{"gene":"AGER","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2004,"finding":"Mouse soluble RAGE (sRAGE) is produced by carboxyl-terminal proteolytic truncation of cell surface RAGE (not by alternative splicing as in humans), is glycosylated, contains disulfide bonds, and binds heparin, which may mediate its distribution in the extracellular matrix and on cell surfaces.","method":"Purification, biochemical characterization (glycosylation analysis, disulfide pattern determination, heparin-binding assay)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct biochemical characterization with multiple orthogonal methods in a single study; single lab","pmids":["15381690"],"is_preprint":false},{"year":2011,"finding":"The solution structure of human sRAGE was determined by synchrotron small-angle X-ray scattering; the monomer adopts a J-like shape, and the homodimer is formed through association of the two N-terminal (V) domains, yielding an elongated structure. Oligomerization is concentration-dependent and is also mediated by Ca²⁺ ions.","method":"Small-angle X-ray scattering (SAXS) structure determination; concentration-dependent oligomerization assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct structural determination by synchrotron SAXS with functional oligomerization validation; single lab with multiple orthogonal methods","pmids":["21865159"],"is_preprint":false},{"year":2005,"finding":"Activation of AGER (RAGE) by its ligand S100B on human pancreatic islets induces PTGS2 (COX-2) expression and prostaglandin E2 production via protein kinase C and oxidative stress signaling pathways.","method":"RT-PCR, Western blot, PGE2 enzyme immunoassay; pharmacological inhibition of PKC and oxidant stress pathways in human islets treated with S100b","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RT-PCR, Western blot, enzyme immunoassay, inhibitor experiments) in a single lab study","pmids":["16341840"],"is_preprint":false},{"year":2010,"finding":"sRAGE directly binds human monocytes and monocyte-derived macrophages, promoting their survival and differentiation to macrophages, and activates the Akt, Erk, and NF-κB intracellular signaling pathways in these cells. sRAGE also induces monocyte and neutrophil migration and pro-inflammatory cytokine/chemokine production in vitro.","method":"Direct binding assay (sRAGE binding to cells), in vitro migration assay, cytokine/chemokine measurement, Western blot for Akt/Erk/NF-κB activation, intratracheal administration in vivo","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays, multiple signaling pathway readouts, in vitro and in vivo experiments; single lab","pmids":["20574008"],"is_preprint":false},{"year":2012,"finding":"AGER promotes pancreatic tumorigenesis by mediating autophagic flux that supports IL-6-induced phosphorylation of STAT3 and its mitochondrial localization, thereby increasing ATP availability and cellular proliferation. Targeted ablation of AGER in a KRAS-driven murine model diminishes autophagic flux and attenuates development of early pancreatic intraepithelial neoplasia (PanIN) lesions. A positive feedback loop exists between autophagy activation and the IL6-pSTAT3 pathway downstream of AGER.","method":"Genetic knockout (Ager-/-) in KRAS-driven mouse model, autophagic flux assays, IL-6/pSTAT3 immunoblotting, mitochondrial fractionation, ATP measurement, cell proliferation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with defined cellular/molecular phenotype plus multiple orthogonal in vitro mechanistic assays; single lab","pmids":["22722139"],"is_preprint":false},{"year":2016,"finding":"AGER activates the hexosamine biosynthetic pathway, leading to enhanced O-GlcNAcylation of c-Jun at Ser73, increasing c-Jun activity and stability. c-Jun in turn enhances AGER transcription, establishing a positive autoregulatory feedback loop that promotes hepatocellular carcinoma tumorigenesis under high-glucose conditions.","method":"AGER overexpression/knockdown in HCC cells, O-GlcNAcylation analysis, site-directed mutagenesis (Ser73), ChIP/transcriptional reporter assays, cell proliferation assays","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification of PTM site (Ser73 O-GlcNAcylation), gain/loss-of-function with multiple readouts; single lab","pmids":["26825459"],"is_preprint":false},{"year":2016,"finding":"The rs2070600 (Gly82Ser) AGER variant functionally reduces sRAGE production: airway epithelial cells overexpressing the RAGE-Ser82 variant produce lower sRAGE levels upon HMGB1 stimulation compared to cells overexpressing the RAGE-Gly82 variant, demonstrating a functional role of this SNP in modulating sRAGE generation.","method":"Transfection of BEAS2B-R1 cells with Gly82 or Ser82 RAGE variants, HMGB1 stimulation, sRAGE ELISA; RNA-Seq for transcript identification; clinical cohort for association","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional experiment with allele comparison plus clinical validation; single lab","pmids":["27755550"],"is_preprint":false},{"year":2017,"finding":"AGER deletion (Ager-/-) in diabetic mice restores adaptive inflammation after hindlimb ischemia by increasing circulating Ly6Chi monocytes and augmenting macrophage infiltration into ischemic muscle, thereby rescuing angiogenesis and blood flow recovery. In vitro, Ager deletion in macrophages reverses the high-glucose-induced shift from tissue-repair to tissue-damage inflammatory gene expression and restores macrophage-endothelial cell interactions.","method":"Genetic knockout (Ager-/-), transgenic Glo1 overexpression, femoral artery ligation model, flow cytometry, immunofluorescence, in vitro macrophage/endothelial co-culture assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in two independent mouse models (Ager-/- and Glo1 transgenic) with multiple orthogonal in vivo and in vitro phenotypic and mechanistic readouts","pmids":["28642238"],"is_preprint":false},{"year":2017,"finding":"sRAGE prevents neutrophilic asthma by blocking HMGB1/RAGE signaling in airway CD11c+ dendritic cells, inhibiting RAGE and IL-23 expression, suppressing Th17 polarization, and reducing neutrophilic inflammation. Adoptive transfer of rHMGB1-activated DCs restored airway inflammation; transfer of DCs activated with rHMGB1 plus sRAGE significantly reduced it.","method":"Murine neutrophilic asthma model, intratracheal sRAGE administration, adoptive DC transfer, in vitro Th17 polarization assay, flow cytometry, cytokine ELISA","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo adoptive transfer and pharmacological blockade, in vitro DC mechanistic assay; single lab","pmids":["29079726"],"is_preprint":false},{"year":2018,"finding":"sRAGE attenuates angiotensin II-induced cardiomyocyte hypertrophy by downregulating RAGE and AT1R expression, reducing HMGB1 and IL-1β secretion, and inhibiting PKC, ERK1/2, NF-κB, and NLRP3 inflammasome activation. RAGE thus drives cardiac hypertrophy through PKC-ERK1/2 and NF-κB-NLRP3-IL-1β pathway activation.","method":"Western blot, fluorescence microscopy (ROS, phospho-p65), ELISA (HMGB1, IL-1β) in H9C2 cells treated with Ang II ± sRAGE","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple signaling readouts using pharmacological inhibition approach; in vitro only, single lab","pmids":["29796842"],"is_preprint":false},{"year":2019,"finding":"AGER is required for caspase-11 inflammasome activation in macrophages: AGER-mediated lipid peroxidation via arachidonate 5-lipoxygenase (ALOX5) enables nDAMP-induced caspase-11 activation, gasdermin D cleavage, IL-1β maturation, and pyroptosis. Global (Ager-/-) or myeloid-specific AGER deletion protects mice from LPS-induced septic death.","method":"Genetic knockout (global and myeloid-conditional Ager-/-), pharmacological inhibition of AGER-ALOX5 pathway, caspase-11/gasdermin D cleavage assays, LDH release, IL-1β ELISA, in vivo LPS sepsis model","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (global and conditional KO) with mechanistic pathway dissection and in vivo rescue; single lab, multiple orthogonal methods","pmids":["31440260"],"is_preprint":false},{"year":2021,"finding":"DCN (decorin) released during ferroptosis binds to AGER on macrophages, triggering NF-κB-dependent production of pro-inflammatory cytokines. Pharmacological and genetic inhibition of the DCN-AGER axis protects against ferroptotic death-related acute pancreatitis and limits tumor-protective immune responses.","method":"Co-immunoprecipitation/binding assay (DCN-AGER), genetic AGER knockout, pharmacological inhibition, in vivo pancreatitis model, cytokine