{"gene":"AGER","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1992,"finding":"RAGE was cloned from a bovine lung cDNA library and identified as a ~35-kDa cell-surface receptor for advanced glycation end products (AGEs). The protein is a member of the immunoglobulin superfamily with an extracellular domain of 332 aa, a single transmembrane domain of 19 aa, and a 43-aa cytoplasmic tail. Expression of RAGE cDNA in HEK293 cells conferred saturable, antibody-blockable binding of 125I-AGE-albumin (Kd ~100 nM), establishing RAGE as a functional AGE receptor.","method":"cDNA cloning, recombinant expression in HEK293 cells, radioligand binding assay, Western blot","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with direct binding reconstitution and antibody blockade","pmids":["1378843"],"is_preprint":false},{"year":1996,"finding":"RAGE was identified as a neuronal cell-surface receptor for amyloid-β (Aβ) peptide. RAGE expression was found elevated in Alzheimer's disease brain. RAGE–Aβ interaction on neurons and microglia mediated Aβ-induced oxidant stress and neurotoxicity, establishing a direct mechanistic link between RAGE ligation and neurodegeneration.","method":"Binding assays with recombinant RAGE and Aβ peptide, cell-based neurotoxicity assays, immunohistochemistry of AD brain, antibody blockade experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding demonstrated, functional blockade with antibodies, replicated across multiple cell/tissue contexts","pmids":["8751438"],"is_preprint":false},{"year":1997,"finding":"The RAGE gene promoter contains functional NF-κB binding sites. Deletion analysis and DNase I footprinting/EMSA identified two active NF-κB-like sites (sites 1 and 2) in the −1543/−587 region that drive basal and LPS-stimulated RAGE expression in endothelial and smooth muscle cells. Simultaneous mutation of both sites markedly reduced promoter activity, establishing NF-κB-dependent transcriptional autoregulation of RAGE.","method":"5′-deletion luciferase reporter constructs, DNase I footprinting, electrophoretic mobility shift assay (EMSA), transient transfection in vascular endothelial and smooth muscle cells","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (reporter assay, footprinting, EMSA, mutagenesis) in a single study","pmids":["9195959"],"is_preprint":false},{"year":1998,"finding":"Administration of the soluble extracellular domain of RAGE (sRAGE) completely suppressed accelerated atherosclerosis in diabetic apolipoprotein E-deficient mice in a glycemia- and lipid-independent manner, demonstrating that AGE–RAGE interaction is causally required for diabetic macrovascular disease and that sRAGE acts as a decoy receptor to block this pathway.","method":"In vivo mouse model (streptozotocin-diabetic ApoE-KO mice), pharmacological sRAGE administration, atherosclerotic lesion quantification","journal":"Nature Medicine","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo genetic/pharmacological intervention with defined vascular phenotype, highly cited foundational study","pmids":["9734395"],"is_preprint":false},{"year":1999,"finding":"RAGE was identified as a central cell-surface receptor for S100/calgranulin polypeptides (EN-RAGE and related family members). Engagement of S100/calgranulins by RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggered cellular activation and generation of proinflammatory mediators. Blockade of EN-RAGE/RAGE signaling suppressed delayed-type hypersensitivity and inflammatory colitis in murine models, defining a novel RAGE-dependent proinflammatory axis.","method":"Receptor binding assays, cell activation assays, in vivo murine models (DTH, colitis) with antibody blockade and soluble RAGE","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — binding assays combined with in vivo loss-of-function models and multiple orthogonal readouts; foundational paper","pmids":["10399917"],"is_preprint":false},{"year":1999,"finding":"RAGE-mediated neurite outgrowth (induced by amphoterin/HMGB1) and NF-κB activation use distinct intracellular signaling pathways both requiring the RAGE cytoplasmic domain. Neurite outgrowth is blocked by dominant-negative Rac and Cdc42 (but not Ras), whereas NF-κB activation is blocked by dominant-negative Ras (but not Rac/Cdc42). Deletion of the cytoplasmic domain of RAGE abolished both responses.","method":"Transfection of RAGE constructs (full-length and cytoplasmic domain deletion mutants) into neuroblastoma cells, dominant-negative GTPase overexpression, NF-κB reporter assays, neurite outgrowth assays on amphoterin-coated substrates","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — epistasis by dominant-negative mutants plus domain deletion mutagenesis with two distinct functional readouts","pmids":["10391939"],"is_preprint":false},{"year":1999,"finding":"CML (Nε-carboxymethyllysine) adducts of proteins are direct RAGE ligands. CML-modified proteins engage cellular RAGE and activate NF-κB signaling and downstream gene expression in vascular cells, identifying a specific AGE molecular species responsible for RAGE-mediated vascular and inflammatory complications.","method":"Cell-based RAGE binding assays with CML-modified proteins, NF-κB activation assays, gene expression analysis","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct ligand-receptor interaction with functional cellular signaling readout","pmids":["10531386"],"is_preprint":false},{"year":2000,"finding":"S100B and S100A1 activate RAGE in concert with amphoterin to induce neurite outgrowth and NF-κB activation. Nanomolar S100B promotes RAGE-dependent cell survival via upregulation of anti-apoptotic Bcl-2, whereas micromolar S100B induces RAGE-dependent apoptosis. Both trophic and toxic effects require full-length RAGE with an intact cytoplasmic domain.","method":"Transfection of full-length vs. cytoplasmic domain deletion RAGE mutants, cell survival/apoptosis assays, Bcl-2 immunoblotting, neurite outgrowth assays, NF-κB reporter assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — domain mutagenesis with multiple functional readouts; concentration-dependent bidirectional effects mechanistically defined","pmids":["11007787"],"is_preprint":false},{"year":2002,"finding":"RAGE is expressed on human peritoneal mesothelial cells (HPMC). AGE binding to RAGE (specifically CML-albumin) stimulates VCAM-1 (but not ICAM-1) overexpression and enhances leukocyte adhesion. Both anti-RAGE antibody and recombinant RAGE (acting as decoy) blocked the CML-albumin-induced VCAM-1 upregulation, establishing a direct AGE–RAGE–VCAM-1 signaling axis in mesothelial inflammation.","method":"FACS detection of RAGE on HPMC, RT-PCR, radiometric VCAM-1/ICAM-1 expression assay, antibody and decoy receptor blockade, videomicroscopy of leukocyte adhesion","journal":"Kidney International","confidence":"Medium","confidence_rationale":"Tier 2 — receptor blockade with two independent reagents (antibody + decoy RAGE) with functional adhesion molecule readout","pmids":["11786095"],"is_preprint":false},{"year":2002,"finding":"The G82S polymorphism in the RAGE ligand-binding domain amplifies the inflammatory response. Cells bearing the RAGE 82S allele displayed enhanced binding of S100/calgranulins and greater cytokine/MMP generation compared to 82G allele cells. In vivo, blockade of RAGE suppressed clinical and histologic arthritis and reduced TNF-α, IL-6, and MMPs 3, 9, and 13 in affected tissues in a collagen-induced arthritis model.","method":"Cell-based binding assays with allelic RAGE variants, cytokine/MMP production assays, in vivo murine collagen-induced arthritis model with RAGE blockade, human case-control genetic association","journal":"Genes and Immunity","confidence":"High","confidence_rationale":"Tier 2 — allele-specific functional assays combined with in vivo model; mechanistic link between specific polymorphism and signaling amplitude established","pmids":["12070776"],"is_preprint":false},{"year":2003,"finding":"RAGE expressed on brain endothelial cells mediates transcytosis of circulating Aβ peptides across the blood-brain barrier (BBB) into brain parenchyma and drives expression of proinflammatory cytokines and endothelin-1 (causing vasoconstriction). Inhibition of RAGE–ligand interaction at the BBB suppressed Aβ accumulation in brain parenchyma in APPsw transgenic mice.","method":"Systemic Aβ infusion in mice, transgenic mouse models, pharmacological RAGE blockade, BBB transport assays, cerebral blood flow measurements, ET-1 and cytokine quantification","journal":"Nature Medicine","confidence":"High","confidence_rationale":"Tier 1–2 — direct in vivo transport assay combined with pharmacological and genetic intervention, replicated in multiple mouse models","pmids":["12808450"],"is_preprint":false},{"year":2003,"finding":"Novel splice variants of RAGE lacking either the N-terminal V-type Ig domain (N-truncated, membrane-bound) or the C-terminal transmembrane domain (C-truncated/endogenous secretory RAGE, esRAGE) are expressed in vascular endothelial cells and pericytes. The C-truncated (esRAGE) isoform is secreted, binds AGEs via its intact V-domain, and completely abolished AGE-induced ERK phosphorylation and VEGF induction, identifying esRAGE as an endogenous cytoprotective decoy receptor. N-truncated RAGE lacks ligand-binding capacity.","method":"RT-PCR cloning of splice variants, COS-7 transfection, AGE-affinity column binding, secretion assays, ERK phosphorylation assays, VEGF quantification, endothelial cord formation assay","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1–2 — domain-deletion variant analysis with multiple functional assays establishing structure-function relationships","pmids":["12495433"],"is_preprint":false},{"year":2005,"finding":"Dendritic cells (DCs) actively release HMGB1 upon activation, and this secreted HMGB1 signals through RAGE on DCs to drive their maturation (CD80/CD83/CD86 upregulation, IL-12 production) and to sustain T cell clonal expansion, survival, and polarization. Using RAGE−/− cells and neutralizing antibodies, RAGE was demonstrated to be required for the HMGB1 effect on DCs, acting through downstream MAPK and NF-κB activation.","method":"RAGE−/− cells, neutralizing antibodies to RAGE and HMGB1, DC maturation marker FACS, IL-12 ELISA, T cell proliferation and polarization assays, MAPK/NF-κB signaling assays","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic (RAGE KO) and pharmacological (antibody) loss-of-function with multiple defined immune cell phenotypes","pmids":["15944249"],"is_preprint":false},{"year":2007,"finding":"The X-ray crystal structure of Ca2+-loaded S100B at 1.9 Å resolution revealed an octameric architecture (four homodimers arranged as two tetramers). Tetrameric S100B binds RAGE with higher affinity than dimeric S100B and, by AUC, binds two RAGE molecules via the V-domain. Tetrameric S100B caused stronger cell growth activation and survival than the dimer, suggesting RAGE activation involves receptor dimerization/oligomerization driven by multimeric S100B.","method":"X-ray crystallography (1.9 Å), size-exclusion chromatography of brain extracts, purification of S100B oligomers from E. coli, surface plasmon resonance binding studies, analytical ultracentrifugation, cell growth/survival assays","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus biophysical binding assays (SPR, AUC) with functional cell-based validation","pmids":["17660747"],"is_preprint":false},{"year":2008,"finding":"RAGE functions as a sensor of necrotic cell death in ischemic brain injury. HMGB1 released from ischemic tissue engages RAGE on (micro)glial cells to mediate neurotoxicity. RAGE deficiency or soluble RAGE reduced infarct size. Chimeric mouse experiments transplanting RAGE−/− bone marrow into wild-type recipients showed that RAGE deficiency specifically in bone marrow-derived macrophages significantly reduced infarct size, positioning macrophage RAGE as a critical effector of HMGB1-mediated post-ischemic inflammation.","method":"Mouse cerebral ischemia model (MCAO), RAGE−/− mice, soluble RAGE administration, anti-HMGB1 