Co-culture assay (precursor osteoblasts + precursor osteoclasts), TRAP staining, siRNA knockdown, RANKL ELISA, qRT-PCR, LPS-induced osteolysis mouse model","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with defined molecular readout (RANKL), in vivo model, single lab","pmids":["24664887"],"is_preprint":false},{"year":2015,"finding":"EGF-induced PTX3 transcriptional activation in head and neck squamous cell carcinoma cells occurs via c-Jun binding to AP-1 sites in the PTX3 promoter, dependent on PI3K/Akt and NF-κB pathways; autocrine PTX3 promotes cell migration, invasion, endothelial cell interaction, and lung metastasis, involving fibronectin, MMP9, and E-cadherin regulation.","method":"c-Jun and NF-κB knockdown, luciferase promoter reporter assay, migration/invasion assays, tail-vein xenograft model, ChIP (AP-1 binding)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay and knockdown identify transcriptional mechanism, in vivo metastasis model, single lab","pmids":["25797258"],"is_preprint":false},{"year":2015,"finding":"PTX3 promotes fibrocyte differentiation in a manner dependent on FcγRI; this pro-fibrocyte effect is dominant over SAP's inhibitory effect in competition. SAP and PTX3 bind FcγRI at different sites.","method":"In vitro fibrocyte differentiation assay, FcγRI blocking, competition binding studies with recombinant proteins, murine lung fibrosis model (immunohistochemistry)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identified by blocking experiment, binding competition studies, functional differentiation assay, single lab","pmids":["25774777"],"is_preprint":false},{"year":2016,"finding":"PTX3 bridges humoral innate and adaptive immunity by binding to splenic marginal zone (MZ) B cells; PTX3 is released by a perifollicular neutrophil subset with an immune activation gene signature, and promotes homeostatic and infection-induced IgM and class-switched IgG antibody production to microbial capsular polysaccharides via T cell-independent and T cell-dependent signals.","method":"PTX3 binding to MZ B cells (flow cytometry), PTX3-deficient mouse immunoglobulin measurement, neutrophil gene expression profiling, infection/immunization models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, loss-of-function in PTX3-deficient mice and humans, infection and immunization models, multiple orthogonal methods","pmids":["27621420"],"is_preprint":false},{"year":2016,"finding":"MSC-derived PTX3 is required for wound healing by promoting fibrin remodeling; Ptx3-/- MSCs show defective pericellular fibrinolysis and migration through fibrin, and when transplanted fail to close wounds normally, with increased fibrin and reduced D-dimer deposition at wound sites.","method":"Murine skin wound model with GFP+ MSCs, confocal microscopy, biochemical fibrin/D-dimer quantification, in vitro fibrinolysis and fibrin migration assays in Ptx3-/- vs WT MSCs","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with direct biochemical readout (fibrin/D-dimer), in vitro mechanistic validation, in vivo transplantation model","pmids":["26763449"],"is_preprint":false},{"year":2017,"finding":"PTX3 expression is regulated by two enhancers: enhancer 1 (230 kb upstream of promoter) responds to inflammatory transcription factors including STAT3; enhancer 2 (in the second exon) is involved in pre-initiation complex assembly. Polycomb repressive complex 2 (PRC2) silences these elements under basal conditions. In colorectal cancer, enhancer 1 is epigenetically inactivated early and acquires STAT3 binding; inhibition of STAT3 phosphorylation restores PTX3 expression.","method":"ChIP-seq, STAT3 inhibitor treatment, DNA methylation analysis, STAT3 knockdown, luciferase reporter assays, 5-aza-dC demethylation","journal":"Oncoimmunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq identifies enhancer occupancy, pharmacological and genetic STAT3 manipulation validates mechanism, multiple orthogonal epigenetic methods","pmids":["28811977"],"is_preprint":false},{"year":2017,"finding":"Oleate induces PTX3 expression and secretion via Akt/NF-κB pathway activation in head and neck squamous cell carcinoma cells; NF-κB activation is essential for oleate-induced PTX3 mRNA stabilization. Oleate-induced PTX3 promotes tumor cell migration, invasion, and EMT (vimentin, MMP-3 upregulation) in an autocrine manner; vimentin is a downstream effector.","method":"Akt/NF-κB inhibitors, siRNA knockdown of PTX3 and vimentin, mRNA stability assay, migration/invasion assays, lung metastasis xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with inhibitors and siRNA, mRNA stability confirmed, in vivo metastasis validation, single lab","pmids":["28489600"],"is_preprint":false},{"year":2019,"finding":"Autocrine PTX3 produced by invasive melanoma cells triggers an IKK/NF-κB signaling pathway that promotes migration, invasion, and TWIST1 expression; this effect is dependent on TLR4 and MYD88, as their knockdown inhibits PTX3-induced migration.","method":"CRISPR/Cas9 PTX3 editing, TLR4/MYD88 siRNA knockdown, NF-κB reporter assay, migration/invasion assays, xenograft lung extravasation model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR loss-of-function, receptor identification by knockdown, in vivo xenograft model, defined signaling mechanism","pmids":["31253871"],"is_preprint":false},{"year":2019,"finding":"C1q promotes PTX3 binding to CD14+ monocytes, and PTX3 synergizes with C1q to promote NLRP3 inflammasome overactivation, gasdermin D (GSDMD)-dependent pyroptosis, and inflammatory cytokine release (TNF-α, IL-1β, IL-6) in monocytes; IL-6 further promotes PTX3+C1q-induced pyroptosis.","method":"Flow cytometry (PTX3/monocyte binding), GSDMD cleavage assay (Western blot), caspase-1 activity, cytokine ELISA, cell death assays","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and GSDMD cleavage measured, NLRP3 pathway intermediates confirmed, single lab","pmids":["31601476"],"is_preprint":false},{"year":2020,"finding":"Doxorubicin induces upregulation and enrichment of PTX3 in tumor-derived small extracellular vesicles (sEVs); CRISPR/Cas9 deletion of PTX3 suppresses chemotherapy-induced sEV-mediated premetastatic niche formation and pulmonary metastasis in triple-negative breast cancer xenografts.","method":"Proteomic analysis of sEVs, CRISPR/Cas9 PTX3 deletion, xenograft mouse metastasis model, pharmacological inhibition of sEV secretion/uptake","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR loss-of-function with defined metastatic phenotype, proteomic identification of PTX3 in sEVs, in vivo validation, single lab","pmids":["33115808"],"is_preprint":false},{"year":2020,"finding":"SH3RF3 interacts with JNK in a JIP-dependent manner, leading to enhanced JNK phosphorylation and JNK-JUN pathway activation, which transcriptionally activates PTX3 expression to expand cancer stem-like cell subpopulations in breast cancer.","method":"Co-immunoprecipitation (SH3RF3-JNK), phospho-JNK Western blot, PTX3 reporter assay, ChIP for JUN at PTX3 promoter, breast cancer organoid culture","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies SH3RF3-JNK complex, ChIP confirms JUN binding at PTX3 promoter, organoid validation, single lab","pmids":["32427938"],"is_preprint":false},{"year":2021,"finding":"PTX3 deficiency in mice worsens bleomycin-induced lung fibrosis with impaired fibrin removal and increased collagen deposition; PTX3 interacts with fibrin and plasminogen to facilitate timely removal of fibrin-rich ECM during tissue repair.","method":"PTX3 knockout mouse BLM model, fibrin and collagen quantification, fibrinolysis assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined biochemical phenotype, single lab, mechanistic interaction inferred from prior binding data","pmids":["34276664"],"is_preprint":false},{"year":2021,"finding":"PTX3 does not directly bind K. pneumoniae or promote opsonophagocytosis of this pathogen; PTX3 controls K. pneumoniae infection in a complement-independent manner by modulating inflammatory responses and reducing fibrin deposition and tissue damage.","method":"Ptx3-/-, Ptx3-/-/C3-/- double-KO mice, bacterial burden quantification, complement interaction assays (negative result for direct binding), histopathology, fibrinogen/fibrin measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with complement-deficient mice definitively places PTX3 action as complement-independent; negative binding result established by direct assay","pmids":["34093560"],"is_preprint":false},{"year":2021,"finding":"PTX3 promotes osteogenic differentiation in an inflammatory environment by positioning itself in the HA-dependent pericellular matrix, promoting HA synthesis and CD44 expression, and activating a FAK/AKT positive feedback loop that further upregulates HAS1/2/3 and CD44; disruption of any component of this HA/CD44/FAK/AKT loop abolishes PTX3's osteogenic effect.","method":"PTX3 gain- and loss-of-function in MC3T3-E1 cells, HA digestion, FAK/AKT inhibitors, CD44 and HAS knockdown, in vivo periodontitis bone regeneration model with local PTX3 treatment, micro-CT","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors and knockdowns define signaling circuit, in vivo validation, single lab","pmids":["34653679"],"is_preprint":false},{"year":2022,"finding":"SPHK1 promotes GBM growth partly through JNK phosphorylation leading to transcriptional activation of PTX3 via JNK-JUN and JNK-ATF3 pathways; SPHK1 and PTX3 form a positive feedback loop that reciprocally increases each other's expression and promotes inflammation.","method":"SPHK1 