measurement","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — receptor-ligand binding identification, genetic loss-of-function, in vivo disease model, multiple orthogonal methods; single lab","pmids":["34964698"],"is_preprint":false},{"year":2021,"finding":"HMGB1 released by alkaliptotic cancer cells binds AGER on macrophages and activates the STING1 pathway to produce pro-inflammatory cytokines (TNF and IL-6). Genetic or pharmacological inhibition of the HMGB1-AGER-STING1 pathway limits cytokine production during alkaliptosis.","method":"Genetic knockdown/knockout of HMGB1, AGER, and STING1; cytokine ELISA; co-culture of alkaliptotic cancer cells with macrophages","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined pathway sequence; single lab","pmids":["33992959"],"is_preprint":false},{"year":2021,"finding":"YAP participates with the transcription factors KLF5, NFIB, and NKX2-1 to regulate AGER expression in alveolar epithelial cells. YAP activation increased AT1 cell numbers and AGER expression; YAP deletion increased AT2 cell gene expression. Motif enrichment and chromatin accessibility analysis identified the transcriptional network.","method":"Transgenic mouse models (YAP activation and deletion), ATAC-seq, transcriptomic analysis, motif enrichment","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss-of-function in vivo with chromatin accessibility and transcriptomic mechanistic data; single lab","pmids":["34466790"],"is_preprint":false},{"year":2018,"finding":"AGER expression in alveolar type 1 (AT1) cells is high in adult lung; the Ager-CreERT2 allele enables lineage labeling and selective killing of AT1 cells. When ~50% of AT1 cells are killed, SFTPC+ AT2 cells proliferate and upregulate Ager expression during repair, establishing AGER as a marker and functional indicator of AT1 cell identity and repair capacity.","method":"Ager-CreERT2 knock-in mouse generation, tamoxifen-induced lineage tracing, Rosa26-DTA AT1 cell ablation, immunofluorescence, cell proliferation quantification","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic tool validated in vivo with functional consequence (AT2 proliferation after AT1 loss); single lab","pmids":["30011373"],"is_preprint":false},{"year":2024,"finding":"Extracellular NCOA4 (secreted by activated macrophages via ATG5/MCOLN1-dependent lysosomal exocytosis, or passively released during GSDMD-mediated pyroptosis) binds AGER (not TLR4) on macrophages and activates NF-κB by promoting NFKBIA degradation, driving septic inflammation and death. Neutralizing antibodies against NCOA4 or AGER delay septic death and reduce organ damage in mouse models.","method":"Co-IP (NCOA4-AGER interaction), genetic knockout (Ager-/-, ATG5, MCOLN1, GSDMD), monoclonal antibody neutralization, in vivo endotoxemia and polymicrobial sepsis models, NF-κB/NFKBIA Western blot","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — receptor-ligand binding identified by Co-IP, genetic KO and antibody neutralization in multiple in vivo models, mechanistic pathway dissection; single lab, multiple orthogonal methods","pmids":["38916095"],"is_preprint":false},{"year":2025,"finding":"AGER mediates resistance to the KRAS-G12D inhibitor MRTX1133 in pancreatic cancer by upregulating macropinocytosis through its interaction with the formin protein DIAPH1, driving RAC1-dependent macropinosome formation, serum albumin internalization, amino acid generation, and glutathione synthesis that inhibits apoptosis.","method":"Co-IP (AGER-DIAPH1 interaction), RAC1 activity assay, macropinocytosis assay, patient-derived xenograft, orthotopic and genetically engineered mouse models, pharmacological inhibitors (RAGE299, EIPA)","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — protein interaction identified by Co-IP, mechanistic pathway confirmed with pharmacological and genetic tools in multiple in vivo models; single lab, multiple orthogonal methods","pmids":["39879317"],"is_preprint":false},{"year":2019,"finding":"miR-182-5p directly targets AGER as a downstream effector in NSCLC cells, and AGER loss mediates NF-κB pathway suppression; LINC00173 acts as a competing endogenous RNA to sequester miR-182-5p and restore AGER expression. Alteration of AGER expression or NF-κB inhibition partially counteracts the proliferation/migration phenotype induced by miR-182-5p.","method":"Luciferase reporter assay (AGER as direct miR-182-5p target), siRNA/overexpression, functional assays (proliferation, migration, apoptosis), NF-κB inhibition","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validated by luciferase reporter, multiple functional assays; single lab","pmids":["31396332"],"is_preprint":false},{"year":2018,"finding":"The AGEs/AGER axis induces ROS generation and apoptosis in adipose tissue-derived stem cells (ADSCs); miR-5591-5p directly targets AGER and suppresses AGEs/AGER-mediated ROS generation and apoptosis via the JNK signaling pathway.","method":"siRNA knockdown of AGER, miR-5591-5p overexpression/inhibition, ROS measurement, apoptosis assay, JNK signaling Western blot, in vivo diabetic wound repair model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function, miRNA-target relationship, defined signaling pathway; single lab","pmids":["29752466"],"is_preprint":false},{"year":2012,"finding":"In the AGER -429T/C promoter polymorphism, the minor C allele is associated with increased AGER promoter activity (measured by luciferase assay), demonstrating a functional effect of this SNP on RAGE expression levels.","method":"Luciferase reporter assay of AGER -429T vs. -429C promoter constructs in BEAS-2B cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro functional assay; single method, single lab","pmids":["22860029"],"is_preprint":false},{"year":2020,"finding":"AGER overexpression in NSCLC H1299 cells decreases cell viability, proliferation, migration, and invasion, and increases apoptosis with upregulation of Bax and downregulation of Bcl-2; AGER knockdown has the opposite effects.","method":"Lentiviral overexpression and siRNA knockdown, MTT assay, flow cytometry, wound-healing assay, Transwell invasion assay, Western blot (Bax, Bcl-2)","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain and loss of function with multiple readouts; in vitro only, single lab","pmids":["32468030"],"is_preprint":false},{"year":2018,"finding":"AGER promotes proliferation, migration, and inhibits apoptosis of cervical squamous cancer cells; AGER protein localizes primarily in the cytoplasm and cytomembrane of these cells. siRNA-mediated AGER blockade suppresses proliferation and migration and stimulates apoptosis.","method":"siRNA knockdown, AGER overexpression, immunofluorescence localization, MTT proliferation assay, migration assay, flow cytometry","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain and loss of function with localization data; in vitro only, single lab","pmids":["29298878"],"is_preprint":false},{"year":2022,"finding":"Cadmium activates AGER-mediated inflammatory signaling via the AGER/PKC/p65 pathway in pancreatic β-cells. Ferroptosis inhibitor Fer-1 antagonizes cadmium-induced AGER-mediated immune activation, placing AGER downstream of ferroptotic lipid peroxidation in the inflammatory cascade.","method":"Transcriptomic analysis, ferroptosis marker assays (GSH, GPX4, lipid peroxidation, mitochondrial ultrastructure), AGER/PKC/p65 pathway Western blot, Fer-1 pharmacological inhibition in MIN6 cells and mice","journal":"The Science of the total environment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic assays with pharmacological intervention; single lab","pmids":["35931150"],"is_preprint":false}],"current_model":"AGER (RAGE) is a multiligand cell-surface receptor of the immunoglobulin superfamily, highly expressed as a transmembrane protein on alveolar type 1 cells and other tissues, that upon binding ligands (AGEs, HMGB1, S100 proteins, DCN, NCOA4, and others) activates NF-κB, PKC/ERK, STAT3, ALOX5-mediated lipid peroxidation, and autophagy pathways to drive inflammation and tumorigenesis; its soluble ectodomain (sRAGE), produced by proteolytic shedding of the transmembrane form or by alternative splicing (esRAGE), forms a J-shaped monomer and elongated homodimer that competitively sequesters RAGE ligands to attenuate signaling, and AGER interacts with DIAPH1 to drive RAC1-dependent macropinocytosis in cancer cells."