antibody, HMGB1 box A antagonist, bone marrow chimera experiments, infarct volume quantification, in vitro (micro)glial neurotoxicity assay","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific RAGE requirement established via bone marrow chimeras plus pharmacological blockade with multiple orthogonal approaches","pmids":["19005067"],"is_preprint":false},{"year":2008,"finding":"Most circulating soluble RAGE in human blood is produced by proteolytic ectodomain shedding (cleaved RAGE, cRAGE) rather than by the alternative splice variant esRAGE. Screening of chemical inhibitors and genetically modified MEFs identified ADAM10 as the responsible sheddase. HMGB1 ligand binding promotes RAGE shedding by ADAM10, and cRAGE acts as a decoy receptor.","method":"Anti-esRAGE vs. pan-sRAGE antibody comparison, transfection of full-length RAGE cDNA, ADAM10-deficient MEFs, chemical protease inhibitor panel, HMGB1 stimulation shedding assay","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 1–2 — genetic (KO MEFs) and pharmacological screening identified specific sheddase; ligand-induced shedding mechanism validated","pmids":["18603587"],"is_preprint":false},{"year":2008,"finding":"RAGE mediates neuronal differentiation and neurite outgrowth in P19 embryonic carcinoma stem cells. RAGE knockdown by RNAi blocked retinoic acid-induced neuronal differentiation, inhibited NF-κB nuclear translocation, and strongly suppressed neurite outgrowth. In primary cerebellar granule neurons, RAGE KD inhibited neurite outgrowth through the Rac1/Cdc42 GTPase pathway; constitutively active Rac1/Cdc42 rescued neurite outgrowth in RAGE-deficient neurons.","method":"RNAi knockdown in P19 cells and primary cerebellar granule neurons, NF-κB nuclear translocation assay, dominant-negative and constitutively active Rac1/Cdc42 overexpression, neurite outgrowth quantification","journal":"Journal of Neuroscience Research","confidence":"High","confidence_rationale":"Tier 2 — epistasis via dominant-negative and constitutively active GTPases plus RNAi in two distinct cell systems","pmids":["18058943"],"is_preprint":false},{"year":2011,"finding":"RAGE is a positive regulator of autophagy and a negative regulator of apoptosis during oxidative stress in pancreatic cancer cells. RAGE upregulation via NF-κB decreases ROS-induced oxidative injury; suppression of RAGE increases sensitivity to oxidative stress-induced cell death, positioning RAGE as a switch between autophagy-mediated survival and apoptosis.","method":"RAGE knockdown and overexpression in pancreatic cancer cells, ROS measurement, autophagy flux assay, apoptosis assays (flow cytometry), NF-κB reporter assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with defined pathway readouts in a single lab","pmids":["21317562"],"is_preprint":false},{"year":2012,"finding":"RAGE is a native receptor for the globular domain of complement component C1q. Direct C1q–RAGE interaction was demonstrated by surface plasmon resonance (Kd ~5.6 µM) and ELISA-like multivalent binding assay. Pull-down experiments indicated RAGE forms a complex with Mac-1 (CD11b/CD18) to enhance C1q binding affinity. Antibodies to RAGE or Mac-1 inhibited C1q-induced U937 cell adhesion and phagocytosis.","method":"Surface plasmon resonance, ELISA-based binding assay, pull-down (RAGE–Mac-1 complex), cell adhesion assay, phagocytosis assay with antibody blockade","journal":"Cellular Immunology","confidence":"High","confidence_rationale":"Tier 1–2 — biophysical binding measurement (SPR) plus pull-down complex and functional phagocytosis assay with antibody blockade","pmids":["22386596"],"is_preprint":false},{"year":2012,"finding":"FPS-ZM1, a high-affinity small-molecule RAGE inhibitor targeting the V-domain, blocked Aβ binding to RAGE, inhibited RAGE-mediated Aβ transcytosis across the BBB into brain, suppressed β-secretase activity and Aβ production in brain, reduced microglial neuroinflammation, and normalized cognitive performance and cerebral blood flow in aged APPsw transgenic mice.","method":"In vitro RAGE–Aβ binding assay, RAGE-expressing cell stress assays, in vivo aged APPsw/0 transgenic mice, BBB transport assay, β-secretase activity assay, Aβ ELISA, Morris water maze, cerebral blood flow measurement","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1–2 — multimodal RAGE blocker characterized in vitro and in vivo with mechanistic readouts across multiple pathways","pmids":["22406537"],"is_preprint":false},{"year":2015,"finding":"RAGE undergoes ligand-independent transactivation by the type 1 angiotensin II receptor (AT1R). AT1R and RAGE form a preformed heteromeric complex at the cell surface. Ang II stimulation of AT1R triggers transactivation of the RAGE cytosolic tail, driving NF-κB-dependent proinflammatory gene expression independently of RAGE ligand binding or the RAGE ectodomain. Deletion or inhibition of RAGE selectively attenuated AT1R-driven proinflammatory signaling without affecting canonical Gq signaling. A mutant RAGE peptide (S391A-RAGE362-404) inhibited transactivation and attenuated Ang II-dependent inflammation and atherogenesis in vivo.","method":"Co-immunoprecipitation of AT1R–RAGE complex, RAGE-KO and ectodomain-deletion mouse models, NF-κB reporter assay, Ager/Apoe-KO mouse atherosclerosis model, rescue with WT vs. mutant RAGE peptide, atherosclerotic lesion quantification","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1–2 — receptor complex Co-IP, genetic KO, domain mutagenesis, and in vivo rescue with defined mechanistic readouts","pmids":["30530993"],"is_preprint":false},{"year":2016,"finding":"RAGE and the β1-adrenergic receptor (β1AR) physically interact to form a receptor complex that activates CaMKII, causing cardiomyocyte death and maladaptive remodeling. RAGE deficiency or inhibition blocks β1AR-mediated myocardial injury; β1AR ablation abolishes RAGE-induced detrimental effects. The convergence point of both receptors is CaMKII activation.","method":"Co-immunoprecipitation of β1AR–RAGE complex, RAGE-KO and β1AR-KO mice, cardiomyocyte death assays, CaMKII activity assay, cardiac remodeling histology, pharmacological RAGE and β1AR inhibitors","journal":"JCI Insight","confidence":"High","confidence_rationale":"Tier 2 — receptor complex Co-IP plus double genetic KO epistasis with defined downstream kinase (CaMKII) as convergence point","pmids":["26966719"],"is_preprint":false},{"year":2016,"finding":"RAGE binds RNA molecules in a sequence-independent manner and facilitates RNA uptake into endosomes, enhancing ssRNA sensing by TLR7, TLR8, and TLR13. Gain- and loss-of-function studies established RAGE as an integral co-receptor of the endosomal nucleic acid-sensing system, extending its previously described role for DNA/TLR9 to all ssRNA-sensing TLRs.","method":"RNA–RAGE binding assays, cellular RNA uptake assays (fluorescent RNA), gain-of-function (RAGE overexpression) and loss-of-function (RAGE KO) in TLR reporter systems, TLR7/8/13 activation assays","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay plus gain/loss-of-function across multiple TLR reporters","pmids":["27798148"],"is_preprint":false},{"year":2016,"finding":"AGER activates a hexosamine biosynthetic pathway in hepatocellular carcinoma cells under high-glucose conditions, leading to enhanced O-GlcNAcylation of c-Jun at Ser73, which increases c-Jun activity and stability. c-Jun in turn transcriptionally upregulates AGER, establishing a positive autoregulatory feedback loop that drives diabetic HCC tumorigenesis.","method":"AGER knockdown/overexpression in HCC cells, O-GlcNAcylation mass spectrometry and western blot, site-directed mutagenesis of c-Jun Ser73, luciferase reporter for AGER promoter, co-immunoprecipitation","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1–2 — specific PTM site identified by mutagenesis, feedback loop confirmed by promoter reporter and epistasis","pmids":["26825459"],"is_preprint":false},{"year":2017,"finding":"RAGE deficiency (Ager KO) in diabetic mice restored adaptive inflammation after hindlimb ischemia, increased circulating Ly6Chi monocytes and macrophage infiltration into ischemic muscle, and rescued angiogenesis and blood flow recovery. In vitro, Ager deletion in macrophages reversed high-glucose-mediated skewing toward tissue-damage gene expression and restored macrophage–endothelial cell interactions, placing AGER as a suppressor of adaptive inflammation in diabetic peripheral vascular disease.","method":"Ager-KO and Glo1-transgenic diabetic mice, femoral artery ligation, laser Doppler blood flow, immunohistochemistry for angiogenesis markers and macrophage content, Ly6Chi monocyte FACS, macrophage-endothelial co-culture assays, gene expression profiling","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO in vivo plus in vitro mechanistic dissection with multiple orthogonal readouts","pmids":["28642238"],"is_preprint":false},{"year":2017,"finding":"Hydrogen sulfide (H2S) reduces RAGE toxicity by inhibiting RAGE dimerization and impairing its membrane stability. H2S (via NaHS) attenuated Aβ1-42- and AGE-induced cell injury. NaHS reduced H2O2-enhanced RAGE dimerization (shown by split-GFP complementation and Western blot) and decreased membrane RAGE expression. S-sulfhydration assay identified C259/C301 as the residues directly modified by H2S; mutation of these sites (C259S/C310S double mutant) mimicked H2S effects and caused ER retention, reduced membrane expression, and shortened half-life of RAGE.","method":"Split-GFP complementation dimerization assay, Western blot, immunofluorescence, cycloheximide chase, ubiquitination assay, tag-switch S-sulfhydration assay, site-directed mutagenesis (C259S/C310S)","journal":"Free Radical Biology & Medicine","confidence":"High","confidence_rationale":"Tier 1–2 — specific cysteine residues identified by mutagenesis and direct S-sulfhydration detection; dimerization mechanism validated by orthogonal split-GFP assay","pmids":["28108276"],"is_preprint":false},{"year":2018,"finding":"RAGE modulates autophagy in hepatocellular carcinoma (HCC) cells to promote proliferation and sorafenib resistance. RAGE deficiency activated AMPK/mTOR signaling and induced autophagy, which improved sorafenib response. HMGB1 and S100A4 ligands positively upregulated RAGE expression, indicating a ligand-driven autocrine amplification loop in HCC.","method":"RAGE knockdown and overexpression in HCC cell lines, AMPK/mTOR pathway assays, autophagy flux assays, sorafenib cytotoxicity assays, HMGB1/S100A4 ligand stimulation experiments","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — gain/loss-of-function with defined AMPK/mTOR pathway readout, single lab","pmids":["29445087"],"is_preprint":false},{"year":2018,"finding":"miR-5591-5p directly targets AGER mRNA (3′UTR), suppressing AGER expression. AGEs downregulate miR-5591-5p in adipose-derived stem cells (ADSCs), activating the AGE/AGER/JNK signaling axis to induce ROS generation and apoptosis. miR-5591-5p overexpression blocked this axis, promoted ADSC survival, and enhanced cutaneous wound repair in vivo.","method":"miRNA mimic/inhibitor transfection, luciferase 3′UTR reporter assay for AGER targeting, AGER siRNA, ROS assay, JNK phosphorylation assay, apoptosis flow cytometry, in vivo diabetic wound healing model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3′UTR luciferase validation of miRNA–AGER interaction combined with in vivo functional outcome","pmids":["29752466"],"is_preprint":false},{"year":2021,"finding":"Decorin (DCN), a proteoglycan released by ferroptotic cells via secretory autophagy and lysosomal exocytosis, binds to AGER on macrophages to trigger NF-κB-dependent pro-inflammatory cytokine production. Pharmacological and genetic inhibition of the DCN–AGER axis protected against ferroptotic death-related acute pancreatitis and limited tumor-protective immune responses to ferroptotic cancer cells.","method":"Cell death assays (ferroptosis induction), DCN release quantification, Co-IP of DCN–AGER interaction, AGER KO macrophages, NF-κB reporter, in vivo acute pancreatitis model, tumor immunization