overexpression/silencing, PTX3 knockdown, phospho-JNK Western blot, reporter assay, orthotopic mouse GBM model","journal":"Acta pharmaceutica sinica B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss of function, signaling pathway confirmed by Western blot, in vivo validation, single lab","pmids":["36562002"],"is_preprint":false},{"year":2023,"finding":"METTL3-mediated m6A modification promotes YTHDF3-dependent degradation of PTX3 mRNA; loss of METTL3 impairs this m6A-YTHDF3 degradation pathway, leading to elevated PTX3 expression that promotes M2 macrophage activation via PI3K/AKT and JAK/STAT6 signaling and modulates STX17-dependent autophagy maturation.","method":"m6A-seq, RIP (YTHDF3-mRNA interaction), METTL3 conditional knockout in myeloid cells, PTX3 knockdown/overexpression, Western blot for PI3K/AKT and JAK/STAT6 pathway","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — m6A-seq identifies modification site, RIP validates reader-mRNA interaction, genetic KO with defined cellular phenotype, multiple signaling pathway readouts","pmids":["37957139"],"is_preprint":false},{"year":2023,"finding":"PRMT1-mediated H4R3me2a epigenetic mark activates PTX3 transcription by promoting YY1 binding to its promoter; reduced PRMT1 in IDH1-mutant gliomas decreases PTX3 expression, leading to impaired autophagic balance and heightened ferritinophagic flux.","method":"ChIP for H4R3me2a and YY1 at PTX3 promoter, PRMT1 knockdown/overexpression, PTX3 siRNA/secretion inhibition, autophagic flux assays, ferritin level measurement","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifies epigenetic writer and transcription factor, functional autophagy readout, single lab","pmids":["36647288"],"is_preprint":false},{"year":2024,"finding":"NAT10-mediated N4-acetylcytidine (ac4C) modification of PTX3 mRNA increases its stability and translation efficiency in fibroblast-like synoviocytes; elevated NAT10 drives PTX3-dependent synovial aggression and immune cell infiltration in rheumatoid arthritis. NAT10 inhibition in vivo attenuates arthritis severity.","method":"ac4C-RIP-seq combined with RNA-seq, RNA immunoprecipitation (NAT10-PTX3 mRNA), NAT10 knockdown and inhibitor (remodelin), synoviocyte migration/invasion assays, CIA and DTHA mouse models","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 1 / Strong — epitranscriptomic RIP-seq identifies modification, direct protein-mRNA RIP validates interaction, genetic and pharmacological loss-of-function, multiple in vivo disease models","pmids":["38724075"],"is_preprint":false},{"year":2017,"finding":"P. aeruginosa GroEL activates PTX3 expression in monocytes via TLR4-dependent NF-κB pathway while simultaneously inhibiting microRNA-9, which normally targets the PTX3 transcript; GroEL-induced PTX3 then acts as an opsonin to promote phagocytosis of S. aureus.","method":"NF-κB inhibitor, microRNA-9 overexpression/inhibition, TLR4 blocking, phagocytosis assay","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual mechanism (NF-κB activation and miR-9 suppression) identified with pathway inhibitors, functional opsonin assay, single lab","pmids":["28031262"],"is_preprint":false}],"current_model":"PTX3 is a multimeric (octameric, with tetramers as functional units stabilized by N-terminal interchain disulfide bonds) secreted glycoprotein stored preformed in neutrophil specific granules and released upon inflammatory stimuli; its transcription is induced by IL-1/TNF/LPS via NF-κB and AP-1 elements in a promoter lacking TATA/CCAAT boxes, positively regulated by glucocorticoids (via dimerization-dependent GR) in stromal cells and by PRMT1-H4R3me2a and NAT10-ac4C epitranscriptomic mechanisms, while being repressed by IFN-γ (via mRNA destabilization in monocytes), PRC2, and m6A-YTHDF3-dependent mRNA degradation; PTX3 functions as a humoral pattern recognition molecule that opsonizes pathogens and zymosan through dectin-1-dependent phagocytosis, activates complement via C1q/ficolin/MBL interactions and modulates it through factor H binding, signals antifungal protection through a TLR4/MD-2/TRIF/IL-10 axis, promotes antibody production by marginal zone B cells via perifollicular neutrophil release, tunes tumor-promoting inflammation by restraining complement-CCL2-macrophage recruitment (oncosuppressor function epigenetically silenced by promoter methylation), promotes fibrin remodeling and tissue repair in wounds and lungs, activates ERK1/2 in cardiac fibroblasts to modulate hypertrophic remodeling, and in cancer cells activates TLR4/NF-κB-driven invasion and metastasis through autocrine signaling."},"narrative":{"mechanistic_narrative":"PTX3 (TSG-14) is a secreted, glycosylated multimeric pattern-recognition glycoprotein that links humoral innate immunity to inflammation, tissue repair, and complement regulation [PMID:7679696, PMID:25679762]. Its expression is induced at the transcriptional level by TNF, IL-1, and LPS in fibroblasts, endothelial cells, and myeloid cells through a TATA/CCAAT-less promoter carrying NF-κB, AP-1, NF-IL6, Sp1, GAS, and Ets elements, with lung epithelial induction routed through JNK rather than NF-κB [PMID:7679696, PMID:7949102, PMID:7592730, PMID:16339571]. Production is shaped by additional layers of control: glucocorticoids exert opposite, cell-type-specific effects through dimerization-independent GR repression in myeloid cells versus dimerization-dependent induction in stromal cells [PMID:18703503]; IFN-γ represses the gene in monocytes by destabilizing its mRNA [PMID:9521058]; distal/intronic enhancers are basally silenced by PRC2 [PMID:28811977]; and the transcript is regulated epitranscriptomically by METTL3/m6A-YTHDF3-mediated decay, NAT10-ac4C stabilization, and PRMT1-H4R3me2a/YY1-driven activation [PMID:37957139, PMID:36647288, PMID:38724075]. Structurally, recombinant PTX3 assembles into covalent octamers built from disulfide-stabilized tetramers, and the tetramer is the functional unit required for extracellular matrix organization [PMID:18223257]. Stored preformed in neutrophil specific granules and rapidly released upon microbial challenge, PTX3 opsonizes zymosan and fungi to drive dectin-1-dependent phagocytosis, mediates antifungal protection against Aspergillus through an MD-2/TLR4/TRIF/IL-10 axis, and bridges innate and adaptive immunity by binding marginal-zone B cells to promote antibody responses [PMID:14726497, PMID:17389238, PMID:25049357, PMID:27621420]. It engages complement components C1q, ficolins, and MBL and the regulators C4BP and factor H to tune complement activation [PMID:22964239], and acts as an extrinsic oncosuppressor by restraining complement-CCL2-driven tumor-promoting macrophage recruitment, a function epigenetically silenced by promoter methylation in human tumors [PMID:25679762]. PTX3 also promotes fibrin remodeling and resolution during wound healing and lung repair through interactions with fibrin and plasminogen [PMID:26763449, PMID:34276664], and activates ERK1/2 in cardiac fibroblasts to exacerbate pressure-overload remodeling [PMID:23372656]. In a context-dependent reversal, autocrine tumor-cell-derived PTX3 drives TLR4/MYD88/NF-κB-dependent migration, invasion, EMT, and metastasis [PMID:25797258, PMID:31253871].","teleology":[{"year":1993,"claim":"Established that PTX3 is an inducible secreted glycoprotein rather than a constitutive product, defining it as an acute inflammatory response gene controlled at transcription by TNF and IL-1.","evidence":"Cell-free transcription/translation, microsome processing, nuclear run-on, and Northern blot in fibroblasts and endothelial cells","pmids":["7679696"],"confidence":"High","gaps":["Did not define promoter elements responsible for cytokine induction","Function of the secreted protein unknown"]},{"year":1994,"claim":"Showed that myeloid cells produce PTX3 and that monocyte versus stromal induction differ mechanistically, hinting at cell-type-specific regulation.","evidence":"Run-on, actinomycin D/cycloheximide, antibody neutralization, and immunoprecipitation in monocytes/macrophages, fibroblasts, and hepatoma cells plus LPS injection in mice","pmids":["7949102","7523502"],"confidence":"High","gaps":["Did not identify the protein-synthesis-dependent factor required in monocytes","In vivo cellular source incompletely mapped"]},{"year":1995,"claim":"Defined the PTX3 promoter architecture, explaining how diverse inflammatory signals converge on its transcription.","evidence":"Primer extension, S1 nuclease protection, and luciferase reporter transfection identifying an initiator element and NF-κB/AP-1/NF-IL6/Sp1/GAS/Ets sites","pmids":["7592730"],"confidence":"High","gaps":["Did not assign which sites mediate which stimulus","Distal regulatory elements not examined"]},{"year":1998,"claim":"Resolved how IFN-γ represses PTX3 and showed the repression is monocyte-restricted, establishing post-transcriptional control via mRNA stability.","evidence":"Northern blot, actinomycin D mRNA-stability assay, and ELISA comparing monocytes to fibroblasts/endothelium","pmids":["9521058"],"confidence":"Medium","gaps":["mRNA destabilizing factor not identified","Mechanism of cell-type specificity unresolved"]},{"year":2000,"claim":"Distinguished signaling requirements for LPS induction in macrophages versus fibroblasts, showing IFN-γ represses through an unconventional STAT1-independent route.","evidence":"Northern blot, cycloheximide, NF-κB EMSA, IκB degradation, and STAT1-null macrophages","pmids":["10733100"],"confidence":"High","gaps":["Identity of the STAT1-independent repressive