},"narrative":{"mechanistic_narrative":"AGER (RAGE) is a multiligand cell-surface receptor that couples recognition of damage-associated ligands to inflammatory and pro-tumorigenic signaling, and it additionally serves as a defining marker and functional determinant of alveolar type 1 (AT1) cell identity in the lung [PMID:30011373, PMID:34466790]. AGER engages a spectrum of ligands released during cell stress and death—S100B [PMID:16341840], HMGB1 [PMID:29079726], decorin (DCN) released during ferroptosis [PMID:34964698], and NCOA4 secreted by activated macrophages [PMID:38916095]—and transduces these signals through PKC/oxidative-stress, ERK, and NF-κB cascades to drive prostaglandin production, cytokine release, and pyroptotic inflammation [PMID:16341840, PMID:29796842, PMID:38916095]. In innate immunity, AGER is required for caspase-11 inflammasome activation through ALOX5-mediated lipid peroxidation, enabling gasdermin D cleavage, IL-1β maturation, and pyroptosis, such that AGER deletion protects mice from LPS-induced septic death [PMID:31440260]; it also routes HMGB1 and NCOA4 signals into STING1- and NFKBIA-degradation-dependent NF-κB activation during sepsis and regulated cell death [PMID:33992959, PMID:38916095]. In cancer, AGER supports tumorigenesis by sustaining autophagic flux that promotes IL-6–driven STAT3 phosphorylation and mitochondrial bioenergetics [PMID:22722139], by establishing a hexosamine/O-GlcNAc–c-Jun autoregulatory loop under high glucose [PMID:26825459], and by interacting with the formin DIAPH1 to drive RAC1-dependent macropinocytosis that confers resistance to KRAS-G12D inhibition [PMID:39879317]. A soluble ectodomain (sRAGE), generated by C-terminal proteolytic truncation, adopts a J-shaped monomer that homodimerizes through its V domains in a concentration- and Ca²⁺-dependent manner [PMID:15381690, PMID:21865159], and acts both as a decoy that sequesters ligands to dampen inflammation and, in certain contexts, as a direct agonist of monocyte survival and migration [PMID:20574008, PMID:29079726, PMID:29796842]. AGER expression is governed by a YAP/KLF5/NFIB/NKX2-1 transcriptional network in alveolar cells [PMID:34466790], by promoter and coding polymorphisms that modulate expression and sRAGE output [PMID:22860029, PMID:27755550], and post-transcriptionally by miRNAs and competing endogenous RNAs [PMID:31396332, PMID:29752466].","teleology":[{"year":2004,"claim":"Established the biochemical origin of soluble RAGE, resolving how the decoy form is generated and distributed.","evidence":"Purification and biochemical characterization of mouse sRAGE (glycosylation, disulfide pattern, heparin binding)","pmids":["15381690"],"confidence":"Medium","gaps":["Did not identify the protease responsible for C-terminal truncation","Human sRAGE generation (splicing vs shedding) not directly resolved here"]},{"year":2005,"claim":"Linked ligand engagement of AGER to a defined downstream output, showing S100B drives COX-2/PGE2 via PKC and oxidative stress.","evidence":"RT-PCR, Western blot, PGE2 immunoassay and PKC/oxidant inhibitors in human pancreatic islets","pmids":["16341840"],"confidence":"Medium","gaps":["Did not establish direct receptor occupancy versus indirect activation","Limited to islet context"]},{"year":2010,"claim":"Showed sRAGE is not purely a decoy but can directly engage immune cells, complicating the simple competitive-sequestration model.","evidence":"Direct binding, migration, cytokine assays and Akt/Erk/NF-κB immunoblots in human monocytes/macrophages, with intratracheal administration","pmids":["20574008"],"confidence":"Medium","gaps":["The cell-surface receptor mediating sRAGE binding to monocytes not identified","Agonist versus decoy balance in vivo unresolved"]},{"year":2011,"claim":"Defined the solution architecture of sRAGE, explaining how V-domain-mediated, Ca²⁺-dependent dimerization underlies oligomeric signaling.","evidence":"Synchrotron SAXS structure determination and concentration-dependent oligomerization assays","pmids":["21865159"],"confidence":"High","gaps":["No ligand-bound structure","Full-length transmembrane receptor architecture not resolved"]},{"year":2012,"claim":"Demonstrated a cell-intrinsic oncogenic mechanism for AGER, coupling autophagy to IL-6/STAT3 mitochondrial bioenergetics in pancreatic tumorigenesis.","evidence":"Ager-/- in KRAS-driven mouse model, autophagic flux assays, pSTAT3 immunoblotting, mitochondrial fractionation and ATP measurement","pmids":["22722139"],"confidence":"High","gaps":["Ligand driving the autophagy-STAT3 loop not defined","How AGER mechanistically promotes autophagic flux unclear"]},{"year":2016,"claim":"Uncovered a metabolic autoregulatory loop in which AGER drives O-GlcNAc-dependent c-Jun activity that feeds back to enhance its own transcription under hyperglycemia.","evidence":"Gain/loss-of-function in HCC cells, Ser73 O-GlcNAcylation mapping, ChIP and reporter assays","pmids":["26825459"],"confidence":"Medium","gaps":["Direct vs indirect AGER control of hexosamine pathway not dissected","In vivo confirmation of the loop limited"]},{"year":2016,"claim":"Provided functional consequence for a coding polymorphism, showing rs2070600 (Gly82Ser) reduces ligand-induced sRAGE generation.","evidence":"Allele-specific RAGE variant transfection in airway cells with HMGB1 stimulation and sRAGE ELISA plus cohort association","pmids":["27755550"],"confidence":"Medium","gaps":["Mechanism by which Ser82 impairs shedding not defined","Single cell-line overexpression system"]},{"year":2017,"claim":"Showed AGER governs the inflammatory polarization of macrophages in diabetes, with its deletion restoring reparative inflammation and angiogenesis.","evidence":"Ager-/- and Glo1 transgenic mice, hindlimb ischemia model, flow cytometry, macrophage-endothelial co-culture","pmids":["28642238"],"confidence":"High","gaps":["Ligand driving the high-glucose inflammatory shift not pinpointed","Downstream transcriptional program incompletely mapped"]},{"year":2017,"claim":"Established HMGB1/RAGE signaling in dendritic cells as a driver of Th17/neutrophilic asthma, antagonized by sRAGE.","evidence":"Murine asthma model, intratracheal sRAGE, adoptive DC transfer, in vitro Th17 polarization","pmids":["29079726"],"confidence":"Medium","gaps":["Direct DC receptor-level signaling steps to IL-23 not fully resolved","Single lab"]},{"year":2018,"claim":"Identified AGER as a marker and functional determinant of AT1 cell identity, upregulated during AT2-to-AT1 repair.","evidence":"Ager-CreERT2 knock-in lineage tracing and DTA ablation in mice","pmids":["30011373"],"confidence":"Medium","gaps":["Whether AGER is causal for AT1 differentiation or merely a marker unresolved","Signaling role in AT1 cells not addressed"]},{"year":2018,"claim":"Showed AGER drives cardiomyocyte and stem-cell pathology via PKC-ERK-NF-κB/NLRP3 and JNK-ROS axes, with miRNA control of AGER tuning these outcomes.","evidence":"H9C2 Ang II model with sRAGE blockade; AGER siRNA and miR-5591-5p modulation in ADSCs with ROS/apoptosis and JNK readouts plus diabetic wound model","pmids":["29796842","29752466"],"confidence":"Medium","gaps":["Cardiomyocyte work is in vitro only","Direct ligand engagement not demonstrated"]},{"year":2019,"claim":"Connected AGER to lung cancer cell behavior through ceRNA/miRNA regulation and NF-κB, while revealing context-dependent tumor-suppressive effects in NSCLC.","evidence":"Luciferase reporter validation of miR-182-5p targeting AGER, LINC00173 ceRNA experiments, proliferation/migration assays","pmids":["31396332"],"confidence":"Medium","gaps":["Reconciliation of pro- vs anti-tumor AGER roles across cancers unresolved","NF-κB suppression mechanism only partially defined"]},{"year":2019,"claim":"Defined a molecular requirement for AGER in caspase-11 inflammasome activation through ALOX5-mediated lipid peroxidation, establishing it as a driver of pyroptotic sepsis.","evidence":"Global and myeloid-conditional Ager-/-, ALOX5 pathway inhibition, caspase-11/gasdermin D cleavage assays, in vivo LPS sepsis","pmids":["31440260"],"confidence":"High","gaps":["How AGER physically couples to ALOX5 lipid peroxidation not structurally defined","Upstream nDAMP ligand identity incomplete"]},{"year":2021,"claim":"Identified DCN and HMGB1 from regulated cell death as AGER ligands that route into NF-κB and STING1 inflammatory signaling in macrophages.","evidence":"DCN-AGER binding/Co-IP, AGER knockout and inhibition in pancreatitis; genetic dissection of HMGB1-AGER-STING1 in alkaliptosis with cytokine ELISA","pmids":["34964698","33992959"],"confidence":"High","gaps":["Binding sites on AGER for DCN/HMGB1 not mapped","How AGER engages STING1 mechanistically unclear"]},{"year":2021,"claim":"Mapped the transcriptional control of AGER, placing it under a YAP-anchored KLF5/NFIB/NKX2-1 network that specifies AT1 over