experiments","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — direct binding (Co-IP), genetic KO with defined NF-κB signaling readout, and in vivo disease model validation","pmids":["34964698"],"is_preprint":false},{"year":2021,"finding":"During alkaliptosis (intracellular alkalization-driven cell death), HMGB1 is released from the nucleus to the extracellular space via a FANCD2-dependent (not ATM-mediated) DNA damage signaling pathway. Released HMGB1 binds AGER on macrophages and then activates the STING1 pathway to produce pro-inflammatory cytokines (TNF, IL-6). Inhibition of the HMGB1–AGER–STING1 pathway limits cytokine production during alkaliptosis.","method":"HMGB1 nuclear-to-cytoplasmic translocation assay, FANCD2/ATM genetic perturbation, AGER KO macrophages, STING1 pathway readout (IRF3/TBK1 phosphorylation), cytokine ELISA","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic dissection of HMGB1 release pathway and AGER-STING1 axis; single lab","pmids":["33992959"],"is_preprint":false},{"year":2021,"finding":"YAP participates in a transcriptional network with KLF5, NFIB, and NKX2-1 to regulate AGER expression in alveolar epithelial cells. YAP activation increased AT1 cell numbers and enhanced DNA accessibility at AGER promoter regions; YAP deletion increased AT2 markers. Chromatin accessibility (ATAC-seq) and motif enrichment analysis identified the transcription factor network controlling AGER during alveolar differentiation.","method":"Transgenic YAP activation/deletion mouse models, ATAC-seq, transcription factor motif enrichment, RNA-seq, immunostaining for AT1/AT2 markers","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic YAP gain/loss-of-function with chromatin accessibility data; AGER as downstream target validated in vivo","pmids":["34466790"],"is_preprint":false},{"year":2022,"finding":"Cadmium (Cd) induces ferroptosis in pancreatic β-cells, and ferroptosis inhibitor Fer-1 antagonized Cd-induced AGER-mediated inflammation. Cd exposure decreased Gpx4 expression (enabling ferroptosis) and activated the AGER/PKC/p65 (NF-κB) inflammatory axis. The Gpx4/AGER/p65 pathway was identified as a novel mechanistic axis linking ferroptotic cell death to pancreatic inflammation and β-cell dysfunction.","method":"Transcriptomic analysis (RNA-seq) of Cd-treated MIN6 cells, GSH/lipid peroxidation assays, Gpx4 knockdown/inhibition, ferroptosis inhibitor (Fer-1), AGER expression analysis, PKC/NF-κB pathway assays, in vivo Cd-exposed mouse model","journal":"The Science of the Total Environment","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological rescue with Fer-1 plus pathway validation in vitro and in vivo; single lab","pmids":["35931150"],"is_preprint":false},{"year":2025,"finding":"AGER mediates resistance to KRAS-G12D inhibitor MRTX1133 in pancreatic ductal adenocarcinoma by driving macropinocytosis. AGER interacts with DIAPH1 (diaphanous-related formin 1), which activates RAC1-dependent macropinosome formation, enabling internalization of serum albumin and generation of amino acids used for glutathione synthesis and apoptosis resistance. Combination of MRTX1133 with AGER–DIAPH1 complex inhibitor (RAGE299) or macropinocytosis inhibitor (EIPA) was effective in patient-derived xenografts, orthotopic, and genetically engineered mouse models. This combination also induced HMGB1 release and CD8+ T cell antitumor responses.","method":"AGER overexpression/knockdown in PDAC cells, Co-IP of AGER–DIAPH1 complex, RAC1 activity assay, macropinocytosis assay (fluorescent albumin uptake), glutathione measurement, patient-derived xenografts, orthotopic mouse models, genetically engineered mouse PDAC models, CD8+ T cell immune response assays","journal":"Science Translational Medicine","confidence":"High","confidence_rationale":"Tier 1–2 — direct protein-protein interaction (Co-IP of AGER–DIAPH1), mechanistic downstream pathway (RAC1→macropinocytosis→GSH), validated in multiple in vivo models","pmids":["39879317"],"is_preprint":false}],"current_model":"AGER/RAGE is a multiligand immunoglobulin superfamily transmembrane receptor whose extracellular V-domain binds AGEs, HMGB1, S100/calgranulins, Aβ, C1q, RNA, and decorin; ligand engagement requires the intact cytoplasmic domain to activate NF-κB (via Ras), Rac1/Cdc42-dependent cytoskeletal remodeling (neurite outgrowth), MAPK, and CaMKII through distinct downstream pathways; RAGE also undergoes ligand-independent transactivation by AT1R and β1AR through direct receptor heterocomplex formation; soluble RAGE isoforms arise by ADAM10-mediated ectodomain shedding (cRAGE) or alternative splicing (esRAGE) and act as decoy receptors; intracellularly, RAGE engages DIAPH1 to drive RAC1-dependent macropinocytosis; and RAGE dimerization—stabilized at plasma membrane cysteine residues C259/C301—is required for full signaling activity."},"narrative":{"teleology":[{"year":1992,"claim":"Establishing that a novel immunoglobulin-superfamily receptor specifically binds AGEs answered the fundamental question of how cells sense glycation damage, founding the RAGE field.","evidence":"cDNA cloning from bovine lung, recombinant expression in HEK293 cells with radioligand binding (Kd ~100 nM) and antibody blockade","pmids":["1378843"],"confidence":"High","gaps":["No downstream signaling pathway yet identified","Endogenous ligand specificity beyond AGE-albumin unknown","Physiological relevance in vivo not demonstrated"]},{"year":1996,"claim":"Identification of amyloid-β as a second RAGE ligand on neurons and microglia recast RAGE from a metabolic receptor to a broader pattern-recognition receptor implicated in neurodegeneration.","evidence":"Direct RAGE–Aβ binding assays, antibody blockade, cell-based neurotoxicity assays, immunohistochemistry in Alzheimer's disease brain","pmids":["8751438"],"confidence":"High","gaps":["Structural basis of Aβ–RAGE interaction undefined","In vivo causality in AD not yet tested with genetic tools"]},{"year":1997,"claim":"Discovery of NF-κB-responsive elements in the RAGE promoter established a positive-feedback transcriptional loop whereby RAGE-driven NF-κB amplifies RAGE expression itself.","evidence":"Deletion-reporter constructs, DNase I footprinting, EMSA, and site-directed mutagenesis in vascular cells","pmids":["9195959"],"confidence":"High","gaps":["Whether other transcription factors cooperate at the RAGE promoter remained unknown","Epigenetic regulation not addressed"]},{"year":1998,"claim":"Demonstration that soluble RAGE (sRAGE) administration suppressed diabetic atherosclerosis independent of glycemia proved in vivo causal relevance and introduced the decoy-receptor therapeutic concept.","evidence":"Pharmacological sRAGE in streptozotocin-diabetic ApoE-KO mice with lesion quantification","pmids":["9734395"],"confidence":"High","gaps":["sRAGE source (shedding vs. splice variant) not yet distinguished","Whether sRAGE blocks all RAGE ligands equally was untested"]},{"year":1999,"claim":"S100/calgranulin family members were identified as proinflammatory RAGE ligands, and the cytoplasmic domain was shown to bifurcate signaling into Ras→NF-κB versus Rac1/Cdc42→cytoskeletal remodeling branches, defining RAGE as a multi-pathway signaling hub.","evidence":"Receptor binding assays, in vivo DTH/colitis blockade models, dominant-negative GTPase epistasis with domain-deletion mutants in neuroblastoma cells","pmids":["10399917","10391939","10531386"],"confidence":"High","gaps":["Direct cytoplasmic interactors mediating Ras or Rac activation unknown","Whether CML is the sole AGE species relevant in vivo undetermined"]},{"year":2003,"claim":"Parallel discoveries that RAGE mediates Aβ transcytosis across the blood–brain barrier and that alternative splicing produces secreted esRAGE as an endogenous decoy defined two critical functional dimensions: RAGE as a transporter of pathogenic cargo and endogenous soluble isoforms as built-in negative regulators.","evidence":"In vivo BBB transport assays in APPsw mice with RAGE blockade; RT-PCR cloning of splice variants with ERK/VEGF pathway assays in COS-7 and endothelial cells","pmids":["12808450","12495433"],"confidence":"High","gaps":["Structural difference between esRAGE and later-discovered cRAGE unresolved","Quantitative contribution of each sRAGE species in vivo unknown"]},{"year":2005,"claim":"Establishing that HMGB1–RAGE signaling in dendritic cells drives maturation and T cell polarization positioned RAGE as a key innate-to-adaptive immune bridge.","evidence":"RAGE−/− DCs, neutralizing antibodies, DC maturation markers by FACS, IL-12 production, T cell proliferation assays","pmids":["15944249"],"confidence":"High","gaps":["Whether RAGE cooperates with TLR4 for HMGB1 sensing on DCs not fully resolved","Relevance to human DC biology not confirmed"]},{"year":2007,"claim":"Crystallographic and biophysical analysis of multimeric S100B–RAGE V-domain interaction revealed that RAGE activation involves receptor oligomerization driven by multivalent ligand assemblies.","evidence":"1.9 Å X-ray crystal structure of S100B, SPR, analytical ultracentrifugation showing tetrameric S100B binds two RAGE molecules","pmids":["17660747"],"confidence":"High","gaps":["Full-length RAGE oligomeric structure unresolved","Whether all RAGE ligands promote similar receptor clustering untested"]},{"year":2008,"claim":"Three convergent advances resolved RAGE's injury-sensing role and its regulation: HMGB1–RAGE on macrophages mediates post-ischemic neuroinflammation (with cell-type specificity via bone marrow chimeras), ADAM10 was identified as the sheddase generating circulating cRAGE, and RAGE/Rac1/Cdc42 drives neuronal differentiation.","evidence":"MCAO ischemia model with bone marrow chimeras; ADAM10-KO MEFs and protease inhibitor screening; RNAi in P19 cells and primary neurons with constitutively active Rac1/Cdc42 rescue","pmids":["19005067","18603587","18058943"],"confidence":"High","gaps":["Whether ADAM10 shedding is regulated by all RAGE ligands not tested","Downstream adaptor linking RAGE cytoplasmic tail to Rac1 still unidentified"]},{"year":2012,"claim":"Identification of C1q as a RAGE ligand (forming a ternary complex with Mac-1) and development of the V-domain inhibitor FPS-ZM1 provided a new innate immune axis and a pharmacological proof-of-concept tool.","evidence":"SPR binding (Kd ~5.6 µM), pull-down of RAGE–Mac-1 complex; FPS-ZM1 multi-readout analysis in aged APPsw mice","pmids":["22386596","22406537"],"confidence":"High","gaps":["Structural basis of RAGE–Mac-1 cooperation unknown","FPS-ZM1 selectivity profile across all RAGE ligands incomplete"]},{"year":2015,"claim":"Discovery that AT1R transactivates RAGE independently of RAGE ligands via a preformed receptor heterocomplex revealed a ligand-independent mode of RAGE signaling that selectively drives NF-κB inflammation downstream of Ang II.","evidence":"Co-IP of AT1R–RAGE complex, RAGE-KO and ectodomain-deletion mouse models, rescue with WT vs. S391A mutant RAGE peptide in Ager/ApoE-KO atherosclerosis model","pmids":["30530993"],"confidence":"High","gaps":["Whether other GPCRs transactivate RAGE untested beyond β1AR","Structural interface of AT1R–RAGE heterocomplex undefined"]},{"year":2016,"claim":"Three studies expanded RAGE's signaling repertoire: β1AR–RAGE heterocomplexes drive CaMKII-dependent cardiomyocyte death; RAGE acts as a co-receptor delivering RNA to endosomal TLR7/8/13; and RAGE feeds a hexosamine/O-GlcNAcylation/c-Jun positive feedback loop in HCC.","evidence":"Co-IP of β1AR–RAGE, double KO epistasis, CaMKII activity; RNA binding/uptake assays with RAGE KO/overexpression in TLR reporter systems; O-GlcNAc mass spectrometry and c-Jun S73 mutagenesis with AGER promoter reporter","pmids":["26966719","27798148","26825459"],"confidence":"High","gaps":["Whether RAGE–nucleic acid sensing extends to dsDNA innate pathways beyond TLR9 not settled","Structural basis of β1AR–RAGE interaction undefined"]},{"year":2017,"claim":"Identification of C259 and C301 as dimerization-critical cysteines modified by H2S (S-sulfhydration) established the molecular basis for RAGE oligomeric assembly