pathway unknown","Protein-synthesis-dependent intermediary not defined"]},{"year":2001,"claim":"Provided the first in vivo gain-of-function evidence that PTX3 protects against endotoxemia and sepsis, linking it to host defense.","evidence":"TSG-14/PTX3 transgenic mice in LPS and CLP models with macrophage NO assays","pmids":["11404378"],"confidence":"High","gaps":["Molecular mechanism of protection not defined","Direct pathogen-binding role not yet established"]},{"year":2004,"claim":"Identified PTX3 as a pathogen opsonin acting through dectin-1, giving it a concrete antifungal effector function.","evidence":"Recombinant PTX3 binding to zymosan and P. brasiliensis, macrophage phagocytosis with dectin-1 blockade, FACS/RT-PCR","pmids":["14726497"],"confidence":"High","gaps":["Direct PTX3-dectin-1 versus indirect bridging not fully distinguished","Generality across pathogens untested at this stage"]},{"year":2007,"claim":"Localized PTX3 to neutrophil specific granules and NETs, explaining its rapid availability at infection sites and a non-redundant antifungal role.","evidence":"Immunofluorescence, subcellular fractionation, NET imaging, and phagocytosis in PTX3-deficient neutrophils against A. fumigatus","pmids":["17389238"],"confidence":"High","gaps":["Granule-targeting/storage mechanism unknown","Receptor mediating neutrophil antifungal recognition not yet identified"]},{"year":2008,"claim":"Defined the disulfide-bonded octameric quaternary structure and showed tetramers are the functional unit for ECM organization.","evidence":"Native/denaturing PAGE, mass spectrometry disulfide mapping, Cys-to-Ser mutagenesis, and ex vivo cumulus matrix rescue in PTX3-deficient mice","pmids":["18223257"],"confidence":"High","gaps":["Structural basis of ligand recognition not solved","Whether all functions require tetramer/octamer untested"]},{"year":2008,"claim":"Explained the paradoxical glucocorticoid regulation of PTX3 as opposite GR mechanisms in hematopoietic versus stromal cells.","evidence":"GR dimerization-deficient mouse cells, cell-type-specific production assays, and in vivo/clinical GC administration","pmids":["18703503"],"confidence":"High","gaps":["Promoter elements distinguishing GR repression from induction not pinpointed","Physiological consequence of GC-raised blood PTX3 unclear"]},{"year":2012,"claim":"Consolidated PTX3's complement interactome, positioning it as both an activator and regulator across classical and lectin pathways.","evidence":"Binding/interaction studies (review with referenced experimental data) for C1q, ficolins, MBL, C4BP, factor H","pmids":["22964239"],"confidence":"Medium","gaps":["Review-level synthesis without a novel experiment","Binding stoichiometry and in vivo balance of activation versus regulation unresolved"]},{"year":2013,"claim":"Demonstrated tissue-protective and ECM-remodeling roles for PTX3 in brain and heart injury, including a defined ERK1/2 signaling readout in cardiac fibroblasts.","evidence":"PTX3-KO and transgenic mice in MCAO stroke, heterotopic heart transplant, and TAC models with BBB/edema, hemodynamics, and pERK1/2 Western blot","pmids":["24346689","24112130","23372656"],"confidence":"High","gaps":["Receptor mediating ERK1/2 activation in fibroblasts not identified","Reconciling protective versus deleterious cardiac roles across injury models unresolved"]},{"year":2014,"claim":"Defined the MD-2/TLR4/TRIF/IL-10 antifungal signaling axis, gave PTX3 an extrinsic oncosuppressor function via complement-CCL2-macrophage restraint, and showed epigenetic silencing in human tumors.","evidence":"In vitro MD-2 binding, Md2/Tlr4-KO infection with adoptive neutrophil transfer; Ptx3-KO carcinogenesis models with complement blockade, CCL2 measurement, and promoter methylation analysis","pmids":["25049357","25679762"],"confidence":"High","gaps":["How PTX3 simultaneously activates and restrains complement contextually not reconciled","Direct receptor for oncosuppressive signaling distinct from MD-2 not defined"]},{"year":2016,"claim":"Established PTX3 as a bridge to adaptive immunity through marginal-zone B-cell binding and as a tissue-repair factor enabling fibrin remodeling.","evidence":"PTX3 binding to MZ B cells, immunoglobulin measurement in PTX3-deficient mice/humans, perifollicular neutrophil profiling; MSC wound model with fibrin/D-dimer biochemistry and fibrinolysis assays","pmids":["27621420","26763449"],"confidence":"High","gaps":["MZ B-cell receptor for PTX3 not identified","Molecular basis of PTX3-promoted pericellular fibrinolysis incompletely defined"]},{"year":2015,"claim":"Revealed a tumor-cell-intrinsic, autocrine PTX3 program in which growth-factor and lipid signaling drive AP-1/NF-κB-dependent PTX3 to promote invasion and metastasis, plus FcγRI-dependent pro-fibrotic differentiation.","evidence":"c-Jun/NF-κB knockdown, promoter reporters/ChIP, mRNA-stability assays, migration/invasion and xenograft metastasis models in HNSCC; FcγRI blocking and competition with SAP in fibrocyte assays","pmids":["25797258","28489600","25774777"],"confidence":"Medium","gaps":["Receptor for autocrine PTX3 not defined in these studies","Reconciliation with oncosuppressor role left to context"]},{"year":2017,"claim":"Resolved the distal regulatory landscape and its STAT3-driven epigenetic remodeling in cancer, and identified a pathogen-driven dual transcriptional/microRNA control of PTX3.","evidence":"ChIP-seq, STAT3 inhibition/knockdown, DNA methylation/5-aza-dC, reporter assays; and TLR4/NF-κB plus miR-9 manipulation with phagocytosis assay for P. aeruginosa GroEL","pmids":["28811977","28031262"],"confidence":"High","gaps":["Functional consequence of enhancer reactivation in tumors not fully tested","miR-9 regulatory node not validated beyond single model"]},{"year":2019,"claim":"Mapped the autocrine tumor-promoting receptor circuit and an inflammasome-amplifying partnership with C1q, expanding PTX3's signaling repertoire.","evidence":"CRISPR PTX3 editing with TLR4/MYD88 knockdown and NF-κB reporter/migration assays in melanoma; flow cytometry, GSDMD cleavage, caspase-1, and cytokine assays for PTX3+C1q in monocytes","pmids":["31253871","31601476"],"confidence":"High","gaps":["Direct PTX3-TLR4 binding versus co-receptor requirement not resolved","In vivo relevance of PTX3-C1q pyroptosis not established"]},{"year":2020,"claim":"Connected PTX3 to chemotherapy-induced metastatic dissemination and to JNK-JUN-driven cancer stemness, deepening its tumor-cell-intrinsic role.","evidence":"sEV proteomics with CRISPR PTX3 deletion in TNBC xenografts; SH3RF3-JNK Co-IP, phospho-JNK, JUN ChIP at PTX3 promoter, and breast organoids","pmids":["33115808","32427938"],"confidence":"Medium","gaps":["Mechanism of PTX3 enrichment in sEVs unclear","Single-lab findings without reciprocal validation of the SH3RF3-JNK-PTX3 axis"]},{"year":2021,"claim":"Placed PTX3 host defense and tissue protection on fibrin clearance, showing a complement-independent mode against K. pneumoniae and a fibrin/plasminogen-dependent repair role in lung fibrosis.","evidence":"Ptx3-KO bleomycin model with fibrin/collagen quantification and fibrinolysis assays; Ptx3-KO and Ptx3/C3 double-KO mice with bacterial burden and negative direct-binding assays","pmids":["34276664","34093560"],"confidence":"Medium","gaps":["Direct biochemical fibrin/plasminogen binding inferred rather than fully reconstituted here","Anti-inflammatory effector mechanism in K. pneumoniae control undefined"]},{"year":2022,"claim":"Identified additional pro-tumor and bone-remodeling circuits where kinase/lipid signaling drives PTX3, including SPHK1-JNK feedback and a HA/CD44/FAK/AKT osteogenic loop.","evidence":"SPHK1 gain/loss with phospho-JNK and reporter assays in orthotopic GBM; PTX3 gain/loss with HA digestion, FAK/AKT inhibitors, CD44/HAS knockdown, and periodontitis micro-CT","pmids":["36562002","34653679"],"confidence":"Medium","gaps":["Single-model evidence for each circuit","How PTX3 engages the HA pericellular matrix mechanistically not resolved"]},{"year":2023,"claim":"Established epitranscriptomic control of PTX3 as a node coupling RNA modification machinery to macrophage polarization and autophagy.","evidence":"m6A-seq, YTHDF3 RIP, METTL3 myeloid KO with PI3K/AKT and JAK/STAT6 readouts; ChIP for H4R3me2a/YY1 with PRMT1 manipulation and autophagic/ferritinophagy assays","pmids":["37957139","36647288"],"confidence":"High","gaps":["Whether PTX3 protein mediates the autophagy phenotype directly or indirectly not fully separated","Cross-talk among the m6A, ac4C, and H4R3me2a layers untested"]},{"year":2024,"claim":"Defined NAT10-ac4C as a stabilizing/translation-enhancing mark on PTX3 mRNA driving synovial aggression, providing a druggable epitranscriptomic axis in rheumatoid arthritis.","evidence":"ac4C-RIP-seq/RNA-seq, NAT10-PTX3 mRNA RIP, NAT10 knockdown and remodelin, synoviocyte invasion assays, and CIA/DTHA models","pmids":["38724075"],"confidence":"High","gaps":["Downstream PTX3 effector pathway in synoviocytes not fully mapped","Single-lab disease-model validation"]},{"year":null,"claim":"The receptor(s) and structural basis by which secreted PTX3 transduces signals across its divergent contexts—antifungal protection, complement tuning, tissue repair, and tumor promotion—remain incompletely defined, as does how the same molecule is both oncosuppressive and pro-metastatic.","evidence":"Not established in the available corpus","pmids":[],"confidence":"Low","gaps":["No unified structural model of ligand/receptor engagement","Mechanistic reconciliation