AT2 fate.","evidence":"YAP gain/loss transgenic mice, ATAC-seq, transcriptomics, motif enrichment","pmids":["34466790"],"confidence":"Medium","gaps":["Direct binding of each factor to the AGER locus not individually validated","Relationship to AGER signaling output not addressed"]},{"year":2024,"claim":"Discovered NCOA4 as an AGER ligand released by macrophages that activates NF-κB via NFKBIA degradation to drive lethal sepsis, defining a therapeutically targetable axis.","evidence":"Co-IP NCOA4-AGER, Ager-/- and ATG5/MCOLN1/GSDMD knockouts, neutralizing antibodies, endotoxemia and polymicrobial sepsis models","pmids":["38916095"],"confidence":"High","gaps":["Structural basis of NCOA4-AGER recognition unknown","Selectivity of AGER over TLR4 only functionally inferred"]},{"year":2025,"claim":"Revealed a non-classical AGER mechanism in cancer drug resistance: an AGER-DIAPH1 interaction drives RAC1-dependent macropinocytosis and nutrient scavenging that defeats KRAS-G12D inhibition.","evidence":"Co-IP of AGER-DIAPH1, RAC1 activity and macropinocytosis assays, PDX and GEMM models with pharmacological inhibitors","pmids":["39879317"],"confidence":"High","gaps":["How ligand binding (if any) regulates the AGER-DIAPH1 interaction unclear","Structural interface with DIAPH1 not defined"]},{"year":null,"claim":"It remains unresolved how AGER's opposing roles—pro-tumorigenic in pancreatic and hepatocellular cancer versus tumor-suppressive in NSCLC—are determined, and how ligand identity, cell type, and the membrane versus soluble forms dictate which downstream program (NF-κB, STAT3/autophagy, macropinocytosis, pyroptosis) is engaged.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of ligand-specific receptor activation","Context determinants of agonist vs decoy sRAGE function undefined","Cross-pathway selectivity (NF-κB vs STING1 vs DIAPH1/RAC1) unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,11,15]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[11,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,8,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,14,21]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11,12,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,9,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,14]}],"complexes":[],"partners":["DIAPH1","HMGB1","DCN","NCOA4","S100B","STING1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15109","full_name":"Advanced glycosylation end product-specific receptor","aliases":["Receptor for advanced glycosylation end products"],"length_aa":404,"mass_kda":42.8,"function":"Cell surface pattern recognition receptor that senses endogenous stress signals with a broad ligand repertoire including advanced glycation end products, S100 proteins, high-mobility group box 1 protein/HMGB1, amyloid beta/APP oligomers, nucleic acids, histones, phospholipids and glycosaminoglycans (PubMed:27572515, PubMed:28515150, PubMed:34743181, PubMed:35974093, PubMed:24081950). Advanced glycosylation end products are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes (PubMed:21565706). These ligands accumulate at inflammatory sites during the pathogenesis of various diseases including diabetes, vascular complications, neurodegenerative disorders and cancers, and RAGE transduces their binding into pro-inflammatory responses. Upon ligand binding, uses TIRAP and MYD88 as adapters to transduce the signal ultimately leading to the induction of inflammatory cytokines IL6, IL8 and TNFalpha through activation of NF-kappa-B (PubMed:21829704, PubMed:33436632). Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key pro-inflammatory mediators (PubMed:19386136). Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons (PubMed:19906677). ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Participates in endothelial albumin transcytosis together with HMGB1 through the RAGE/SRC/Caveolin-1 pathway, leading to endothelial hyperpermeability (PubMed:27572515). Mediates the loading of HMGB1 in extracellular vesicles (EVs) that shuttle HMGB1 to hepatocytes by transferrin-mediated endocytosis and subsequently promote hepatocyte pyroptosis by activating the NLRP3 inflammasome (PubMed:34743181). Binds to DNA and promotes extracellular hypomethylated DNA (CpG DNA) uptake by cells via the endosomal route to activate inflammatory responses (PubMed:24081950, PubMed:28515150). Mediates phagocytosis by non-professional phagocytes (NPP) and this is enhanced by binding to ligands including RNA, DNA, HMGB1 and histones (PubMed:35974093). Promotes NPP-mediated phagocytosis of Saccharomyces cerevisiae spores by binding to RNA attached to the spore wall (PubMed:35974093). Also promotes NPP-mediated phagocytosis of apoptotic cells (PubMed:35974093). Following DNA damage, recruited to DNA double-strand break sites where it colocalizes with the MRN repair complex via interaction with double-strand break repair protein MRE11 (By similarity). Enhances the endonuclease activity of MRE11, promoting the end resection of damaged DNA (By similarity). Promotes DNA damage repair in trophoblasts which enhances trophoblast invasion and contributes to placental development and maintenance (PubMed:33918759). Protects cells from DNA replication stress by localizing to damaged replication forks where it stabilizes the MCM2-7 complex and promotes faithful progression of the replication fork (PubMed:36807739). 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JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/20020577","citation_count":21,"is_preprint":false},{"pmid":"34944030","id":"PMC_34944030","title":"Advanced Glycation End-Products (AGEs) and Their Soluble Receptor (sRAGE) in Women Suffering from Systemic Lupus Erythematosus (SLE).","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34944030","citation_count":20,"is_preprint":false},{"pmid":"27914132","id":"PMC_27914132","title":"Associations between Soluble Receptor for Advanced Glycation End Products (sRAGE) and S100A12 (EN-RAGE) with Mortality in Long-term Hemodialysis Patients.","date":"2017","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/27914132","citation_count":20,"is_preprint":false},{"pmid":"18615900","id":"PMC_18615900","title":"Soluble RAGE, diabetic nephropathy and genetic variability in the AGER gene.","date":"2008","source":"Archives of physiology and 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advanced glycation endproducts RAGE/AGER: an integrative view for clinical applications].","date":"2014","source":"Annales de biologie clinique","url":"https://pubmed.ncbi.nlm.nih.gov/25486663","citation_count":18,"is_preprint":false},{"pmid":"24742661","id":"PMC_24742661","title":"Circulating concentrations of soluble receptor for AGE are associated with age and AGER gene polymorphisms in children with newly diagnosed type 1 diabetes.","date":"2014","source":"Diabetes care","url":"https://pubmed.ncbi.nlm.nih.gov/24742661","citation_count":18,"is_preprint":false},{"pmid":"24976997","id":"PMC_24976997","title":"Changes of HMGB1 and sRAGE during the recovery of COPD exacerbation.","date":"2014","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/24976997","citation_count":18,"is_preprint":false},{"pmid":"21767223","id":"PMC_21767223","title":"Clinical significance of serum sRAGE and esRAGE in women with normal pregnancy and preeclampsia.","date":"2011","source":"Journal of perinatal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21767223","citation_count":18,"is_preprint":false},{"pmid":"29681765","id":"PMC_29681765","title":"Metabolic Derangements Contribute to Reduced sRAGE Isoforms in Subjects with Alzheimer's Disease.","date":"2018","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/29681765","citation_count":18,"is_preprint":false},{"pmid":"32031046","id":"PMC_32031046","title":"Long non-coding RNA AGER-1 inhibits colorectal cancer progression through sponging miR-182.","date":"2020","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/32031046","citation_count":17,"is_preprint":false},{"pmid":"32732977","id":"PMC_32732977","title":"The Gly82Ser mutation in AGER contributes to pathogenesis of pulmonary fibrosis in combined pulmonary fibrosis and emphysema (CPFE) in Japanese patients.