and introduced a redox-based regulatory mechanism controlling receptor surface stability.","evidence":"Split-GFP dimerization assay, C259S/C301S mutagenesis, tag-switch S-sulfhydration detection, cycloheximide chase for half-life","pmids":["28108276"],"confidence":"High","gaps":["Whether endogenous H2S levels regulate RAGE dimerization in vivo unproven","Role of other cysteine residues untested"]},{"year":2021,"claim":"Decorin released from ferroptotic cells was identified as a novel RAGE ligand on macrophages, linking ferroptosis to NF-κB-dependent sterile inflammation; separately, HMGB1–RAGE was shown to activate STING1 during alkaliptosis.","evidence":"Co-IP of DCN–AGER, AGER KO macrophages, NF-κB reporter, acute pancreatitis model; FANCD2 genetic perturbation, AGER KO macrophages, STING1/TBK1/IRF3 pathway readout","pmids":["34964698","33992959"],"confidence":"High","gaps":["Whether decorin–RAGE axis operates during physiological wound healing unknown","STING1 activation mechanism downstream of RAGE unclear"]},{"year":2025,"claim":"RAGE was shown to drive macropinocytosis via DIAPH1→RAC1 to scavenge amino acids for glutathione synthesis, conferring resistance to KRAS-G12D inhibitor MRTX1133 in pancreatic cancer—identifying the first direct cytoplasmic adaptor (DIAPH1) for RAGE.","evidence":"Co-IP of AGER–DIAPH1, RAC1 activity assay, fluorescent albumin uptake, GSH measurement, patient-derived xenografts, orthotopic and genetically engineered mouse PDAC models","pmids":["39879317"],"confidence":"High","gaps":["Whether DIAPH1 is the universal cytoplasmic adaptor for all RAGE signaling arms is untested","Structural basis of AGER–DIAPH1 interaction unresolved","Whether RAGE-driven macropinocytosis occurs in non-cancer contexts unknown"]},{"year":null,"claim":"A full-length RAGE signaling complex structure—including the cytoplasmic tail bound to DIAPH1 and/or other adaptors—has not been solved; how a single 43-residue cytoplasmic tail activates at least four distinct downstream cascades (NF-κB, Rac1/Cdc42, CaMKII, STING1) remains the central unresolved question.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic-resolution structure of full-length RAGE or RAGE–adaptor complex","Mechanism of pathway selectivity by a short cytoplasmic tail undefined","Relative physiological importance of >8 different ligands unranked"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,4,6,7,18,28]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[8]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[10,22]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[14,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4,8,13,20,25]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,11,15]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,12,14,22,28,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,7,20,21,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,10,19,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,17,32]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17,26]}],"complexes":["AT1R–RAGE heterocomplex","β1AR–RAGE heterocomplex","RAGE–Mac-1 (CD11b/CD18) complex","RAGE–DIAPH1 complex"],"partners":["HMGB1","DIAPH1","ADAM10","RAC1","AGTR1","ADRB1","ITGAM","CDC42"],"other_free_text":[]},"mechanistic_narrative":"AGER (RAGE) is a multiligand pattern-recognition receptor of the immunoglobulin superfamily that transduces danger signals from advanced glycation end products (AGEs), HMGB1, S100/calgranulins, amyloid-β, complement C1q, decorin, and extracellular RNA into NF-κB, MAPK, Rac1/Cdc42, and CaMKII signaling cascades, thereby orchestrating inflammatory, neurodegenerative, and metabolic responses [PMID:1378843, PMID:8751438, PMID:10399917, PMID:22386596, PMID:27798148, PMID:34964698]. Ligand engagement at the extracellular V-type Ig domain requires an intact 43-residue cytoplasmic tail, which bifurcates signaling: Ras-dependent NF-κB activation versus Rac1/Cdc42-dependent cytoskeletal remodeling and neurite outgrowth; additionally, RAGE undergoes ligand-independent transactivation through preformed heterocomplexes with AT1R and β1AR [PMID:10391939, PMID:30530993, PMID:26966719]. Soluble decoy isoforms arise by ADAM10-mediated ectodomain shedding (cRAGE) or alternative splicing (esRAGE) and competitively antagonize RAGE signaling, while RAGE dimerization—stabilized by transmembrane cysteines C259/C301—is required for full signaling activity [PMID:18603587, PMID:12495433, PMID:28108276]. Intracellularly, RAGE engages DIAPH1 to activate RAC1-dependent macropinocytosis, conferring amino acid scavenging and therapy resistance in pancreatic cancer [PMID:39879317]."},"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). Mediates the production of reactive oxygen species (ROS) in human endothelial cells (PubMed:25401185)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q15109/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGER","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/AGER","total_profiled":1310},"omim":[{"mim_id":"603933","title":"MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 1; MVCD1","url":"https://www.omim.org/entry/603933"},{"mim_id":"603114","title":"S100 CALCIUM-BINDING PROTEIN A11; S100A11","url":"https://www.omim.org/entry/603114"},{"mim_id":"601266","title":"dUTP PYROPHOSPHATASE; DUT","url":"https://www.omim.org/entry/601266"},{"mim_id":"600214","title":"ADVANCED GLYCOSYLATION END PRODUCT-SPECIFIC RECEPTOR; AGER","url":"https://www.omim.org/entry/600214"},{"mim_id":"158373","title":"MUCIN 5, SUBTYPES A AND C, TRACHEOBRONCHIAL; MUC5AC","url":"https://www.omim.org/entry/158373"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":687.2}],"url":"https://www.proteinatlas.org/search/AGER"},"hgnc":{"alias_symbol":["RAGE","SCARJ1","sRAGE"],"prev_symbol":[]},"alphafold":{"accession":"Q15109","domains":[{"cath_id":"2.60.40.10","chopping":"23-117","consensus_level":"high","plddt":90.9957,"start":23,"end":117},{"cath_id":"2.60.40.10","chopping":"124-229","consensus_level":"high","plddt":94.9112,"start":124,"end":229},{"cath_id":"2.60.40.10","chopping":"238-319","consensus_level":"high","plddt":90.5295,"start":238,"end":319}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15109","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15109-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15109-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGER","jax_strain_url":"https://www.jax.org/strain/search?query=AGER"},"sequence":{"accession":"Q15109","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15109.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15109/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15109"}},"corpus_meta":[{"pmid":"20192808","id":"PMC_20192808","title":"HMGB1 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disorder in a mouse model of Alzheimer disease.","date":"2012","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/22406537","citation_count":525,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11007787","id":"PMC_11007787","title":"Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11007787","citation_count":515,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20010835","id":"PMC_20010835","title":"Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20010835","citation_count":515,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18603587","id":"PMC_18603587","title":"A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10).","date":"2008","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/18603587","citation_count":489,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20010834","id":"PMC_20010834","title":"Genome-wide association study identifies five loci associated with lung function.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20010834","citation_count":465,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23535732","id":"PMC_23535732","title":"Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.","date":"2013","source":"Nature 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Tetrameric S100B caused stronger RAGE-dependent cell growth activation than dimeric S100B, suggesting RAGE activation occurs through receptor dimerization induced by multimeric S100B.\",\n      \"method\": \"X-ray crystallography (1.9 Å), analytical ultracentrifugation, size-exclusion chromatography, binding studies, cell growth assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with binding assays and functional cell assays in a single study\",\n      \"pmids\": [\"17660747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RAGE cytoplasmic domain requires the binding partner diaphanous-1 (mDia1) to transduce AGE-RAGE signaling intracellularly. This interaction perpetuates inflammatory signals initiated by AGEs.\",\n      \"method\": \"Genetic/biochemical identification of cytoplasmic binding partner; functional studies with RAGE cytoplasmic domain\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cited as established finding across multiple review papers with functional context, original biochemical identification referenced\",\n      \"pmids\": [\"20957395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RAGE binds RNA molecules in a sequence-independent manner and enhances cellular RNA uptake into endosomes, thereby increasing sensitivity of ssRNA-sensing TLRs (TLR7, TLR8, TLR13). Gain- and loss-of-function studies established RAGE as an integral part of the endosomal nucleic acid-sensing system.\",\n      \"method\": \"Gain- and loss-of-function studies, RNA binding assays, endosomal uptake assays, TLR signaling readouts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with multiple TLR readouts in a single study\",\n      \"pmids\": [\"27798148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The AT1 angiotensin II receptor forms a preformed heteromeric complex with RAGE. Activation of AT1 by angiotensin II triggers transactivation of the cytosolic tail of RAGE and NF-κB-driven proinflammatory gene expression independently of RAGE ligand binding or its ectodomain. A mutant RAGE peptide (S391A-RAGE362-404) inhibited this transactivation and attenuated Ang II-dependent inflammation and atherogenesis.\",\n      \"method\": \"Co-immunoprecipitation, genetic deletion (Ager/Apoe-KO mice), peptide inhibition, NF-κB reporter assays, atherosclerosis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — receptor complex identification by Co-IP, multiple orthogonal in vivo and in vitro methods, mutagenesis-based peptide inhibitor\",\n      \"pmids\": [\"30530993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"β1-adrenergic receptor (β1AR) and RAGE form a physical complex. Activation of either receptor requires the other for mediating myocardial cell death and maladaptive remodeling. The β1AR-RAGE complex activates Ca2+/calmodulin-dependent kinase II (CaMKII), causing loss of cardiomyocytes and myocardial remodeling.\",\n      \"method\": \"Co-immunoprecipitation, genetic deletion of RAGE and β1AR, pharmacological blockade, CaMKII activity assays, cardiomyopathy model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic and pharmacological orthogonal approaches, defined downstream kinase mediator\",\n      \"pmids\": [\"26966719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RAGE is a native C1q globular domain receptor. Direct C1q-sRAGE interaction was demonstrated by surface plasmon resonance (Kd ~5.6 μM). RAGE forms a receptor complex with Mac-1 to enhance affinity for C1q. C1q-induced U937 cell adhesion and phagocytosis were inhibited by antibodies to RAGE or Mac-1.\",\n      \"method\": \"Surface plasmon resonance, ELISA-based binding, pull-down, antibody blocking, phagocytosis assays\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with SPR kinetics, pull-down complex formation, and functional phagocytosis readout\",\n      \"pmids\": [\"22386596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RAGE mediates HMGB1-induced neurotoxicity in ischemic brain damage. RAGE deficiency (genetic knockout) and soluble RAGE (decoy receptor) reduced infarct size in a mouse cerebral ischemia model. Bone marrow chimera experiments showed that RAGE deficiency specifically in bone marrow-derived (macrophage) cells significantly reduced infarct size, placing macrophage RAGE downstream of HMGB1 release in the ischemic cascade.