of opposing tumor roles unresolved","In vivo human relevance of cancer-cell-intrinsic TLR4/MYD88 signaling untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[7,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,19]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[18,27]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,9]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[10,33]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,18,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[19,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,27]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[35,37]}],"complexes":[],"partners":["C1Q","MD-2","TLR4","FCN1","FCN2","MBL","CFH","FCGR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26022","full_name":"Pentraxin-related protein PTX3","aliases":["Pentaxin-related protein PTX3","Tumor necrosis factor alpha-induced protein 5","TNF alpha-induced protein 5","Tumor necrosis factor-inducible gene 14 protein","TSG-14"],"length_aa":381,"mass_kda":42.0,"function":"Plays a role in the regulation of innate resistance to pathogens, inflammatory reactions, possibly clearance of self-components and female fertility","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P26022/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTX3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTX3","total_profiled":1310},"omim":[{"mim_id":"613652","title":"C1q DEFICIENCY 1; C1QD1","url":"https://www.omim.org/entry/613652"},{"mim_id":"613442","title":"PENTRAXIN 4; PTX4","url":"https://www.omim.org/entry/613442"},{"mim_id":"602669","title":"PAIRED-LIKE HOMEODOMAIN TRANSCRIPTION FACTOR 3; PITX3","url":"https://www.omim.org/entry/602669"},{"mim_id":"602492","title":"PENTRAXIN 3; PTX3","url":"https://www.omim.org/entry/602492"},{"mim_id":"602149","title":"PAIRED-LIKE HOMEODOMAIN TRANSCRIPTION FACTOR 1; PITX1","url":"https://www.omim.org/entry/602149"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":230.2},{"tissue":"urinary bladder","ntpm":177.9}],"url":"https://www.proteinatlas.org/search/PTX3"},"hgnc":{"alias_symbol":["TSG-14"],"prev_symbol":["TNFAIP5"]},"alphafold":{"accession":"P26022","domains":[{"cath_id":"2.60.120.200","chopping":"183-381","consensus_level":"high","plddt":94.9218,"start":183,"end":381}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26022","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26022-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26022-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTX3","jax_strain_url":"https://www.jax.org/strain/search?query=PTX3"},"sequence":{"accession":"P26022","fasta_url":"https://rest.uniprot.org/uniprotkb/P26022.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26022/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26022"}},"corpus_meta":[{"pmid":"17389238","id":"PMC_17389238","title":"The humoral pattern 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translation with microsomes, nuclear run-on analysis, Northern blot\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in cell-free system, direct transcriptional run-on analysis, glycosylation and signal peptide cleavage confirmed biochemically in a founding paper replicated by subsequent studies\",\n      \"pmids\": [\"7679696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"PTX3 is expressed and released by monocytes/macrophages and myeloid cell lines in response to LPS or IL-1β at the transcriptional level; induction in monocytes requires de novo protein synthesis, is inhibited by IL-4, and is not mediated by secondary TNF or IL-1 signals.\",\n      \"method\": \"Northern blot, nuclear run-on analysis, actinomycin D and cycloheximide treatment, antibody neutralization, PTX3-specific antiserum for protein detection\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (run-on, inhibitors, antibody neutralization) in a focused mechanistic study replicated across subsequent literature\",\n      \"pmids\": [\"7949102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"TSG-14/PTX3 protein is produced by fibroblasts and hepatoma cells in response to TNF, IL-1, IL-6, or dexamethasone, but hepatocytes are not the major site of TSG-14 synthesis in vivo after LPS injection in mice.\",\n      \"method\": \"Immunoprecipitation, Northern blot, LPS injection in mice with tissue analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation, in vivo tissue analysis, single lab with two orthogonal methods\",\n      \"pmids\": [\"7523502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The TSG-14/PTX3 promoter lacks TATA and CCAAT boxes, uses an initiator element for transcription initiation, and contains NF-IL6, AP-1, NF-κB, Sp1, GAS, and Ets binding sites; TNF-inducible promoter activity was demonstrated by reporter gene transfection.\",\n      \"method\": \"Primer extension, S1 nuclease protection, luciferase reporter transfection, sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct promoter dissection by reporter assay and transcription start site mapping with multiple orthogonal methods\",\n      \"pmids\": [\"7592730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IFN-γ inhibits PTX3 gene expression in human monocytes by reducing PTX3 mRNA stability and transcription, and suppresses PTX3 protein secretion; this inhibition is monocyte-specific and does not occur in fibroblasts or endothelial cells.\",\n      \"method\": \"Northern blot, actinomycin D mRNA stability assay, ELISA for protein, cell-type comparison experiments\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability and transcription assessed by orthogonal approaches, cell-type specificity confirmed, single lab\",\n      \"pmids\": [\"9521058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"LPS-induced TSG-14/PTX3 expression in macrophages (but not fibroblasts) requires de novo protein synthesis, is delayed compared to fibroblasts, is inhibited by IFN-γ through an unconventional STAT1-independent mechanism not involving NF-κB inhibition, and is blocked by the antioxidant PDTC (which inhibits NF-κB).\",\n      \"method\": \"Northern blot, cycloheximide treatment, NF-κB EMSA, IκB degradation assay, STAT1 null mouse macrophages\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical methods including knockout cells, single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"10733100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TSG-14/PTX3 transgenic mice overexpressing the murine gene are more resistant to LPS-induced endotoxic shock and CLP-induced sepsis; macrophages from transgenic mice produce higher nitric oxide in response to IFN-γ, TNF-α, and LPS due to increased IFN-γ responsiveness.\",\n      \"method\": \"Transgenic mouse generation, LPS endotoxemia model, CLP sepsis model, NO assay in macrophage cultures\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic gain-of-function with defined survival phenotype, replicated in two transgenic lines, macrophage mechanism identified\",\n      \"pmids\": [\"11404378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Recombinant PTX3 binds to zymosan particles and Paracoccidioides brasiliensis yeast cells and acts as an opsonin to promote macrophage phagocytosis; this opsonic activity is dependent on dectin-1 receptor signaling.\",\n      \"method\": \"Recombinant PTX3 binding assay, transgenic mouse macrophage phagocytosis assay, dectin-1 blockade, FACS, RT-PCR\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding assay with recombinant protein, receptor blockade identifying dectin-1 dependency, orthogonal methods in one study\",\n      \"pmids\": [\"14726497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TNF-α induces PTX3 expression in human lung epithelial cells via the JNK signaling pathway; blockade of JNK1 or JNK2 by pharmacological inhibitor SP600125 or siRNA knockdown significantly reduced PTX3 expression, while NF-κB, ERK, and p38 MAPK inhibitors had no effect. Expression requires both transcriptional and translational regulation.\",\n      \"method\": \"Pharmacological inhibitors, siRNA knockdown, actinomycin D, cycloheximide, in vivo LPS injection in rats\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — pathway dissection using specific inhibitors and siRNA knockdown of JNK1/JNK2 individually, orthogonal verification in vivo\",\n      \"pmids\": [\"16339571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTX3 is stored in specific (lactoferrin-positive) granules of neutrophils and undergoes rapid release in response to microbial recognition and inflammatory signals; released PTX3 partially localizes in neutrophil extracellular traps (NETs). PTX3-deficient neutrophils have defective microbial recognition and phagocytosis of Aspergillus fumigatus.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, PTX3-deficient mouse neutrophils, phagocytosis assay, NET visualization\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct subcellular localization by fractionation and imaging, loss-of-function with specific phenotypic readout, replicated in subsequent papers\",\n      \"pmids\": [\"17389238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human recombinant PTX3 is predominantly composed of covalently linked octamers; Cys47, Cys49, and Cys103 in the N-terminal domain form three interchain disulfide bonds stabilizing a tetrameric unit, and Cys317 and Cys318 in the C-terminal domain link two tetramers into an octamer. PTX3 tetramers (but not predominantly dimeric mutants) are the functional units required for cumulus extracellular matrix organization.