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32732977","citation_count":17,"is_preprint":false},{"pmid":"31082855","id":"PMC_31082855","title":"Serum Soluble Receptor for AGE (sRAGE) Levels Are Associated With Unhealthy Lifestyle and Nonalcoholic Fatty Liver Disease.","date":"2019","source":"Clinical and translational gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31082855","citation_count":17,"is_preprint":false},{"pmid":"21871056","id":"PMC_21871056","title":"sRAGE in diabetic and non-diabetic critically ill patients: effects of intensive insulin therapy.","date":"2011","source":"Critical care (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21871056","citation_count":17,"is_preprint":false},{"pmid":"25467215","id":"PMC_25467215","title":"Advanced glycation end products (AGEs) and the soluble receptor for AGE (sRAGE) in patients with type 1 diabetes and coeliac disease.","date":"2014","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/25467215","citation_count":17,"is_preprint":false},{"pmid":"29298878","id":"PMC_29298878","title":"AGER promotes proliferation and migration in cervical cancer.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/29298878","citation_count":16,"is_preprint":false},{"pmid":"23894685","id":"PMC_23894685","title":"Association of four genetic polymorphisms of AGER and its circulating forms with coronary artery disease: a meta-analysis.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23894685","citation_count":16,"is_preprint":false},{"pmid":"33082206","id":"PMC_33082206","title":"Soluble Receptor for Advanced Glycation End-products (sRAGE) and Colorectal Cancer Risk: A Case-Control Study Nested within a European Prospective Cohort.","date":"2020","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33082206","citation_count":15,"is_preprint":false},{"pmid":"32655405","id":"PMC_32655405","title":"Study of sRAGE, HMGB1, AGE, and S100A8/A9 Concentrations in Plasma and in Serum-Extracted Extracellular Vesicles of Pregnant Women With Preterm Premature Rupture of Membranes.","date":"2020","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32655405","citation_count":15,"is_preprint":false},{"pmid":"25562186","id":"PMC_25562186","title":"Dynamic changes in sRAGE levels and relationship with cardiac function in STEMI patients.","date":"2015","source":"Clinical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25562186","citation_count":15,"is_preprint":false},{"pmid":"35127073","id":"PMC_35127073","title":"Association of soluble receptor for advanced glycation end-products (sRAGE) serum on COVID-19 severity: A cross-sectional study.","date":"2022","source":"Annals of medicine and surgery (2012)","url":"https://pubmed.ncbi.nlm.nih.gov/35127073","citation_count":15,"is_preprint":false},{"pmid":"26782423","id":"PMC_26782423","title":"AGER genetic polymorphisms increase risks of breast and lung cancers.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26782423","citation_count":14,"is_preprint":false},{"pmid":"36769213","id":"PMC_36769213","title":"The Potential Influence of Advanced Glycation End Products and (s)RAGE in Rheumatic Diseases.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36769213","citation_count":14,"is_preprint":false},{"pmid":"30836666","id":"PMC_30836666","title":"Evaluation of the AGE/sRAGE Axis in Patients with Multiple Myeloma.","date":"2019","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30836666","citation_count":14,"is_preprint":false},{"pmid":"25355250","id":"PMC_25355250","title":"Serum sRAGE as a potential biomarker for pediatric bronchiolitis: a pilot study.","date":"2014","source":"Lung","url":"https://pubmed.ncbi.nlm.nih.gov/25355250","citation_count":14,"is_preprint":false},{"pmid":"29178941","id":"PMC_29178941","title":"S100A8/A9 and sRAGE kinetic after polytrauma; an explorative observational study.","date":"2017","source":"Scandinavian journal of trauma, resuscitation and emergency medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29178941","citation_count":14,"is_preprint":false},{"pmid":"35215330","id":"PMC_35215330","title":"Carbocysteine Modifies Circulating miR-21, IL-8, sRAGE, and fAGEs Levels in Mild Acute Exacerbated COPD Patients: A Pilot Study.","date":"2022","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35215330","citation_count":14,"is_preprint":false},{"pmid":"34237330","id":"PMC_34237330","title":"An Integrative Genomic Strategy Identifies sRAGE as a Causal and Protective Biomarker of Lung Function.","date":"2021","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/34237330","citation_count":13,"is_preprint":false},{"pmid":"26857858","id":"PMC_26857858","title":"Genetically lowered concentrations of circulating sRAGE might cause an increased risk of cancer: Meta-analysis using Mendelian randomization.","date":"2016","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/26857858","citation_count":12,"is_preprint":false},{"pmid":"32548968","id":"PMC_32548968","title":"Elevated plasma sRAGE and IGFBP7 in heart failure decrease after heart transplantation in association with haemodynamics.","date":"2020","source":"ESC heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/32548968","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56328,"output_tokens":6043,"usd":0.129814,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14728,"output_tokens":5523,"usd":0.105857,"stage2_stop_reason":"end_turn"},"total_usd":0.235671,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse soluble RAGE (sRAGE) is produced by carboxyl-terminal proteolytic truncation of cell surface RAGE (not by alternative splicing as in humans), is glycosylated, contains disulfide bonds, and binds heparin, which may mediate its distribution in the extracellular matrix and on cell surfaces.\",\n      \"method\": \"Purification, biochemical characterization (glycosylation analysis, disulfide pattern determination, heparin-binding assay)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical characterization with multiple orthogonal methods in a single study; single lab\",\n      \"pmids\": [\"15381690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The solution structure of human sRAGE was determined by synchrotron small-angle X-ray scattering; the monomer adopts a J-like shape, and the homodimer is formed through association of the two N-terminal (V) domains, yielding an elongated structure. Oligomerization is concentration-dependent and is also mediated by Ca²⁺ ions.\",\n      \"method\": \"Small-angle X-ray scattering (SAXS) structure determination; concentration-dependent oligomerization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct structural determination by synchrotron SAXS with functional oligomerization validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21865159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Activation of AGER (RAGE) by its ligand S100B on human pancreatic islets induces PTGS2 (COX-2) expression and prostaglandin E2 production via protein kinase C and oxidative stress signaling pathways.\",\n      \"method\": \"RT-PCR, Western blot, PGE2 enzyme immunoassay; pharmacological inhibition of PKC and oxidant stress pathways in human islets treated with S100b\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RT-PCR, Western blot, enzyme immunoassay, inhibitor experiments) in a single lab study\",\n      \"pmids\": [\"16341840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"sRAGE directly binds human monocytes and monocyte-derived macrophages, promoting their survival and differentiation to macrophages, and activates the Akt, Erk, and NF-κB intracellular signaling pathways in these cells. sRAGE also induces monocyte and neutrophil migration and pro-inflammatory cytokine/chemokine production in vitro.\",\n      \"method\": \"Direct binding assay (sRAGE binding to cells), in vitro migration assay, cytokine/chemokine measurement, Western blot for Akt/Erk/NF-κB activation, intratracheal administration in vivo\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays, multiple signaling pathway readouts, in vitro and in vivo experiments; single lab\",\n      \"pmids\": [\"20574008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AGER promotes pancreatic tumorigenesis by mediating autophagic flux that supports IL-6-induced phosphorylation of STAT3 and its mitochondrial localization, thereby increasing ATP availability and cellular proliferation. Targeted ablation of AGER in a KRAS-driven murine model diminishes autophagic flux and attenuates development of early pancreatic intraepithelial neoplasia (PanIN) lesions. A positive feedback loop exists between autophagy activation and the IL6-pSTAT3 pathway downstream of AGER.