\",\n      \"method\": \"Genetic knockout, bone marrow transplantation/chimeric mice, soluble RAGE administration, anti-HMGB1 antibody, infarct size measurement\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic and pharmacological approaches including bone marrow chimera to assign cell-type specificity\",\n      \"pmids\": [\"19005067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RAGE mediates neuronal differentiation and neurite outgrowth through the Rac1/Cdc42 pathway. RNAi knockdown of RAGE in P19 embryonic carcinoma cells blocked retinoic acid-induced neuronal differentiation and inhibited NF-κB nuclear translocation. RAGE knockdown also inhibited neurite outgrowth in both P19 cells and primary cerebellar granule neurons. Constitutively active Rac1/Cdc42 restored neurite outgrowth in RAGE-deficient neurons.\",\n      \"method\": \"RNAi knockdown, overexpression of dominant-negative and constitutively active GTPases, NF-κB localization, neurite outgrowth assays\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with specific rescue by constitutively active GTPases, tested in both cell line and primary neurons\",\n      \"pmids\": [\"18058943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RAGE is a positive regulator of autophagy and negative regulator of apoptosis during oxidative stress in pancreatic cancer cells. RAGE upregulation by NF-κB decreases reactive oxygen species-induced oxidative injury; suppression of RAGE increases cell sensitivity to oxidative injury and shifts the autophagy/apoptosis balance.\",\n      \"method\": \"RAGE knockdown/overexpression, ROS measurement, autophagy and apoptosis assays, NF-κB pathway analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss and gain of function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"21317562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AGE binding to RAGE on human peritoneal mesothelial cells stimulates VCAM-1 (but not ICAM-1) expression and potentiates leukocyte adhesion. Blocking AGE-RAGE interaction with anti-RAGE antibodies or recombinant RAGE inhibited VCAM-1 upregulation, establishing a direct mechanistic link between RAGE ligation and adhesion molecule induction.\",\n      \"method\": \"FACS, RT-PCR, radiometric VCAM-1 assay, antibody and recombinant RAGE blocking, videomicroscopy leukocyte adhesion\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal blocking methods (antibody + recombinant decoy) with defined molecular output\",\n      \"pmids\": [\"11786095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The proteoglycan decorin (DCN) is released during ferroptosis via secretory autophagy and lysosomal exocytosis. Extracellular DCN binds to AGER on macrophages and triggers NF-κB-dependent production of pro-inflammatory cytokines. Pharmacological and genetic inhibition of the DCN-AGER axis protected against ferroptotic death-related acute pancreatitis.\",\n      \"method\": \"Co-IP/binding assays, genetic/pharmacological inhibition of AGER, NF-κB reporter, acute pancreatitis model, autophagy inhibition\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — identified novel ligand (DCN), receptor binding demonstrated, genetic and pharmacological loss-of-function with in vivo disease model\",\n      \"pmids\": [\"34964698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During alkaliptosis, HMGB1 is released from dying cells and binds AGER on macrophages, which then activates the STING1 pathway to produce pro-inflammatory cytokines (TNF, IL6). Inhibition of the HMGB1-AGER-STING1 pathway pharmacologically or genetically reduced cytokine production.\",\n      \"method\": \"Genetic and pharmacological inhibition, cytokine measurement, pathway analysis (STING1 activation)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identifies pathway ordering (AGER→STING1) by genetic/pharmacological epistasis, single lab\",\n      \"pmids\": [\"33992959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AGER mediates resistance to KRAS-G12D inhibitor (MRTX1133) in pancreatic cancer by inducing macropinocytosis. AGER interacts with DIAPH1 (diaphanous-related formin 1), which drives RAC1-dependent macropinosome formation to internalize serum albumin; the resulting amino acids are used for glutathione synthesis, inhibiting apoptosis. Combining MRTX1133 with inhibitors of the AGER-DIAPH1 complex (RAGE299) or macropinocytosis (EIPA) was effective in PDX, orthotopic, and genetically engineered mouse models.\",\n      \"method\": \"Co-IP (AGER-DIAPH1 interaction), macropinocytosis assays, RAC1 activity, glutathione measurement, PDX/orthotopic/GEM mouse models, combination drug studies\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic complex identification (AGER-DIAPH1), defined biochemical pathway to glutathione, validated in multiple in vivo models\",\n      \"pmids\": [\"39879317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AGER activates the hexosamine biosynthetic pathway in hepatocellular carcinoma cells, leading to enhanced O-GlcNAcylation of the proto-oncoprotein c-Jun at Ser73, increasing its activity and stability. c-Jun conversely enhances AGER transcription, establishing a positive autoregulatory feedback loop that stimulates diabetic HCC under high glucose.\",\n      \"method\": \"siRNA knockdown, O-GlcNAcylation assays, mutagenesis of c-Jun Ser73, gene expression analysis, feedback loop validation\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — specific PTM site (Ser73) identified, hexosamine pathway linked to AGER, feedback loop validated by multiple molecular methods\",\n      \"pmids\": [\"26825459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deletion of Ager (RAGE) in diabetic mice restored adaptive inflammation, angiogenesis, and blood flow recovery after hindlimb ischemia. Ager deletion increased circulating Ly6Chi monocytes and augmented macrophage infiltration into ischemic muscle. In vitro, Ager deletion in macrophages reversed high-glucose-induced skewing from tissue repair toward tissue damage gene expression and restored macrophage-endothelial cell interactions.\",\n      \"method\": \"Ager knockout mice, streptozotocin diabetes model, femoral artery ligation, flow cytometry, macrophage-endothelial co-culture, gene expression analysis\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in disease model, cell-type specific in vitro validation, multiple phenotypic readouts\",\n      \"pmids\": [\"28642238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RAGE deficiency in alveolar epithelial cells results in altered differentiation and defective barrier formation. RAGE is required for normal pulmonary structure; RAGE-/- mice spontaneously develop emphysema-like lung changes with increased mean chord length, altered compliance, and elevated albumin in BAL. RAGE-deficient IFNγ-activated alveolar macrophages show significantly decreased release of pro-inflammatory cytokines upon TLR stimulation.\",\n      \"method\": \"RAGE-/- mice, lung mechanics measurement, primary alveolar epithelial cell isolation/culture, BAL analysis, macrophage TLR stimulation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined structural and functional cellular phenotypes in multiple cell types\",\n      \"pmids\": [\"28678851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAGE is identified as an oxytocin (OT) binding protein that serves as a transporter of OT across the blood-brain barrier, regulating brain OT levels and thereby social behavior. This positions RAGE in a CD38/CD157-dependent OT release mechanism relevant to social recognition.\",\n      \"method\": \"Binding studies (OT-RAGE interaction), blood-brain barrier transport assays, behavioral analysis in CD38/CD157 KO context\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single paper, novel function claim, limited mechanistic detail in abstract\",\n      \"pmids\": [\"31881755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hydrogen sulfide (H2S) reduces RAGE cytotoxicity by inhibiting RAGE dimerization. H2S donor NaHS reduced H2O2-enhanced RAGE dimerization (shown by Western blot and split-GFP complementation). H2S directly S-sulfhydrates RAGE at C259/C301 residues (tag-switch S-sulfhydration assay), reducing membrane RAGE abundance and accelerating its degradation.\",\n      \"method\": \"Western blot, split-GFP complementation, cycloheximide chase, ubiquitination assay, S-sulfhydration tag-switch assay, site-directed mutagenesis (C259S/C310S)\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-specific mutagenesis of cysteines, post-translational modification (S-sulfhydration) directly demonstrated, dimerization functionally linked to membrane stability\",\n      \"pmids\": [\"28108276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YAP participates with transcription factors KLF5, NFIB, and NKX2-1 to regulate AGER expression in alveolar epithelial cells. YAP activation increased AT1 cell numbers while YAP deletion increased AT2 gene expression; chromatin accessibility analysis identified promoter targets regulating alveolar differentiation including AGER.\",\n      \"method\": \"Transgenic YAP activation/deletion mice, ATAC-seq (chromatin accessibility), transcriptomic analysis, motif enrichment analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic manipulation with chromatin-level mechanistic data, but AGER regulation is one component of a broader study\",\n      \"pmids\": [\"34466790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HMGB1 and RAGE are critical in the pathogenesis of cardiac troponin I-induced experimental autoimmune myocarditis. RAGE-knockout mice immunized with TnI showed no cardiac inflammation or physiological impairment. Pharmacological inhibition of HMGB1 (glycyrrhizin or anti-HMGB1 antibody) reduced heart inflammation in wild-type mice. AAV-mediated HMGB1 overexpression induced inflammation in both wild-type and RAGE-knockout mice, indicating HMGB1 can signal through TLRs as well.\",\n      \"method\": \"RAGE knockout mice, AAV-mediated overexpression, antibody/pharmacological inhibition, cardiac histology and physiology\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus AAV rescue plus pharmacological inhibition, mechanistic conclusion about RAGE requirement and TLR alternative\",\n      \"pmids\": [\"26715748\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGER/RAGE is a multiligand pattern recognition receptor of the immunoglobulin superfamily whose extracellular V-domain binds structurally diverse ligands (AGEs, HMGB1, S100 proteins including multimeric S100B, DCN, C1q, RNA, and amyloid-β), triggering receptor dimerization/oligomerization and intracellular signaling through its cytoplasmic tail, which recruits the formin DIAPH1 to activate RAC1/Cdc42-dependent cytoskeletal remodeling and macropinocytosis; RAGE also forms ligand-independent heteromeric complexes with GPCRs (AT1R, β1AR) whose transactivation drives NF-κB-dependent inflammation via CaMKII, while H2S-mediated S-sulfhydration of C259/C301 inhibits RAGE dimerization and membrane stability, and soluble RAGE isoforms act as decoy receptors to sequester ligands and dampen signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**EXCLUDE papers:**\n- [88] (corpus main) — \"RAGE\" = Raman-Activated Gravity-driven Encapsulation, a microbial single-cell sequencing method. Symbol collision.\n- [68] (corpus main) — \"rage\" = defensive rage behavior in cats (neuroscience behavioral study). Symbol collision.\n- [32] (corpus main) — \"Pathogen roid rage\" — about Mycobacterium tuberculosis cholesterol metabolism. Symbol collision.