\",\n      \"method\": \"Native and denaturing PAGE, mass spectrometry, Cys-to-Ser site-directed mutagenesis, ex vivo cumulus matrix rescue assay in PTX3-deficient mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with recombinant mutants, mass spectrometry-based disulfide mapping, functional validation in ex vivo biological assay, multiple orthogonal methods\",\n      \"pmids\": [\"18223257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Glucocorticoids have divergent cell-type-specific effects on PTX3 production: in myeloid dendritic cells and macrophages (hematopoietic cells), GR represses PTX3 transcription in a dimerization-independent manner via interference with NF-κB/AP-1; in fibroblasts and endothelial cells (non-hematopoietic), GR acts as a dimerization-dependent transcription factor to induce PTX3 expression. GC administration in vivo increases blood PTX3 levels.\",\n      \"method\": \"Cell-specific PTX3 production assays, GR dimerization-deficient mouse cells, in vivo GC administration in mice and humans (Cushing syndrome patients)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dimerization-deficient mouse cells distinguish GR mechanisms, orthogonal in vivo and clinical validation, multiple cell types tested\",\n      \"pmids\": [\"18703503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTX3 and TSG-6 are co-regulated in monocytes, macrophages, and myeloid dendritic cells; both proteins are stored in neutrophil granules; IL-10 synergizes with TLR-mediated PTX3 induction but inhibits TSG-6, while IL-4 suppresses both. TSG-6 co-localizes with PTX3 in inflammatory infiltrates.\",\n      \"method\": \"RT-PCR, ELISA, immunohistochemistry, cell stimulation assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple cell types and cytokine conditions tested, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"19389798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEBPD (C/EBPδ) transcriptionally activates PTX3 expression in astrocytes, and astrocyte-derived PTX3 attenuates macrophage-mediated phagocytosis of damaged neuron cells, contributing to accumulation of damaged neurons as a hallmark of Alzheimer's disease pathogenesis.\",\n      \"method\": \"Global gene expression profiling, reporter assay, PTX3 knockdown/overexpression, phagocytosis assay\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation confirmed by reporter assay, functional phagocytosis assay, single lab with two orthogonal approaches\",\n      \"pmids\": [\"21112127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTX3 interacts with C1q, ficolin-1, ficolin-2, and mannose-binding lectin (MBL) in the classical and lectin complement pathways, and also interacts with complement regulators C4b-binding protein and factor H; these interactions result in cooperative pathogen recognition and complement activation or regulation.\",\n      \"method\": \"Binding assays (as reviewed with referenced experimental data), interaction studies\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding partners identified, referenced experimental data, but review paper summarizing prior results; no single novel experiment in this paper\",\n      \"pmids\": [\"22964239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTX3 deficiency in mice impairs blood-brain barrier integrity and resolution of brain edema after ischemic injury, associated with impaired glial scar formation and altered scar-associated extracellular matrix production; IL-1 is identified as a key driver of PTX3 expression in the brain after experimental stroke.\",\n      \"method\": \"PTX3 gene-deleted mice, middle cerebral artery occlusion model, BBB integrity assay, brain edema measurement, immunohistochemistry\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular phenotype and ECM analysis, single lab\",\n      \"pmids\": [\"24346689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTX3 attenuates cardiac ischemia-reperfusion injury in a transplantation model by reducing cardiomyocyte apoptosis, neutrophil/macrophage infiltration, and restricting γδ T-cell expansion with decreased IL-23/IL-17A expression; neutralizing PTX3 antibody worsened injury.\",\n      \"method\": \"Murine heterotopic heart transplant model, neutralizing antibody, exogenous PTX3 administration, troponin T measurement, hemodynamic assessment, flow cytometry for γδ T cells\",\n      \"journal\": \"Transplant international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function (exogenous PTX3) and loss-of-function (neutralizing antibody) with defined hemodynamic and immune phenotype, single lab\",\n      \"pmids\": [\"24112130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTX3 exacerbates pressure overload-induced left ventricular dysfunction; recombinant PTX3 phosphorylates ERK1/2 in cardiac fibroblasts. PTX3-KO mice show attenuated ERK1/2 and NF-κB phosphorylation, reduced IL-6 and CTGF production after TAC; PTX3 transgenic mice show enhanced adverse remodeling and fibrosis.\",\n      \"method\": \"PTX3 knockout and cardiac-specific transgenic mice, transverse aortic constriction model, echocardiography, Western blot (pERK1/2), in vitro recombinant PTX3 treatment of cardiac fibroblasts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic approaches (KO and TG) with defined mechanistic signaling readout (ERK1/2 phosphorylation) and in vitro receptor validation\",\n      \"pmids\": [\"23372656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts antifungal protection against Aspergillus fumigatus through TLR4/MD-2-mediated TRIF-dependent signaling, converging on IL-10 production; MD-2-deficient mice phenocopy TLR4-deficient mice in aspergillosis susceptibility and cannot be rescued by PTX3 treatment unless reconstituted with MD-2-competent neutrophils.\",\n      \"method\": \"In vitro MD-2 binding assay, Md2-/- and Tlr4-/- mouse infection models, adoptive neutrophil transfer, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding assay, multiple knockout mouse models, adoptive transfer rescue experiment, defined signaling pathway\",\n      \"pmids\": [\"25049357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTX3 acts as an extrinsic oncosuppressor by regulating complement-dependent, macrophage-sustained tumor-promoting inflammation; PTX3 deficiency amplifies complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression is epigenetically silenced by promoter methylation in selected human tumors (leiomyosarcomas, colorectal cancer).\",\n      \"method\": \"Ptx3-/- mice in carcinogenesis models, pharmacological complement blocking, CCL2 measurement, macrophage depletion, DNA methylation analysis, gene-targeted mouse epistasis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with complement pathway, pharmacological blocking, multiple tumor models, epigenetic mechanism validated\",\n      \"pmids\": [\"25679762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTX3 stimulates osteoclastogenesis indirectly by increasing RANKL mRNA expression and protein secretion from precursor osteoblasts, accompanied by increased RUNX2 expression; PTX3 siRNA knockdown in precursor osteoblasts suppresses RANKL production and reduces osteoclastogenesis in co-culture.\",\n      \"method\": \"Co-culture assay (precursor osteoblasts + precursor osteoclasts), TRAP staining, siRNA knockdown, RANKL ELISA, qRT-PCR, LPS-induced osteolysis mouse model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with defined molecular readout (RANKL), in vivo model, single lab\",\n      \"pmids\": [\"24664887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EGF-induced PTX3 transcriptional activation in head and neck squamous cell carcinoma cells occurs via c-Jun binding to AP-1 sites in the PTX3 promoter, dependent on PI3K/Akt and NF-κB pathways; autocrine PTX3 promotes cell migration, invasion, endothelial cell interaction, and lung metastasis, involving fibronectin, MMP9, and E-cadherin regulation.\",\n      \"method\": \"c-Jun and NF-κB knockdown, luciferase promoter reporter assay, migration/invasion assays, tail-vein xenograft model, ChIP (AP-1 binding)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay and knockdown identify transcriptional mechanism, in vivo metastasis model, single lab\",\n      \"pmids\": [\"25797258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTX3 promotes fibrocyte differentiation in a manner dependent on FcγRI; this pro-fibrocyte effect is dominant over SAP's inhibitory effect in competition. SAP and PTX3 bind FcγRI at different sites.\",\n      \"method\": \"In vitro fibrocyte differentiation assay, FcγRI blocking, competition binding studies with recombinant proteins, murine lung fibrosis model (immunohistochemistry)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identified by blocking experiment, binding competition studies, functional differentiation assay, single lab\",\n      \"pmids\": [\"25774777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTX3 bridges humoral innate and adaptive immunity by binding to splenic marginal zone (MZ) B cells; PTX3 is released by a perifollicular neutrophil subset with an immune activation gene signature, and promotes homeostatic and infection-induced IgM and class-switched IgG antibody production to microbial capsular polysaccharides via T cell-independent and T cell-dependent signals.