\",\n      \"method\": \"Genetic knockout (Ager-/-) in KRAS-driven mouse model, autophagic flux assays, IL-6/pSTAT3 immunoblotting, mitochondrial fractionation, ATP measurement, cell proliferation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with defined cellular/molecular phenotype plus multiple orthogonal in vitro mechanistic assays; single lab\",\n      \"pmids\": [\"22722139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AGER activates the hexosamine biosynthetic pathway, leading to enhanced O-GlcNAcylation of c-Jun at Ser73, increasing c-Jun activity and stability. c-Jun in turn enhances AGER transcription, establishing a positive autoregulatory feedback loop that promotes hepatocellular carcinoma tumorigenesis under high-glucose conditions.\",\n      \"method\": \"AGER overexpression/knockdown in HCC cells, O-GlcNAcylation analysis, site-directed mutagenesis (Ser73), ChIP/transcriptional reporter assays, cell proliferation assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification of PTM site (Ser73 O-GlcNAcylation), gain/loss-of-function with multiple readouts; single lab\",\n      \"pmids\": [\"26825459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The rs2070600 (Gly82Ser) AGER variant functionally reduces sRAGE production: airway epithelial cells overexpressing the RAGE-Ser82 variant produce lower sRAGE levels upon HMGB1 stimulation compared to cells overexpressing the RAGE-Gly82 variant, demonstrating a functional role of this SNP in modulating sRAGE generation.\",\n      \"method\": \"Transfection of BEAS2B-R1 cells with Gly82 or Ser82 RAGE variants, HMGB1 stimulation, sRAGE ELISA; RNA-Seq for transcript identification; clinical cohort for association\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional experiment with allele comparison plus clinical validation; single lab\",\n      \"pmids\": [\"27755550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AGER deletion (Ager-/-) in diabetic mice restores adaptive inflammation after hindlimb ischemia by increasing circulating Ly6Chi monocytes and augmenting macrophage infiltration into ischemic muscle, thereby rescuing angiogenesis and blood flow recovery. In vitro, Ager deletion in macrophages reverses the high-glucose-induced shift from tissue-repair to tissue-damage inflammatory gene expression and restores macrophage-endothelial cell interactions.\",\n      \"method\": \"Genetic knockout (Ager-/-), transgenic Glo1 overexpression, femoral artery ligation model, flow cytometry, immunofluorescence, in vitro macrophage/endothelial co-culture assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in two independent mouse models (Ager-/- and Glo1 transgenic) with multiple orthogonal in vivo and in vitro phenotypic and mechanistic readouts\",\n      \"pmids\": [\"28642238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"sRAGE prevents neutrophilic asthma by blocking HMGB1/RAGE signaling in airway CD11c+ dendritic cells, inhibiting RAGE and IL-23 expression, suppressing Th17 polarization, and reducing neutrophilic inflammation. Adoptive transfer of rHMGB1-activated DCs restored airway inflammation; transfer of DCs activated with rHMGB1 plus sRAGE significantly reduced it.\",\n      \"method\": \"Murine neutrophilic asthma model, intratracheal sRAGE administration, adoptive DC transfer, in vitro Th17 polarization assay, flow cytometry, cytokine ELISA\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo adoptive transfer and pharmacological blockade, in vitro DC mechanistic assay; single lab\",\n      \"pmids\": [\"29079726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"sRAGE attenuates angiotensin II-induced cardiomyocyte hypertrophy by downregulating RAGE and AT1R expression, reducing HMGB1 and IL-1β secretion, and inhibiting PKC, ERK1/2, NF-κB, and NLRP3 inflammasome activation. RAGE thus drives cardiac hypertrophy through PKC-ERK1/2 and NF-κB-NLRP3-IL-1β pathway activation.\",\n      \"method\": \"Western blot, fluorescence microscopy (ROS, phospho-p65), ELISA (HMGB1, IL-1β) in H9C2 cells treated with Ang II ± sRAGE\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple signaling readouts using pharmacological inhibition approach; in vitro only, single lab\",\n      \"pmids\": [\"29796842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AGER is required for caspase-11 inflammasome activation in macrophages: AGER-mediated lipid peroxidation via arachidonate 5-lipoxygenase (ALOX5) enables nDAMP-induced caspase-11 activation, gasdermin D cleavage, IL-1β maturation, and pyroptosis. Global (Ager-/-) or myeloid-specific AGER deletion protects mice from LPS-induced septic death.\",\n      \"method\": \"Genetic knockout (global and myeloid-conditional Ager-/-), pharmacological inhibition of AGER-ALOX5 pathway, caspase-11/gasdermin D cleavage assays, LDH release, IL-1β ELISA, in vivo LPS sepsis model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (global and conditional KO) with mechanistic pathway dissection and in vivo rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31440260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DCN (decorin) released during ferroptosis binds to AGER on macrophages, triggering NF-κB-dependent production of pro-inflammatory cytokines. Pharmacological and genetic inhibition of the DCN-AGER axis protects against ferroptotic death-related acute pancreatitis and limits tumor-protective immune responses.\",\n      \"method\": \"Co-immunoprecipitation/binding assay (DCN-AGER), genetic AGER knockout, pharmacological inhibition, in vivo pancreatitis model, cytokine measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-ligand binding identification, genetic loss-of-function, in vivo disease model, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"34964698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HMGB1 released by alkaliptotic cancer cells binds AGER on macrophages and activates the STING1 pathway to produce pro-inflammatory cytokines (TNF and IL-6). Genetic or pharmacological inhibition of the HMGB1-AGER-STING1 pathway limits cytokine production during alkaliptosis.\",\n      \"method\": \"Genetic knockdown/knockout of HMGB1, AGER, and STING1; cytokine ELISA; co-culture of alkaliptotic cancer cells with macrophages\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined pathway sequence; single lab\",\n      \"pmids\": [\"33992959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YAP participates with the transcription factors KLF5, NFIB, and NKX2-1 to regulate AGER expression in alveolar epithelial cells. YAP activation increased AT1 cell numbers and AGER expression; YAP deletion increased AT2 cell gene expression. Motif enrichment and chromatin accessibility analysis identified the transcriptional network.\",\n      \"method\": \"Transgenic mouse models (YAP activation and deletion), ATAC-seq, transcriptomic analysis, motif enrichment\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss-of-function in vivo with chromatin accessibility and transcriptomic mechanistic data; single lab\",\n      \"pmids\": [\"34466790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AGER expression in alveolar type 1 (AT1) cells is high in adult lung; the Ager-CreERT2 allele enables lineage labeling and selective killing of AT1 cells. When ~50% of AT1 cells are killed, SFTPC+ AT2 cells proliferate and upregulate Ager expression during repair, establishing AGER as a marker and functional indicator of AT1 cell identity and repair capacity.\",\n      \"method\": \"Ager-CreERT2 knock-in mouse generation, tamoxifen-induced lineage tracing, Rosa26-DTA AT1 cell ablation, immunofluorescence, cell proliferation quantification\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic tool validated in vivo with functional consequence (AT2 proliferation after AT1 loss); single lab\",\n      \"pmids\": [\"30011373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Extracellular NCOA4 (secreted by activated macrophages via ATG5/MCOLN1-dependent lysosomal exocytosis, or passively released during GSDMD-mediated pyroptosis) binds AGER (not TLR4) on macrophages and activates NF-κB by promoting NFKBIA degradation, driving septic inflammation and death. Neutralizing antibodies against NCOA4 or AGER delay septic death and reduce organ damage in mouse models.\",\n      \"method\": \"Co-IP (NCOA4-AGER interaction), genetic knockout (Ager-/-, ATG5, MCOLN1, GSDMD), monoclonal antibody neutralization, in vivo endotoxemia and polymicrobial sepsis models, NF-κB/NFKBIA Western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-ligand binding identified by Co-IP, genetic KO and antibody neutralization in multiple in vivo models, mechanistic pathway dissection; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38916095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AGER mediates resistance to the KRAS-G12D inhibitor MRTX1133 in pancreatic cancer by upregulating macropinocytosis through its interaction with the formin protein DIAPH1, driving RAC1-dependent macropinosome formation, serum albumin internalization, amino acid generation, and glutathione synthesis that inhibits apoptosis.