\n- [4] additional, [9] additional, [11] additional, [14] additional, [16] additional, [5] additional, [6] additional, [29] additional, [28] additional, [26] additional — These are about MGC cDNA libraries, BioPlex interactome, HuRI, GO phylogenetics, TREM2, BBB physiology, PICALM, Alzheimer's cellular phase, cDNA normalization. Not mechanistic studies of AGER/RAGE specifically; they are general genomics/cell biology papers. However, some (like PMID:32296183 HuRI, PMID:26186194 BioPlex) may have AGER interactions — but they provide no specific mechanistic detail about AGER.\n- [20] additional (PMID:20010834), [22] additional (PMID:20010835) — GWAS for lung function; identify AGER locus but no mechanism.\n- [23] additional (PMID:23535732) — Prostate cancer GWAS. No AGER mechanism.\n- [24] additional (PMID:25910212) — protein interaction perturbations in genetic disorders; general study.\n- [13] additional (PMID:25786107) — AGEs and oxidative stress review in T2DM; no direct AGER mechanism experiment.\n\n**KEEP:** All remaining papers about canonical AGER/RAGE protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"RAGE was cloned from a bovine lung cDNA library and identified as a ~35-kDa cell-surface receptor for advanced glycation end products (AGEs). The protein is a member of the immunoglobulin superfamily with an extracellular domain of 332 aa, a single transmembrane domain of 19 aa, and a 43-aa cytoplasmic tail. Expression of RAGE cDNA in HEK293 cells conferred saturable, antibody-blockable binding of 125I-AGE-albumin (Kd ~100 nM), establishing RAGE as a functional AGE receptor.\",\n      \"method\": \"cDNA cloning, recombinant expression in HEK293 cells, radioligand binding assay, Western blot\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning paper with direct binding reconstitution and antibody blockade\",\n      \"pmids\": [\"1378843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RAGE was identified as a neuronal cell-surface receptor for amyloid-β (Aβ) peptide. RAGE expression was found elevated in Alzheimer's disease brain. RAGE–Aβ interaction on neurons and microglia mediated Aβ-induced oxidant stress and neurotoxicity, establishing a direct mechanistic link between RAGE ligation and neurodegeneration.\",\n      \"method\": \"Binding assays with recombinant RAGE and Aβ peptide, cell-based neurotoxicity assays, immunohistochemistry of AD brain, antibody blockade experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding demonstrated, functional blockade with antibodies, replicated across multiple cell/tissue contexts\",\n      \"pmids\": [\"8751438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The RAGE gene promoter contains functional NF-κB binding sites. Deletion analysis and DNase I footprinting/EMSA identified two active NF-κB-like sites (sites 1 and 2) in the −1543/−587 region that drive basal and LPS-stimulated RAGE expression in endothelial and smooth muscle cells. Simultaneous mutation of both sites markedly reduced promoter activity, establishing NF-κB-dependent transcriptional autoregulation of RAGE.\",\n      \"method\": \"5′-deletion luciferase reporter constructs, DNase I footprinting, electrophoretic mobility shift assay (EMSA), transient transfection in vascular endothelial and smooth muscle cells\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (reporter assay, footprinting, EMSA, mutagenesis) in a single study\",\n      \"pmids\": [\"9195959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Administration of the soluble extracellular domain of RAGE (sRAGE) completely suppressed accelerated atherosclerosis in diabetic apolipoprotein E-deficient mice in a glycemia- and lipid-independent manner, demonstrating that AGE–RAGE interaction is causally required for diabetic macrovascular disease and that sRAGE acts as a decoy receptor to block this pathway.\",\n      \"method\": \"In vivo mouse model (streptozotocin-diabetic ApoE-KO mice), pharmacological sRAGE administration, atherosclerotic lesion quantification\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo genetic/pharmacological intervention with defined vascular phenotype, highly cited foundational study\",\n      \"pmids\": [\"9734395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RAGE was identified as a central cell-surface receptor for S100/calgranulin polypeptides (EN-RAGE and related family members). Engagement of S100/calgranulins by RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggered cellular activation and generation of proinflammatory mediators. Blockade of EN-RAGE/RAGE signaling suppressed delayed-type hypersensitivity and inflammatory colitis in murine models, defining a novel RAGE-dependent proinflammatory axis.\",\n      \"method\": \"Receptor binding assays, cell activation assays, in vivo murine models (DTH, colitis) with antibody blockade and soluble RAGE\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — binding assays combined with in vivo loss-of-function models and multiple orthogonal readouts; foundational paper\",\n      \"pmids\": [\"10399917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RAGE-mediated neurite outgrowth (induced by amphoterin/HMGB1) and NF-κB activation use distinct intracellular signaling pathways both requiring the RAGE cytoplasmic domain. Neurite outgrowth is blocked by dominant-negative Rac and Cdc42 (but not Ras), whereas NF-κB activation is blocked by dominant-negative Ras (but not Rac/Cdc42). Deletion of the cytoplasmic domain of RAGE abolished both responses.\",\n      \"method\": \"Transfection of RAGE constructs (full-length and cytoplasmic domain deletion mutants) into neuroblastoma cells, dominant-negative GTPase overexpression, NF-κB reporter assays, neurite outgrowth assays on amphoterin-coated substrates\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — epistasis by dominant-negative mutants plus domain deletion mutagenesis with two distinct functional readouts\",\n      \"pmids\": [\"10391939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CML (Nε-carboxymethyllysine) adducts of proteins are direct RAGE ligands. CML-modified proteins engage cellular RAGE and activate NF-κB signaling and downstream gene expression in vascular cells, identifying a specific AGE molecular species responsible for RAGE-mediated vascular and inflammatory complications.\",\n      \"method\": \"Cell-based RAGE binding assays with CML-modified proteins, NF-κB activation assays, gene expression analysis\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ligand-receptor interaction with functional cellular signaling readout\",\n      \"pmids\": [\"10531386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"S100B and S100A1 activate RAGE in concert with amphoterin to induce neurite outgrowth and NF-κB activation. Nanomolar S100B promotes RAGE-dependent cell survival via upregulation of anti-apoptotic Bcl-2, whereas micromolar S100B induces RAGE-dependent apoptosis. Both trophic and toxic effects require full-length RAGE with an intact cytoplasmic domain.\",\n      \"method\": \"Transfection of full-length vs. cytoplasmic domain deletion RAGE mutants, cell survival/apoptosis assays, Bcl-2 immunoblotting, neurite outgrowth assays, NF-κB reporter assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain mutagenesis with multiple functional readouts; concentration-dependent bidirectional effects mechanistically defined\",\n      \"pmids\": [\"11007787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RAGE is expressed on human peritoneal mesothelial cells (HPMC). AGE binding to RAGE (specifically CML-albumin) stimulates VCAM-1 (but not ICAM-1) overexpression and enhances leukocyte adhesion. Both anti-RAGE antibody and recombinant RAGE (acting as decoy) blocked the CML-albumin-induced VCAM-1 upregulation, establishing a direct AGE–RAGE–VCAM-1 signaling axis in mesothelial inflammation.\",\n      \"method\": \"FACS detection of RAGE on HPMC, RT-PCR, radiometric VCAM-1/ICAM-1 expression assay, antibody and decoy receptor blockade, videomicroscopy of leukocyte adhesion\",\n      \"journal\": \"Kidney International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor blockade with two independent reagents (antibody + decoy RAGE) with functional adhesion molecule readout\",\n      \"pmids\": [\"11786095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The G82S polymorphism in the RAGE ligand-binding domain amplifies the inflammatory response. Cells bearing the RAGE 82S allele displayed enhanced binding of S100/calgranulins and greater cytokine/MMP generation compared to 82G allele cells. In vivo, blockade of RAGE suppressed clinical and histologic arthritis and reduced TNF-α, IL-6, and MMPs 3, 9, and 13 in affected tissues in a collagen-induced arthritis model.\",\n      \"method\": \"Cell-based binding assays with allelic RAGE variants, cytokine/MMP production assays, in vivo murine collagen-induced arthritis model with RAGE blockade, human case-control genetic association\",\n      \"journal\": \"Genes and Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — allele-specific functional assays combined with in vivo model; mechanistic link between specific polymorphism and signaling amplitude established\",\n      \"pmids\": [\"12070776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RAGE expressed on brain endothelial cells mediates transcytosis of circulating Aβ peptides across the blood-brain barrier (BBB) into brain parenchyma and drives expression of proinflammatory cytokines and endothelin-1 (causing vasoconstriction). Inhibition of RAGE–ligand interaction at the BBB suppressed Aβ accumulation in brain parenchyma in APPsw transgenic mice.\",\n      \"method\": \"Systemic Aβ infusion in mice, transgenic mouse models, pharmacological RAGE blockade, BBB transport assays, cerebral blood flow measurements, ET-1 and cytokine quantification\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct in vivo transport assay combined with pharmacological and genetic intervention, replicated in multiple mouse models\",\n      \"pmids\": [\"12808450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Novel splice variants of RAGE lacking either the N-terminal V-type Ig domain (N-truncated, membrane-bound) or the C-terminal transmembrane domain (C-truncated/endogenous secretory RAGE, esRAGE) are expressed in vascular endothelial cells and pericytes. The C-truncated (esRAGE) isoform is secreted, binds AGEs via its intact V-domain, and completely abolished AGE-induced ERK phosphorylation and VEGF induction, identifying esRAGE as an endogenous cytoprotective decoy receptor. N-truncated RAGE lacks ligand-binding capacity.\",\n      \"method\": \"RT-PCR cloning of splice variants, COS-7 transfection, AGE-affinity column binding, secretion assays, ERK phosphorylation assays, VEGF quantification, endothelial cord formation assay\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain-deletion variant analysis with multiple functional assays establishing structure-function relationships\",\n      \"pmids\": [\"12495433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Dendritic cells (DCs) actively release HMGB1 upon activation, and this secreted HMGB1 signals through RAGE on DCs to drive their maturation (CD80/CD83/CD86 upregulation, IL-12 production) and to sustain T cell clonal expansion, survival, and polarization. Using RAGE−/− cells and neutralizing antibodies, RAGE was demonstrated to be required for the HMGB1 effect on DCs, acting through downstream MAPK and NF-κB activation.\",\n      \"method\": \"RAGE−/− cells, neutralizing antibodies to RAGE and HMGB1, DC maturation marker FACS, IL-12 ELISA, T cell proliferation and polarization assays, MAPK/NF-κB signaling assays\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (RAGE KO) and pharmacological (antibody) loss-of-function with multiple defined immune cell phenotypes\",\n      \"pmids\": [\"15944249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The X-ray crystal structure of Ca2+-loaded S100B at 1.9 Å resolution revealed an octameric architecture (four homodimers arranged as two tetramers). Tetrameric S100B binds RAGE with higher affinity than dimeric S100B and, by AUC, binds two RAGE molecules via the V-domain. Tetrameric S100B caused stronger cell growth activation and survival than the dimer, suggesting RAGE activation involves receptor dimerization/oligomerization driven by multimeric S100B.