\",\n      \"method\": \"PTX3 binding to MZ B cells (flow cytometry), PTX3-deficient mouse immunoglobulin measurement, neutrophil gene expression profiling, infection/immunization models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, loss-of-function in PTX3-deficient mice and humans, infection and immunization models, multiple orthogonal methods\",\n      \"pmids\": [\"27621420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MSC-derived PTX3 is required for wound healing by promoting fibrin remodeling; Ptx3-/- MSCs show defective pericellular fibrinolysis and migration through fibrin, and when transplanted fail to close wounds normally, with increased fibrin and reduced D-dimer deposition at wound sites.\",\n      \"method\": \"Murine skin wound model with GFP+ MSCs, confocal microscopy, biochemical fibrin/D-dimer quantification, in vitro fibrinolysis and fibrin migration assays in Ptx3-/- vs WT MSCs\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with direct biochemical readout (fibrin/D-dimer), in vitro mechanistic validation, in vivo transplantation model\",\n      \"pmids\": [\"26763449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTX3 expression is regulated by two enhancers: enhancer 1 (230 kb upstream of promoter) responds to inflammatory transcription factors including STAT3; enhancer 2 (in the second exon) is involved in pre-initiation complex assembly. Polycomb repressive complex 2 (PRC2) silences these elements under basal conditions. In colorectal cancer, enhancer 1 is epigenetically inactivated early and acquires STAT3 binding; inhibition of STAT3 phosphorylation restores PTX3 expression.\",\n      \"method\": \"ChIP-seq, STAT3 inhibitor treatment, DNA methylation analysis, STAT3 knockdown, luciferase reporter assays, 5-aza-dC demethylation\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq identifies enhancer occupancy, pharmacological and genetic STAT3 manipulation validates mechanism, multiple orthogonal epigenetic methods\",\n      \"pmids\": [\"28811977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Oleate induces PTX3 expression and secretion via Akt/NF-κB pathway activation in head and neck squamous cell carcinoma cells; NF-κB activation is essential for oleate-induced PTX3 mRNA stabilization. Oleate-induced PTX3 promotes tumor cell migration, invasion, and EMT (vimentin, MMP-3 upregulation) in an autocrine manner; vimentin is a downstream effector.\",\n      \"method\": \"Akt/NF-κB inhibitors, siRNA knockdown of PTX3 and vimentin, mRNA stability assay, migration/invasion assays, lung metastasis xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with inhibitors and siRNA, mRNA stability confirmed, in vivo metastasis validation, single lab\",\n      \"pmids\": [\"28489600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Autocrine PTX3 produced by invasive melanoma cells triggers an IKK/NF-κB signaling pathway that promotes migration, invasion, and TWIST1 expression; this effect is dependent on TLR4 and MYD88, as their knockdown inhibits PTX3-induced migration.\",\n      \"method\": \"CRISPR/Cas9 PTX3 editing, TLR4/MYD88 siRNA knockdown, NF-κB reporter assay, migration/invasion assays, xenograft lung extravasation model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR loss-of-function, receptor identification by knockdown, in vivo xenograft model, defined signaling mechanism\",\n      \"pmids\": [\"31253871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C1q promotes PTX3 binding to CD14+ monocytes, and PTX3 synergizes with C1q to promote NLRP3 inflammasome overactivation, gasdermin D (GSDMD)-dependent pyroptosis, and inflammatory cytokine release (TNF-α, IL-1β, IL-6) in monocytes; IL-6 further promotes PTX3+C1q-induced pyroptosis.\",\n      \"method\": \"Flow cytometry (PTX3/monocyte binding), GSDMD cleavage assay (Western blot), caspase-1 activity, cytokine ELISA, cell death assays\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and GSDMD cleavage measured, NLRP3 pathway intermediates confirmed, single lab\",\n      \"pmids\": [\"31601476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Doxorubicin induces upregulation and enrichment of PTX3 in tumor-derived small extracellular vesicles (sEVs); CRISPR/Cas9 deletion of PTX3 suppresses chemotherapy-induced sEV-mediated premetastatic niche formation and pulmonary metastasis in triple-negative breast cancer xenografts.\",\n      \"method\": \"Proteomic analysis of sEVs, CRISPR/Cas9 PTX3 deletion, xenograft mouse metastasis model, pharmacological inhibition of sEV secretion/uptake\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR loss-of-function with defined metastatic phenotype, proteomic identification of PTX3 in sEVs, in vivo validation, single lab\",\n      \"pmids\": [\"33115808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SH3RF3 interacts with JNK in a JIP-dependent manner, leading to enhanced JNK phosphorylation and JNK-JUN pathway activation, which transcriptionally activates PTX3 expression to expand cancer stem-like cell subpopulations in breast cancer.\",\n      \"method\": \"Co-immunoprecipitation (SH3RF3-JNK), phospho-JNK Western blot, PTX3 reporter assay, ChIP for JUN at PTX3 promoter, breast cancer organoid culture\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies SH3RF3-JNK complex, ChIP confirms JUN binding at PTX3 promoter, organoid validation, single lab\",\n      \"pmids\": [\"32427938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTX3 deficiency in mice worsens bleomycin-induced lung fibrosis with impaired fibrin removal and increased collagen deposition; PTX3 interacts with fibrin and plasminogen to facilitate timely removal of fibrin-rich ECM during tissue repair.\",\n      \"method\": \"PTX3 knockout mouse BLM model, fibrin and collagen quantification, fibrinolysis assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined biochemical phenotype, single lab, mechanistic interaction inferred from prior binding data\",\n      \"pmids\": [\"34276664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTX3 does not directly bind K. pneumoniae or promote opsonophagocytosis of this pathogen; PTX3 controls K. pneumoniae infection in a complement-independent manner by modulating inflammatory responses and reducing fibrin deposition and tissue damage.\",\n      \"method\": \"Ptx3-/-, Ptx3-/-/C3-/- double-KO mice, bacterial burden quantification, complement interaction assays (negative result for direct binding), histopathology, fibrinogen/fibrin measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with complement-deficient mice definitively places PTX3 action as complement-independent; negative binding result established by direct assay\",\n      \"pmids\": [\"34093560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTX3 promotes osteogenic differentiation in an inflammatory environment by positioning itself in the HA-dependent pericellular matrix, promoting HA synthesis and CD44 expression, and activating a FAK/AKT positive feedback loop that further upregulates HAS1/2/3 and CD44; disruption of any component of this HA/CD44/FAK/AKT loop abolishes PTX3's osteogenic effect.\",\n      \"method\": \"PTX3 gain- and loss-of-function in MC3T3-E1 cells, HA digestion, FAK/AKT inhibitors, CD44 and HAS knockdown, in vivo periodontitis bone regeneration model with local PTX3 treatment, micro-CT\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors and knockdowns define signaling circuit, in vivo validation, single lab\",\n      \"pmids\": [\"34653679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPHK1 promotes GBM growth partly through JNK phosphorylation leading to transcriptional activation of PTX3 via JNK-JUN and JNK-ATF3 pathways; SPHK1 and PTX3 form a positive feedback loop that reciprocally increases each other's expression and promotes inflammation.\",\n      \"method\": \"SPHK1 overexpression/silencing, PTX3 knockdown, phospho-JNK Western blot, reporter assay, orthotopic mouse GBM model\",\n      \"journal\": \"Acta pharmaceutica sinica B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss of function, signaling pathway confirmed by Western blot, in vivo validation, single lab\",\n      \"pmids\": [\"36562002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3-mediated m6A modification promotes YTHDF3-dependent degradation of PTX3 mRNA; loss of METTL3 impairs this m6A-YTHDF3 degradation pathway, leading to elevated PTX3 expression that promotes M2 macrophage activation via PI3K/AKT and JAK/STAT6 signaling and modulates STX17-dependent autophagy maturation.\",\n      \"method\": \"m6A-seq, RIP (YTHDF3-mRNA interaction), METTL3 conditional knockout in myeloid cells, PTX3 knockdown/overexpression, Western blot for PI3K/AKT and JAK/STAT6 pathway\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — m6A-seq identifies modification site, RIP validates reader-mRNA interaction, genetic KO with defined cellular phenotype, multiple signaling pathway readouts\",\n      \"pmids\": [\"37957139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT1-mediated H4R3me2a epigenetic mark activates PTX3 transcription by promoting YY1 binding to its promoter; reduced PRMT1 in IDH1-mutant gliomas decreases PTX3 expression, leading to impaired autophagic balance and heightened ferritinophagic flux.\",\n      \"method\": \"ChIP for H4R3me2a and YY1 at PTX3 promoter, PRMT1 knockdown/overexpression, PTX3 siRNA/secretion inhibition, autophagic flux assays, ferritin level measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifies epigenetic writer and transcription factor, functional autophagy readout, single lab\",\n      \"pmids\": [\"36647288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10-mediated N4-acetylcytidine (ac4C) modification of PTX3 mRNA increases its stability and translation efficiency in fibroblast-like synoviocytes; elevated NAT10 drives PTX3-dependent synovial aggression and immune cell infiltration in rheumatoid arthritis. NAT10 inhibition in vivo attenuates arthritis severity.