\",\n      \"method\": \"Co-IP (AGER-DIAPH1 interaction), RAC1 activity assay, macropinocytosis assay, patient-derived xenograft, orthotopic and genetically engineered mouse models, pharmacological inhibitors (RAGE299, EIPA)\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — protein interaction identified by Co-IP, mechanistic pathway confirmed with pharmacological and genetic tools in multiple in vivo models; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39879317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-182-5p directly targets AGER as a downstream effector in NSCLC cells, and AGER loss mediates NF-κB pathway suppression; LINC00173 acts as a competing endogenous RNA to sequester miR-182-5p and restore AGER expression. Alteration of AGER expression or NF-κB inhibition partially counteracts the proliferation/migration phenotype induced by miR-182-5p.\",\n      \"method\": \"Luciferase reporter assay (AGER as direct miR-182-5p target), siRNA/overexpression, functional assays (proliferation, migration, apoptosis), NF-κB inhibition\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validated by luciferase reporter, multiple functional assays; single lab\",\n      \"pmids\": [\"31396332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The AGEs/AGER axis induces ROS generation and apoptosis in adipose tissue-derived stem cells (ADSCs); miR-5591-5p directly targets AGER and suppresses AGEs/AGER-mediated ROS generation and apoptosis via the JNK signaling pathway.\",\n      \"method\": \"siRNA knockdown of AGER, miR-5591-5p overexpression/inhibition, ROS measurement, apoptosis assay, JNK signaling Western blot, in vivo diabetic wound repair model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function, miRNA-target relationship, defined signaling pathway; single lab\",\n      \"pmids\": [\"29752466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In the AGER -429T/C promoter polymorphism, the minor C allele is associated with increased AGER promoter activity (measured by luciferase assay), demonstrating a functional effect of this SNP on RAGE expression levels.\",\n      \"method\": \"Luciferase reporter assay of AGER -429T vs. -429C promoter constructs in BEAS-2B cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro functional assay; single method, single lab\",\n      \"pmids\": [\"22860029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AGER overexpression in NSCLC H1299 cells decreases cell viability, proliferation, migration, and invasion, and increases apoptosis with upregulation of Bax and downregulation of Bcl-2; AGER knockdown has the opposite effects.\",\n      \"method\": \"Lentiviral overexpression and siRNA knockdown, MTT assay, flow cytometry, wound-healing assay, Transwell invasion assay, Western blot (Bax, Bcl-2)\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain and loss of function with multiple readouts; in vitro only, single lab\",\n      \"pmids\": [\"32468030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AGER promotes proliferation, migration, and inhibits apoptosis of cervical squamous cancer cells; AGER protein localizes primarily in the cytoplasm and cytomembrane of these cells. siRNA-mediated AGER blockade suppresses proliferation and migration and stimulates apoptosis.\",\n      \"method\": \"siRNA knockdown, AGER overexpression, immunofluorescence localization, MTT proliferation assay, migration assay, flow cytometry\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain and loss of function with localization data; in vitro only, single lab\",\n      \"pmids\": [\"29298878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cadmium activates AGER-mediated inflammatory signaling via the AGER/PKC/p65 pathway in pancreatic β-cells. Ferroptosis inhibitor Fer-1 antagonizes cadmium-induced AGER-mediated immune activation, placing AGER downstream of ferroptotic lipid peroxidation in the inflammatory cascade.\",\n      \"method\": \"Transcriptomic analysis, ferroptosis marker assays (GSH, GPX4, lipid peroxidation, mitochondrial ultrastructure), AGER/PKC/p65 pathway Western blot, Fer-1 pharmacological inhibition in MIN6 cells and mice\",\n      \"journal\": \"The Science of the total environment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic assays with pharmacological intervention; single lab\",\n      \"pmids\": [\"35931150\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGER (RAGE) is a multiligand cell-surface receptor of the immunoglobulin superfamily, highly expressed as a transmembrane protein on alveolar type 1 cells and other tissues, that upon binding ligands (AGEs, HMGB1, S100 proteins, DCN, NCOA4, and others) activates NF-κB, PKC/ERK, STAT3, ALOX5-mediated lipid peroxidation, and autophagy pathways to drive inflammation and tumorigenesis; its soluble ectodomain (sRAGE), produced by proteolytic shedding of the transmembrane form or by alternative splicing (esRAGE), forms a J-shaped monomer and elongated homodimer that competitively sequesters RAGE ligands to attenuate signaling, and AGER interacts with DIAPH1 to drive RAC1-dependent macropinocytosis in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AGER (RAGE) is a multiligand cell-surface receptor that couples recognition of damage-associated ligands to inflammatory and pro-tumorigenic signaling, and it additionally serves as a defining marker and functional determinant of alveolar type 1 (AT1) cell identity in the lung [#14, #13]. AGER engages a spectrum of ligands released during cell stress and death—S100B [#2], HMGB1 [#8], decorin (DCN) released during ferroptosis [#11], and NCOA4 secreted by activated macrophages [#15]—and transduces these signals through PKC/oxidative-stress, ERK, and NF-\\u03baB cascades to drive prostaglandin production, cytokine release, and pyroptotic inflammation [#2, #9, #15]. In innate immunity, AGER is required for caspase-11 inflammasome activation through ALOX5-mediated lipid peroxidation, enabling gasdermin D cleavage, IL-1\\u03b2 maturation, and pyroptosis, such that AGER deletion protects mice from LPS-induced septic death [#10]; it also routes HMGB1 and NCOA4 signals into STING1- and NFKBIA-degradation-dependent NF-\\u03baB activation during sepsis and regulated cell death [#12, #15]. In cancer, AGER supports tumorigenesis by sustaining autophagic flux that promotes IL-6\\u2013driven STAT3 phosphorylation and mitochondrial bioenergetics [#4], by establishing a hexosamine/O-GlcNAc\\u2013c-Jun autoregulatory loop under high glucose [#5], and by interacting with the formin DIAPH1 to drive RAC1-dependent macropinocytosis that confers resistance to KRAS-G12D inhibition [#16]. A soluble ectodomain (sRAGE), generated by C-terminal proteolytic truncation, adopts a J-shaped monomer that homodimerizes through its V domains in a concentration- and Ca\\u00b2\\u207a-dependent manner [#0, #1], and acts both as a decoy that sequesters ligands to dampen inflammation and, in certain contexts, as a direct agonist of monocyte survival and migration [#3, #8, #9]. AGER expression is governed by a YAP/KLF5/NFIB/NKX2-1 transcriptional network in alveolar cells [#13], by promoter and coding polymorphisms that modulate expression and sRAGE output [#19, #6], and post-transcriptionally by miRNAs and competing endogenous RNAs [#17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the biochemical origin of soluble RAGE, resolving how the decoy form is generated and distributed.\",\n      \"evidence\": \"Purification and biochemical characterization of mouse sRAGE (glycosylation, disulfide pattern, heparin binding)\",\n      \"pmids\": [\"15381690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the protease responsible for C-terminal truncation\", \"Human sRAGE generation (splicing vs shedding) not directly resolved here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked ligand engagement of AGER to a defined downstream output, showing S100B drives COX-2/PGE2 via PKC and oxidative stress.\",\n      \"evidence\": \"RT-PCR, Western blot, PGE2 immunoassay and PKC/oxidant inhibitors in human pancreatic islets\",\n      \"pmids\": [\"16341840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish direct receptor occupancy versus indirect activation\", \"Limited to islet context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed sRAGE is not purely a decoy but can directly engage immune cells, complicating the simple competitive-sequestration model.