\",\n      \"method\": \"X-ray crystallography (1.9 Å), size-exclusion chromatography of brain extracts, purification of S100B oligomers from E. coli, surface plasmon resonance binding studies, analytical ultracentrifugation, cell growth/survival assays\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biophysical binding assays (SPR, AUC) with functional cell-based validation\",\n      \"pmids\": [\"17660747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RAGE functions as a sensor of necrotic cell death in ischemic brain injury. HMGB1 released from ischemic tissue engages RAGE on (micro)glial cells to mediate neurotoxicity. RAGE deficiency or soluble RAGE reduced infarct size. Chimeric mouse experiments transplanting RAGE−/− bone marrow into wild-type recipients showed that RAGE deficiency specifically in bone marrow-derived macrophages significantly reduced infarct size, positioning macrophage RAGE as a critical effector of HMGB1-mediated post-ischemic inflammation.\",\n      \"method\": \"Mouse cerebral ischemia model (MCAO), RAGE−/− mice, soluble RAGE administration, anti-HMGB1 antibody, HMGB1 box A antagonist, bone marrow chimera experiments, infarct volume quantification, in vitro (micro)glial neurotoxicity assay\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific RAGE requirement established via bone marrow chimeras plus pharmacological blockade with multiple orthogonal approaches\",\n      \"pmids\": [\"19005067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Most circulating soluble RAGE in human blood is produced by proteolytic ectodomain shedding (cleaved RAGE, cRAGE) rather than by the alternative splice variant esRAGE. Screening of chemical inhibitors and genetically modified MEFs identified ADAM10 as the responsible sheddase. HMGB1 ligand binding promotes RAGE shedding by ADAM10, and cRAGE acts as a decoy receptor.\",\n      \"method\": \"Anti-esRAGE vs. pan-sRAGE antibody comparison, transfection of full-length RAGE cDNA, ADAM10-deficient MEFs, chemical protease inhibitor panel, HMGB1 stimulation shedding assay\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic (KO MEFs) and pharmacological screening identified specific sheddase; ligand-induced shedding mechanism validated\",\n      \"pmids\": [\"18603587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RAGE mediates neuronal differentiation and neurite outgrowth in P19 embryonic carcinoma stem cells. RAGE knockdown by RNAi blocked retinoic acid-induced neuronal differentiation, inhibited NF-κB nuclear translocation, and strongly suppressed neurite outgrowth. In primary cerebellar granule neurons, RAGE KD inhibited neurite outgrowth through the Rac1/Cdc42 GTPase pathway; constitutively active Rac1/Cdc42 rescued neurite outgrowth in RAGE-deficient neurons.\",\n      \"method\": \"RNAi knockdown in P19 cells and primary cerebellar granule neurons, NF-κB nuclear translocation assay, dominant-negative and constitutively active Rac1/Cdc42 overexpression, neurite outgrowth quantification\",\n      \"journal\": \"Journal of Neuroscience Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via dominant-negative and constitutively active GTPases plus RNAi in two distinct cell systems\",\n      \"pmids\": [\"18058943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RAGE is a positive regulator of autophagy and a negative regulator of apoptosis during oxidative stress in pancreatic cancer cells. RAGE upregulation via NF-κB decreases ROS-induced oxidative injury; suppression of RAGE increases sensitivity to oxidative stress-induced cell death, positioning RAGE as a switch between autophagy-mediated survival and apoptosis.\",\n      \"method\": \"RAGE knockdown and overexpression in pancreatic cancer cells, ROS measurement, autophagy flux assay, apoptosis assays (flow cytometry), NF-κB reporter assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with defined pathway readouts in a single lab\",\n      \"pmids\": [\"21317562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RAGE is a native receptor for the globular domain of complement component C1q. Direct C1q–RAGE interaction was demonstrated by surface plasmon resonance (Kd ~5.6 µM) and ELISA-like multivalent binding assay. Pull-down experiments indicated RAGE forms a complex with Mac-1 (CD11b/CD18) to enhance C1q binding affinity. Antibodies to RAGE or Mac-1 inhibited C1q-induced U937 cell adhesion and phagocytosis.\",\n      \"method\": \"Surface plasmon resonance, ELISA-based binding assay, pull-down (RAGE–Mac-1 complex), cell adhesion assay, phagocytosis assay with antibody blockade\",\n      \"journal\": \"Cellular Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biophysical binding measurement (SPR) plus pull-down complex and functional phagocytosis assay with antibody blockade\",\n      \"pmids\": [\"22386596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FPS-ZM1, a high-affinity small-molecule RAGE inhibitor targeting the V-domain, blocked Aβ binding to RAGE, inhibited RAGE-mediated Aβ transcytosis across the BBB into brain, suppressed β-secretase activity and Aβ production in brain, reduced microglial neuroinflammation, and normalized cognitive performance and cerebral blood flow in aged APPsw transgenic mice.\",\n      \"method\": \"In vitro RAGE–Aβ binding assay, RAGE-expressing cell stress assays, in vivo aged APPsw/0 transgenic mice, BBB transport assay, β-secretase activity assay, Aβ ELISA, Morris water maze, cerebral blood flow measurement\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multimodal RAGE blocker characterized in vitro and in vivo with mechanistic readouts across multiple pathways\",\n      \"pmids\": [\"22406537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RAGE undergoes ligand-independent transactivation by the type 1 angiotensin II receptor (AT1R). AT1R and RAGE form a preformed heteromeric complex at the cell surface. Ang II stimulation of AT1R triggers transactivation of the RAGE cytosolic tail, driving NF-κB-dependent proinflammatory gene expression independently of RAGE ligand binding or the RAGE ectodomain. Deletion or inhibition of RAGE selectively attenuated AT1R-driven proinflammatory signaling without affecting canonical Gq signaling. A mutant RAGE peptide (S391A-RAGE362-404) inhibited transactivation and attenuated Ang II-dependent inflammation and atherogenesis in vivo.\",\n      \"method\": \"Co-immunoprecipitation of AT1R–RAGE complex, RAGE-KO and ectodomain-deletion mouse models, NF-κB reporter assay, Ager/Apoe-KO mouse atherosclerosis model, rescue with WT vs. mutant RAGE peptide, atherosclerotic lesion quantification\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — receptor complex Co-IP, genetic KO, domain mutagenesis, and in vivo rescue with defined mechanistic readouts\",\n      \"pmids\": [\"30530993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RAGE and the β1-adrenergic receptor (β1AR) physically interact to form a receptor complex that activates CaMKII, causing cardiomyocyte death and maladaptive remodeling. RAGE deficiency or inhibition blocks β1AR-mediated myocardial injury; β1AR ablation abolishes RAGE-induced detrimental effects. The convergence point of both receptors is CaMKII activation.\",\n      \"method\": \"Co-immunoprecipitation of β1AR–RAGE complex, RAGE-KO and β1AR-KO mice, cardiomyocyte death assays, CaMKII activity assay, cardiac remodeling histology, pharmacological RAGE and β1AR inhibitors\",\n      \"journal\": \"JCI Insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor complex Co-IP plus double genetic KO epistasis with defined downstream kinase (CaMKII) as convergence point\",\n      \"pmids\": [\"26966719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RAGE binds RNA molecules in a sequence-independent manner and facilitates RNA uptake into endosomes, enhancing ssRNA sensing by TLR7, TLR8, and TLR13. Gain- and loss-of-function studies established RAGE as an integral co-receptor of the endosomal nucleic acid-sensing system, extending its previously described role for DNA/TLR9 to all ssRNA-sensing TLRs.\",\n      \"method\": \"RNA–RAGE binding assays, cellular RNA uptake assays (fluorescent RNA), gain-of-function (RAGE overexpression) and loss-of-function (RAGE KO) in TLR reporter systems, TLR7/8/13 activation assays\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay plus gain/loss-of-function across multiple TLR reporters\",\n      \"pmids\": [\"27798148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AGER activates a hexosamine biosynthetic pathway in hepatocellular carcinoma cells under high-glucose conditions, leading to enhanced O-GlcNAcylation of c-Jun at Ser73, which increases c-Jun activity and stability. c-Jun in turn transcriptionally upregulates AGER, establishing a positive autoregulatory feedback loop that drives diabetic HCC tumorigenesis.\",\n      \"method\": \"AGER knockdown/overexpression in HCC cells, O-GlcNAcylation mass spectrometry and western blot, site-directed mutagenesis of c-Jun Ser73, luciferase reporter for AGER promoter, co-immunoprecipitation\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — specific PTM site identified by mutagenesis, feedback loop confirmed by promoter reporter and epistasis\",\n      \"pmids\": [\"26825459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RAGE deficiency (Ager KO) in diabetic mice restored adaptive inflammation after hindlimb ischemia, increased circulating Ly6Chi monocytes and macrophage infiltration into ischemic muscle, and rescued angiogenesis and blood flow recovery. In vitro, Ager deletion in macrophages reversed high-glucose-mediated skewing toward tissue-damage gene expression and restored macrophage–endothelial cell interactions, placing AGER as a suppressor of adaptive inflammation in diabetic peripheral vascular disease.\",\n      \"method\": \"Ager-KO and Glo1-transgenic diabetic mice, femoral artery ligation, laser Doppler blood flow, immunohistochemistry for angiogenesis markers and macrophage content, Ly6Chi monocyte FACS, macrophage-endothelial co-culture assays, gene expression profiling\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo plus in vitro mechanistic dissection with multiple orthogonal readouts\",\n      \"pmids\": [\"28642238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hydrogen sulfide (H2S) reduces RAGE toxicity by inhibiting RAGE dimerization and impairing its membrane stability. H2S (via NaHS) attenuated Aβ1-42- and AGE-induced cell injury. NaHS reduced H2O2-enhanced RAGE dimerization (shown by split-GFP complementation and Western blot) and decreased membrane RAGE expression. S-sulfhydration assay identified C259/C301 as the residues directly modified by H2S; mutation of these sites (C259S/C310S double mutant) mimicked H2S effects and caused ER retention, reduced membrane expression, and shortened half-life of RAGE.\",\n      \"method\": \"Split-GFP complementation dimerization assay, Western blot, immunofluorescence, cycloheximide chase, ubiquitination assay, tag-switch S-sulfhydration assay, site-directed mutagenesis (C259S/C310S)\",\n      \"journal\": \"Free Radical Biology & Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — specific cysteine residues identified by mutagenesis and direct S-sulfhydration detection; dimerization mechanism validated by orthogonal split-GFP assay\",\n      \"pmids\": [\"28108276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAGE modulates autophagy in hepatocellular carcinoma (HCC) cells to promote proliferation and sorafenib resistance. RAGE deficiency activated AMPK/mTOR signaling and induced autophagy, which improved sorafenib response. HMGB1 and S100A4 ligands positively upregulated RAGE expression, indicating a ligand-driven autocrine amplification loop in HCC.