\",\n      \"method\": \"ac4C-RIP-seq combined with RNA-seq, RNA immunoprecipitation (NAT10-PTX3 mRNA), NAT10 knockdown and inhibitor (remodelin), synoviocyte migration/invasion assays, CIA and DTHA mouse models\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — epitranscriptomic RIP-seq identifies modification, direct protein-mRNA RIP validates interaction, genetic and pharmacological loss-of-function, multiple in vivo disease models\",\n      \"pmids\": [\"38724075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"P. aeruginosa GroEL activates PTX3 expression in monocytes via TLR4-dependent NF-κB pathway while simultaneously inhibiting microRNA-9, which normally targets the PTX3 transcript; GroEL-induced PTX3 then acts as an opsonin to promote phagocytosis of S. aureus.\",\n      \"method\": \"NF-κB inhibitor, microRNA-9 overexpression/inhibition, TLR4 blocking, phagocytosis assay\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual mechanism (NF-κB activation and miR-9 suppression) identified with pathway inhibitors, functional opsonin assay, single lab\",\n      \"pmids\": [\"28031262\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTX3 is a multimeric (octameric, with tetramers as functional units stabilized by N-terminal interchain disulfide bonds) secreted glycoprotein stored preformed in neutrophil specific granules and released upon inflammatory stimuli; its transcription is induced by IL-1/TNF/LPS via NF-κB and AP-1 elements in a promoter lacking TATA/CCAAT boxes, positively regulated by glucocorticoids (via dimerization-dependent GR) in stromal cells and by PRMT1-H4R3me2a and NAT10-ac4C epitranscriptomic mechanisms, while being repressed by IFN-γ (via mRNA destabilization in monocytes), PRC2, and m6A-YTHDF3-dependent mRNA degradation; PTX3 functions as a humoral pattern recognition molecule that opsonizes pathogens and zymosan through dectin-1-dependent phagocytosis, activates complement via C1q/ficolin/MBL interactions and modulates it through factor H binding, signals antifungal protection through a TLR4/MD-2/TRIF/IL-10 axis, promotes antibody production by marginal zone B cells via perifollicular neutrophil release, tunes tumor-promoting inflammation by restraining complement-CCL2-macrophage recruitment (oncosuppressor function epigenetically silenced by promoter methylation), promotes fibrin remodeling and tissue repair in wounds and lungs, activates ERK1/2 in cardiac fibroblasts to modulate hypertrophic remodeling, and in cancer cells activates TLR4/NF-κB-driven invasion and metastasis through autocrine signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTX3 (TSG-14) is a secreted, glycosylated multimeric pattern-recognition glycoprotein that links humoral innate immunity to inflammation, tissue repair, and complement regulation [#0, #19]. Its expression is induced at the transcriptional level by TNF, IL-1, and LPS in fibroblasts, endothelial cells, and myeloid cells through a TATA/CCAAT-less promoter carrying NF-\\u03baB, AP-1, NF-IL6, Sp1, GAS, and Ets elements, with lung epithelial induction routed through JNK rather than NF-\\u03baB [#0, #1, #3, #8]. Production is shaped by additional layers of control: glucocorticoids exert opposite, cell-type-specific effects through dimerization-independent GR repression in myeloid cells versus dimerization-dependent induction in stromal cells [#11]; IFN-\\u03b3 represses the gene in monocytes by destabilizing its mRNA [#4]; distal/intronic enhancers are basally silenced by PRC2 [#25]; and the transcript is regulated epitranscriptomically by METTL3/m6A-YTHDF3-mediated decay, NAT10-ac4C stabilization, and PRMT1-H4R3me2a/YY1-driven activation [#35, #36, #37]. Structurally, recombinant PTX3 assembles into covalent octamers built from disulfide-stabilized tetramers, and the tetramer is the functional unit required for extracellular matrix organization [#10]. Stored preformed in neutrophil specific granules and rapidly released upon microbial challenge, PTX3 opsonizes zymosan and fungi to drive dectin-1-dependent phagocytosis, mediates antifungal protection against Aspergillus through an MD-2/TLR4/TRIF/IL-10 axis, and bridges innate and adaptive immunity by binding marginal-zone B cells to promote antibody responses [#7, #9, #18, #23]. It engages complement components C1q, ficolins, and MBL and the regulators C4BP and factor H to tune complement activation [#14], and acts as an extrinsic oncosuppressor by restraining complement-CCL2-driven tumor-promoting macrophage recruitment, a function epigenetically silenced by promoter methylation in human tumors [#19]. PTX3 also promotes fibrin remodeling and resolution during wound healing and lung repair through interactions with fibrin and plasminogen [#24, #31], and activates ERK1/2 in cardiac fibroblasts to exacerbate pressure-overload remodeling [#17]. In a context-dependent reversal, autocrine tumor-cell-derived PTX3 drives TLR4/MYD88/NF-\\u03baB-dependent migration, invasion, EMT, and metastasis [#21, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that PTX3 is an inducible secreted glycoprotein rather than a constitutive product, defining it as an acute inflammatory response gene controlled at transcription by TNF and IL-1.\",\n      \"evidence\": \"Cell-free transcription/translation, microsome processing, nuclear run-on, and Northern blot in fibroblasts and endothelial cells\",\n      \"pmids\": [\"7679696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define promoter elements responsible for cytokine induction\", \"Function of the secreted protein unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed that myeloid cells produce PTX3 and that monocyte versus stromal induction differ mechanistically, hinting at cell-type-specific regulation.\",\n      \"evidence\": \"Run-on, actinomycin D/cycloheximide, antibody neutralization, and immunoprecipitation in monocytes/macrophages, fibroblasts, and hepatoma cells plus LPS injection in mice\",\n      \"pmids\": [\"7949102\", \"7523502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the protein-synthesis-dependent factor required in monocytes\", \"In vivo cellular source incompletely mapped\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined the PTX3 promoter architecture, explaining how diverse inflammatory signals converge on its transcription.\",\n      \"evidence\": \"Primer extension, S1 nuclease protection, and luciferase reporter transfection identifying an initiator element and NF-\\u03baB/AP-1/NF-IL6/Sp1/GAS/Ets sites\",\n      \"pmids\": [\"7592730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not assign which sites mediate which stimulus\", \"Distal regulatory elements not examined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved how IFN-\\u03b3 represses PTX3 and showed the repression is monocyte-restricted, establishing post-transcriptional control via mRNA stability.\",\n      \"evidence\": \"Northern blot, actinomycin D mRNA-stability assay, and ELISA comparing monocytes to fibroblasts/endothelium\",\n      \"pmids\": [\"9521058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mRNA destabilizing factor not identified\", \"Mechanism of cell-type specificity unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Distinguished signaling requirements for LPS induction in macrophages versus fibroblasts, showing IFN-\\u03b3 represses through an unconventional STAT1-independent route.\",\n      \"evidence\": \"Northern blot, cycloheximide, NF-\\u03baB EMSA, I\\u03baB degradation, and STAT1-null macrophages\",\n      \"pmids\": [\"10733100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the STAT1-independent repressive pathway unknown\", \"Protein-synthesis-dependent intermediary not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Provided the first in vivo gain-of-function evidence that PTX3 protects against endotoxemia and sepsis, linking it to host defense.\",\n      \"evidence\": \"TSG-14/PTX3 transgenic mice in LPS and CLP models with macrophage NO assays\",\n      \"pmids\": [\"11404378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of protection not defined\", \"Direct pathogen-binding role not yet established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified PTX3 as a pathogen opsonin acting through dectin-1, giving it a concrete antifungal effector function.\",\n      \"evidence\": \"Recombinant PTX3 binding to zymosan and P. brasiliensis, macrophage phagocytosis with dectin-1 blockade, FACS/RT-PCR\",\n      \"pmids\": [\"14726497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PTX3-dectin-1 versus indirect bridging not fully distinguished\", \"Generality across pathogens untested at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Localized PTX3 to neutrophil specific granules and NETs, explaining its rapid availability at infection sites and a non-redundant antifungal role.\",\n      \"evidence\": \"Immunofluorescence, subcellular fractionation, NET imaging, and phagocytosis in PTX3-deficient neutrophils against A. fumigatus\",\n      \"pmids\": [\"17389238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Granule-targeting/storage mechanism unknown\", \"Receptor mediating neutrophil antifungal recognition not yet identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the disulfide-bonded octameric quaternary structure and showed tetramers are the functional unit for ECM organization.