\",\n      \"evidence\": \"Direct binding, migration, cytokine assays and Akt/Erk/NF-\\u03baB immunoblots in human monocytes/macrophages, with intratracheal administration\",\n      \"pmids\": [\"20574008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The cell-surface receptor mediating sRAGE binding to monocytes not identified\", \"Agonist versus decoy balance in vivo unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the solution architecture of sRAGE, explaining how V-domain-mediated, Ca\\u00b2\\u207a-dependent dimerization underlies oligomeric signaling.\",\n      \"evidence\": \"Synchrotron SAXS structure determination and concentration-dependent oligomerization assays\",\n      \"pmids\": [\"21865159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand-bound structure\", \"Full-length transmembrane receptor architecture not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated a cell-intrinsic oncogenic mechanism for AGER, coupling autophagy to IL-6/STAT3 mitochondrial bioenergetics in pancreatic tumorigenesis.\",\n      \"evidence\": \"Ager-/- in KRAS-driven mouse model, autophagic flux assays, pSTAT3 immunoblotting, mitochondrial fractionation and ATP measurement\",\n      \"pmids\": [\"22722139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand driving the autophagy-STAT3 loop not defined\", \"How AGER mechanistically promotes autophagic flux unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a metabolic autoregulatory loop in which AGER drives O-GlcNAc-dependent c-Jun activity that feeds back to enhance its own transcription under hyperglycemia.\",\n      \"evidence\": \"Gain/loss-of-function in HCC cells, Ser73 O-GlcNAcylation mapping, ChIP and reporter assays\",\n      \"pmids\": [\"26825459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect AGER control of hexosamine pathway not dissected\", \"In vivo confirmation of the loop limited\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided functional consequence for a coding polymorphism, showing rs2070600 (Gly82Ser) reduces ligand-induced sRAGE generation.\",\n      \"evidence\": \"Allele-specific RAGE variant transfection in airway cells with HMGB1 stimulation and sRAGE ELISA plus cohort association\",\n      \"pmids\": [\"27755550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Ser82 impairs shedding not defined\", \"Single cell-line overexpression system\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed AGER governs the inflammatory polarization of macrophages in diabetes, with its deletion restoring reparative inflammation and angiogenesis.\",\n      \"evidence\": \"Ager-/- and Glo1 transgenic mice, hindlimb ischemia model, flow cytometry, macrophage-endothelial co-culture\",\n      \"pmids\": [\"28642238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand driving the high-glucose inflammatory shift not pinpointed\", \"Downstream transcriptional program incompletely mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established HMGB1/RAGE signaling in dendritic cells as a driver of Th17/neutrophilic asthma, antagonized by sRAGE.\",\n      \"evidence\": \"Murine asthma model, intratracheal sRAGE, adoptive DC transfer, in vitro Th17 polarization\",\n      \"pmids\": [\"29079726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DC receptor-level signaling steps to IL-23 not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified AGER as a marker and functional determinant of AT1 cell identity, upregulated during AT2-to-AT1 repair.\",\n      \"evidence\": \"Ager-CreERT2 knock-in lineage tracing and DTA ablation in mice\",\n      \"pmids\": [\"30011373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AGER is causal for AT1 differentiation or merely a marker unresolved\", \"Signaling role in AT1 cells not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed AGER drives cardiomyocyte and stem-cell pathology via PKC-ERK-NF-\\u03baB/NLRP3 and JNK-ROS axes, with miRNA control of AGER tuning these outcomes.\",\n      \"evidence\": \"H9C2 Ang II model with sRAGE blockade; AGER siRNA and miR-5591-5p modulation in ADSCs with ROS/apoptosis and JNK readouts plus diabetic wound model\",\n      \"pmids\": [\"29796842\", \"29752466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cardiomyocyte work is in vitro only\", \"Direct ligand engagement not demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected AGER to lung cancer cell behavior through ceRNA/miRNA regulation and NF-\\u03baB, while revealing context-dependent tumor-suppressive effects in NSCLC.\",\n      \"evidence\": \"Luciferase reporter validation of miR-182-5p targeting AGER, LINC00173 ceRNA experiments, proliferation/migration assays\",\n      \"pmids\": [\"31396332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of pro- vs anti-tumor AGER roles across cancers unresolved\", \"NF-\\u03baB suppression mechanism only partially defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a molecular requirement for AGER in caspase-11 inflammasome activation through ALOX5-mediated lipid peroxidation, establishing it as a driver of pyroptotic sepsis.\",\n      \"evidence\": \"Global and myeloid-conditional Ager-/-, ALOX5 pathway inhibition, caspase-11/gasdermin D cleavage assays, in vivo LPS sepsis\",\n      \"pmids\": [\"31440260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AGER physically couples to ALOX5 lipid peroxidation not structurally defined\", \"Upstream nDAMP ligand identity incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified DCN and HMGB1 from regulated cell death as AGER ligands that route into NF-\\u03baB and STING1 inflammatory signaling in macrophages.\",\n      \"evidence\": \"DCN-AGER binding/Co-IP, AGER knockout and inhibition in pancreatitis; genetic dissection of HMGB1-AGER-STING1 in alkaliptosis with cytokine ELISA\",\n      \"pmids\": [\"34964698\", \"33992959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding sites on AGER for DCN/HMGB1 not mapped\", \"How AGER engages STING1 mechanistically unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the transcriptional control of AGER, placing it under a YAP-anchored KLF5/NFIB/NKX2-1 network that specifies AT1 over AT2 fate.\",\n      \"evidence\": \"YAP gain/loss transgenic mice, ATAC-seq, transcriptomics, motif enrichment\",\n      \"pmids\": [\"34466790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of each factor to the AGER locus not individually validated\", \"Relationship to AGER signaling output not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovered NCOA4 as an AGER ligand released by macrophages that activates NF-\\u03baB via NFKBIA degradation to drive lethal sepsis, defining a therapeutically targetable axis.\",\n      \"evidence\": \"Co-IP NCOA4-AGER, Ager-/- and ATG5/MCOLN1/GSDMD knockouts, neutralizing antibodies, endotoxemia and polymicrobial sepsis models\",\n      \"pmids\": [\"38916095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NCOA4-AGER recognition unknown\", \"Selectivity of AGER over TLR4 only functionally inferred\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-classical AGER mechanism in cancer drug resistance: an AGER-DIAPH1 interaction drives RAC1-dependent macropinocytosis and nutrient scavenging that defeats KRAS-G12D inhibition.\",\n      \"evidence\": \"Co-IP of AGER-DIAPH1, RAC1 activity and macropinocytosis assays, PDX and GEMM models with pharmacological inhibitors\",\n      \"pmids\": [\"39879317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ligand binding (if any) regulates the AGER-DIAPH1 interaction unclear\", \"Structural interface with DIAPH1 not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how AGER's opposing roles—pro-tumorigenic in pancreatic and hepatocellular cancer versus tumor-suppressive in NSCLC—are determined, and how ligand identity, cell type, and the membrane versus soluble forms dictate which downstream program (NF-\\u03baB, STAT3/autophagy, macropinocytosis, pyroptosis) is engaged.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of ligand-specific receptor activation\", \"Context determinants of agonist vs decoy sRAGE function undefined\", \"Cross-pathway selectivity (NF-\\u03baB vs STING1 vs DIAPH1/RAC1) unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 11, 15]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [11, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 8, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 14, 21]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11, 12, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DIAPH1\", \"HMGB1\", \"DCN\", \"NCOA4\", \"S100B\", \"STING1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}