\",\n      \"evidence\": \"Native/denaturing PAGE, mass spectrometry disulfide mapping, Cys-to-Ser mutagenesis, and ex vivo cumulus matrix rescue in PTX3-deficient mice\",\n      \"pmids\": [\"18223257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ligand recognition not solved\", \"Whether all functions require tetramer/octamer untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Explained the paradoxical glucocorticoid regulation of PTX3 as opposite GR mechanisms in hematopoietic versus stromal cells.\",\n      \"evidence\": \"GR dimerization-deficient mouse cells, cell-type-specific production assays, and in vivo/clinical GC administration\",\n      \"pmids\": [\"18703503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter elements distinguishing GR repression from induction not pinpointed\", \"Physiological consequence of GC-raised blood PTX3 unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Consolidated PTX3's complement interactome, positioning it as both an activator and regulator across classical and lectin pathways.\",\n      \"evidence\": \"Binding/interaction studies (review with referenced experimental data) for C1q, ficolins, MBL, C4BP, factor H\",\n      \"pmids\": [\"22964239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis without a novel experiment\", \"Binding stoichiometry and in vivo balance of activation versus regulation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated tissue-protective and ECM-remodeling roles for PTX3 in brain and heart injury, including a defined ERK1/2 signaling readout in cardiac fibroblasts.\",\n      \"evidence\": \"PTX3-KO and transgenic mice in MCAO stroke, heterotopic heart transplant, and TAC models with BBB/edema, hemodynamics, and pERK1/2 Western blot\",\n      \"pmids\": [\"24346689\", \"24112130\", \"23372656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating ERK1/2 activation in fibroblasts not identified\", \"Reconciling protective versus deleterious cardiac roles across injury models unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the MD-2/TLR4/TRIF/IL-10 antifungal signaling axis, gave PTX3 an extrinsic oncosuppressor function via complement-CCL2-macrophage restraint, and showed epigenetic silencing in human tumors.\",\n      \"evidence\": \"In vitro MD-2 binding, Md2/Tlr4-KO infection with adoptive neutrophil transfer; Ptx3-KO carcinogenesis models with complement blockade, CCL2 measurement, and promoter methylation analysis\",\n      \"pmids\": [\"25049357\", \"25679762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PTX3 simultaneously activates and restrains complement contextually not reconciled\", \"Direct receptor for oncosuppressive signaling distinct from MD-2 not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established PTX3 as a bridge to adaptive immunity through marginal-zone B-cell binding and as a tissue-repair factor enabling fibrin remodeling.\",\n      \"evidence\": \"PTX3 binding to MZ B cells, immunoglobulin measurement in PTX3-deficient mice/humans, perifollicular neutrophil profiling; MSC wound model with fibrin/D-dimer biochemistry and fibrinolysis assays\",\n      \"pmids\": [\"27621420\", \"26763449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MZ B-cell receptor for PTX3 not identified\", \"Molecular basis of PTX3-promoted pericellular fibrinolysis incompletely defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a tumor-cell-intrinsic, autocrine PTX3 program in which growth-factor and lipid signaling drive AP-1/NF-\\u03baB-dependent PTX3 to promote invasion and metastasis, plus Fc\\u03b3RI-dependent pro-fibrotic differentiation.\",\n      \"evidence\": \"c-Jun/NF-\\u03baB knockdown, promoter reporters/ChIP, mRNA-stability assays, migration/invasion and xenograft metastasis models in HNSCC; Fc\\u03b3RI blocking and competition with SAP in fibrocyte assays\",\n      \"pmids\": [\"25797258\", \"28489600\", \"25774777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor for autocrine PTX3 not defined in these studies\", \"Reconciliation with oncosuppressor role left to context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the distal regulatory landscape and its STAT3-driven epigenetic remodeling in cancer, and identified a pathogen-driven dual transcriptional/microRNA control of PTX3.\",\n      \"evidence\": \"ChIP-seq, STAT3 inhibition/knockdown, DNA methylation/5-aza-dC, reporter assays; and TLR4/NF-\\u03baB plus miR-9 manipulation with phagocytosis assay for P. aeruginosa GroEL\",\n      \"pmids\": [\"28811977\", \"28031262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of enhancer reactivation in tumors not fully tested\", \"miR-9 regulatory node not validated beyond single model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped the autocrine tumor-promoting receptor circuit and an inflammasome-amplifying partnership with C1q, expanding PTX3's signaling repertoire.\",\n      \"evidence\": \"CRISPR PTX3 editing with TLR4/MYD88 knockdown and NF-\\u03baB reporter/migration assays in melanoma; flow cytometry, GSDMD cleavage, caspase-1, and cytokine assays for PTX3+C1q in monocytes\",\n      \"pmids\": [\"31253871\", \"31601476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PTX3-TLR4 binding versus co-receptor requirement not resolved\", \"In vivo relevance of PTX3-C1q pyroptosis not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected PTX3 to chemotherapy-induced metastatic dissemination and to JNK-JUN-driven cancer stemness, deepening its tumor-cell-intrinsic role.\",\n      \"evidence\": \"sEV proteomics with CRISPR PTX3 deletion in TNBC xenografts; SH3RF3-JNK Co-IP, phospho-JNK, JUN ChIP at PTX3 promoter, and breast organoids\",\n      \"pmids\": [\"33115808\", \"32427938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PTX3 enrichment in sEVs unclear\", \"Single-lab findings without reciprocal validation of the SH3RF3-JNK-PTX3 axis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed PTX3 host defense and tissue protection on fibrin clearance, showing a complement-independent mode against K. pneumoniae and a fibrin/plasminogen-dependent repair role in lung fibrosis.\",\n      \"evidence\": \"Ptx3-KO bleomycin model with fibrin/collagen quantification and fibrinolysis assays; Ptx3-KO and Ptx3/C3 double-KO mice with bacterial burden and negative direct-binding assays\",\n      \"pmids\": [\"34276664\", \"34093560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical fibrin/plasminogen binding inferred rather than fully reconstituted here\", \"Anti-inflammatory effector mechanism in K. pneumoniae control undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified additional pro-tumor and bone-remodeling circuits where kinase/lipid signaling drives PTX3, including SPHK1-JNK feedback and a HA/CD44/FAK/AKT osteogenic loop.\",\n      \"evidence\": \"SPHK1 gain/loss with phospho-JNK and reporter assays in orthotopic GBM; PTX3 gain/loss with HA digestion, FAK/AKT inhibitors, CD44/HAS knockdown, and periodontitis micro-CT\",\n      \"pmids\": [\"36562002\", \"34653679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-model evidence for each circuit\", \"How PTX3 engages the HA pericellular matrix mechanistically not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established epitranscriptomic control of PTX3 as a node coupling RNA modification machinery to macrophage polarization and autophagy.\",\n      \"evidence\": \"m6A-seq, YTHDF3 RIP, METTL3 myeloid KO with PI3K/AKT and JAK/STAT6 readouts; ChIP for H4R3me2a/YY1 with PRMT1 manipulation and autophagic/ferritinophagy assays\",\n      \"pmids\": [\"37957139\", \"36647288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PTX3 protein mediates the autophagy phenotype directly or indirectly not fully separated\", \"Cross-talk among the m6A, ac4C, and H4R3me2a layers untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined NAT10-ac4C as a stabilizing/translation-enhancing mark on PTX3 mRNA driving synovial aggression, providing a druggable epitranscriptomic axis in rheumatoid arthritis.\",\n      \"evidence\": \"ac4C-RIP-seq/RNA-seq, NAT10-PTX3 mRNA RIP, NAT10 knockdown and remodelin, synoviocyte invasion assays, and CIA/DTHA models\",\n      \"pmids\": [\"38724075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream PTX3 effector pathway in synoviocytes not fully mapped\", \"Single-lab disease-model validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor(s) and structural basis by which secreted PTX3 transduces signals across its divergent contexts—antifungal protection, complement tuning, tissue repair, and tumor promotion—remain incompletely defined, as does how the same molecule is both oncosuppressive and pro-metastatic.\",\n      \"evidence\": \"Not established in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model of ligand/receptor engagement\", \"Mechanistic reconciliation of opposing tumor roles unresolved\", \"In vivo human relevance of cancer-cell-intrinsic TLR4/MYD88 signaling untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [7, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 19]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [18, 27]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [10, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 18, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 27]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [35, 37]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"C1q\", \"MD-2\", \"TLR4\", \"FCN1\", \"FCN2\", \"MBL\", \"CFH\", \"FCGR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}