\",\n      \"method\": \"RAGE knockdown and overexpression in HCC cell lines, AMPK/mTOR pathway assays, autophagy flux assays, sorafenib cytotoxicity assays, HMGB1/S100A4 ligand stimulation experiments\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss-of-function with defined AMPK/mTOR pathway readout, single lab\",\n      \"pmids\": [\"29445087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-5591-5p directly targets AGER mRNA (3′UTR), suppressing AGER expression. AGEs downregulate miR-5591-5p in adipose-derived stem cells (ADSCs), activating the AGE/AGER/JNK signaling axis to induce ROS generation and apoptosis. miR-5591-5p overexpression blocked this axis, promoted ADSC survival, and enhanced cutaneous wound repair in vivo.\",\n      \"method\": \"miRNA mimic/inhibitor transfection, luciferase 3′UTR reporter assay for AGER targeting, AGER siRNA, ROS assay, JNK phosphorylation assay, apoptosis flow cytometry, in vivo diabetic wound healing model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′UTR luciferase validation of miRNA–AGER interaction combined with in vivo functional outcome\",\n      \"pmids\": [\"29752466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Decorin (DCN), a proteoglycan released by ferroptotic cells via secretory autophagy and lysosomal exocytosis, binds to AGER on macrophages to trigger NF-κB-dependent pro-inflammatory cytokine production. Pharmacological and genetic inhibition of the DCN–AGER axis protected against ferroptotic death-related acute pancreatitis and limited tumor-protective immune responses to ferroptotic cancer cells.\",\n      \"method\": \"Cell death assays (ferroptosis induction), DCN release quantification, Co-IP of DCN–AGER interaction, AGER KO macrophages, NF-κB reporter, in vivo acute pancreatitis model, tumor immunization experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding (Co-IP), genetic KO with defined NF-κB signaling readout, and in vivo disease model validation\",\n      \"pmids\": [\"34964698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During alkaliptosis (intracellular alkalization-driven cell death), HMGB1 is released from the nucleus to the extracellular space via a FANCD2-dependent (not ATM-mediated) DNA damage signaling pathway. Released HMGB1 binds AGER on macrophages and then activates the STING1 pathway to produce pro-inflammatory cytokines (TNF, IL-6). Inhibition of the HMGB1–AGER–STING1 pathway limits cytokine production during alkaliptosis.\",\n      \"method\": \"HMGB1 nuclear-to-cytoplasmic translocation assay, FANCD2/ATM genetic perturbation, AGER KO macrophages, STING1 pathway readout (IRF3/TBK1 phosphorylation), cytokine ELISA\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic dissection of HMGB1 release pathway and AGER-STING1 axis; single lab\",\n      \"pmids\": [\"33992959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YAP participates in a transcriptional network with KLF5, NFIB, and NKX2-1 to regulate AGER expression in alveolar epithelial cells. YAP activation increased AT1 cell numbers and enhanced DNA accessibility at AGER promoter regions; YAP deletion increased AT2 markers. Chromatin accessibility (ATAC-seq) and motif enrichment analysis identified the transcription factor network controlling AGER during alveolar differentiation.\",\n      \"method\": \"Transgenic YAP activation/deletion mouse models, ATAC-seq, transcription factor motif enrichment, RNA-seq, immunostaining for AT1/AT2 markers\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic YAP gain/loss-of-function with chromatin accessibility data; AGER as downstream target validated in vivo\",\n      \"pmids\": [\"34466790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cadmium (Cd) induces ferroptosis in pancreatic β-cells, and ferroptosis inhibitor Fer-1 antagonized Cd-induced AGER-mediated inflammation. Cd exposure decreased Gpx4 expression (enabling ferroptosis) and activated the AGER/PKC/p65 (NF-κB) inflammatory axis. The Gpx4/AGER/p65 pathway was identified as a novel mechanistic axis linking ferroptotic cell death to pancreatic inflammation and β-cell dysfunction.\",\n      \"method\": \"Transcriptomic analysis (RNA-seq) of Cd-treated MIN6 cells, GSH/lipid peroxidation assays, Gpx4 knockdown/inhibition, ferroptosis inhibitor (Fer-1), AGER expression analysis, PKC/NF-κB pathway assays, in vivo Cd-exposed mouse model\",\n      \"journal\": \"The Science of the Total Environment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological rescue with Fer-1 plus pathway validation in vitro and in vivo; single lab\",\n      \"pmids\": [\"35931150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AGER mediates resistance to KRAS-G12D inhibitor MRTX1133 in pancreatic ductal adenocarcinoma by driving macropinocytosis. AGER interacts with DIAPH1 (diaphanous-related formin 1), which activates RAC1-dependent macropinosome formation, enabling internalization of serum albumin and generation of amino acids used for glutathione synthesis and apoptosis resistance. Combination of MRTX1133 with AGER–DIAPH1 complex inhibitor (RAGE299) or macropinocytosis inhibitor (EIPA) was effective in patient-derived xenografts, orthotopic, and genetically engineered mouse models. This combination also induced HMGB1 release and CD8+ T cell antitumor responses.\",\n      \"method\": \"AGER overexpression/knockdown in PDAC cells, Co-IP of AGER–DIAPH1 complex, RAC1 activity assay, macropinocytosis assay (fluorescent albumin uptake), glutathione measurement, patient-derived xenografts, orthotopic mouse models, genetically engineered mouse PDAC models, CD8+ T cell immune response assays\",\n      \"journal\": \"Science Translational Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct protein-protein interaction (Co-IP of AGER–DIAPH1), mechanistic downstream pathway (RAC1→macropinocytosis→GSH), validated in multiple in vivo models\",\n      \"pmids\": [\"39879317\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGER/RAGE is a multiligand immunoglobulin superfamily transmembrane receptor whose extracellular V-domain binds AGEs, HMGB1, S100/calgranulins, Aβ, C1q, RNA, and decorin; ligand engagement requires the intact cytoplasmic domain to activate NF-κB (via Ras), Rac1/Cdc42-dependent cytoskeletal remodeling (neurite outgrowth), MAPK, and CaMKII through distinct downstream pathways; RAGE also undergoes ligand-independent transactivation by AT1R and β1AR through direct receptor heterocomplex formation; soluble RAGE isoforms arise by ADAM10-mediated ectodomain shedding (cRAGE) or alternative splicing (esRAGE) and act as decoy receptors; intracellularly, RAGE engages DIAPH1 to drive RAC1-dependent macropinocytosis; and RAGE dimerization—stabilized at plasma membrane cysteine residues C259/C301—is required for full signaling activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AGER (RAGE) is a multiligand pattern recognition receptor of the immunoglobulin superfamily that integrates diverse extracellular danger signals—including AGEs, HMGB1, S100 proteins, decorin, C1q, and RNA—to drive NF-κB-dependent inflammation, cell adhesion, autophagy, and cytoskeletal remodeling. Ligand-induced receptor dimerization/oligomerization, exemplified by multimeric S100B binding the V-domain [PMID:17660747], activates intracellular signaling through the cytoplasmic tail via the formin DIAPH1, which engages RAC1/Cdc42-dependent macropinocytosis and neurite outgrowth [PMID:18058943, PMID:39879317]. RAGE also forms ligand-independent heteromeric complexes with GPCRs (AT1R, β1AR), enabling transactivation of its cytoplasmic tail to propagate CaMKII- and NF-κB-mediated inflammatory and cardiomyopathic signaling [PMID:30530993, PMID:26966719]. Post-translational regulation by H2S-mediated S-sulfhydration at C259/C301 inhibits RAGE dimerization and accelerates its degradation, while in the lung RAGE is constitutively required for alveolar epithelial differentiation and barrier integrity [PMID:28108276, PMID:28678851].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that RAGE ligation directly induces adhesion molecule expression: AGE binding to RAGE on mesothelial cells was shown to upregulate VCAM-1 and potentiate leukocyte adhesion, demonstrating a direct receptor-to-effector link between AGE-RAGE signaling and vascular inflammation.\",\n      \"evidence\": \"Antibody and recombinant RAGE blocking of VCAM-1 induction on human peritoneal mesothelial cells\",\n      \"pmids\": [\"11786095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling intermediates between RAGE ligation and VCAM-1 transcription were not identified\", \"Whether other RAGE ligands similarly induce VCAM-1 was untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolving how multimerization of S100B controls RAGE activation: crystal structures and binding studies showed that tetrameric/oligomeric S100B binds the V-domain with higher affinity than dimeric S100B and induces receptor dimerization, establishing ligand oligomeric state as a determinant of signaling strength.\",\n      \"evidence\": \"X-ray crystallography at 1.9 Å, analytical ultracentrifugation, and cell growth assays\",\n      \"pmids\": [\"17660747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full-length RAGE dimer/oligomer complex was not resolved\", \"Whether other S100 family ligands use the same oligomerization-dependent mechanism was not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining RAGE's intracellular effectors and cell-type-specific pathological roles: RAGE was shown to signal through Rac1/Cdc42 to drive neurite outgrowth and NF-κB translocation, and bone marrow chimera experiments placed macrophage RAGE downstream of HMGB1 in ischemic brain damage.\",\n      \"evidence\": \"RNAi knockdown with constitutively active GTPase rescue in neurons; bone marrow chimeric RAGE-KO mice in cerebral ischemia model\",\n      \"pmids\": [\"18058943\", \"19005067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the cytoplasmic tail couples to Rac1/Cdc42 activation was not molecularly defined\", \"Whether RAGE on non-macrophage brain cells contributes to ischemia was not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying DIAPH1 as the cytoplasmic tail effector that transduces AGE-RAGE signaling: the formin diaphanous-1 was identified as a direct binding partner of the RAGE intracellular domain, providing the missing link between receptor ligation and downstream inflammatory signaling.\",\n      \"evidence\": \"Biochemical identification of DIAPH1-RAGE cytoplasmic domain interaction with functional signaling studies\",\n      \"pmids\": [\"20957395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the RAGE-DIAPH1 interaction was not determined\", \"Whether DIAPH1 is the sole cytoplasmic effector or one of several was unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating RAGE's role in autophagy regulation: RAGE was shown to promote autophagy and suppress apoptosis during oxidative stress in pancreatic cancer cells, linking RAGE to a pro-survival metabolic program beyond classical inflammation.\",\n      \"evidence\": \"RAGE knockdown/overexpression with autophagy and apoptosis assays under oxidative stress in cancer cells\",\n      \"pmids\": [\"21317562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular pathway from RAGE to autophagy induction was not defined\", \"Generalizability beyond pancreatic cancer was not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expanding RAGE's ligand repertoire to complement C1q: RAGE was identified as a C1q receptor that cooperates with Mac-1 to enhance C1q-dependent phagocytosis, placing RAGE at the interface of innate immunity and complement recognition.\",\n      \"evidence\": \"Surface plasmon resonance (Kd ~5.6 µM), pull-down, and antibody blocking of C1q-dependent phagocytosis in U937 cells\",\n      \"pmids\": [\"22386596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of RAGE-C1q interaction for complement-mediated clearance was not established\", \"Whether RAGE-Mac-1 complex formation is constitutive or ligand-induced was not determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing RAGE as essential for autoimmune myocarditis while revealing redundancy with TLRs: RAGE-KO mice were fully protected from troponin I-induced cardiac inflammation, but AAV-mediated HMGB1 overexpression could bypass RAGE via TLRs, defining parallel inflammatory receptor pathways.\",\n      \"evidence\": \"RAGE-KO mice, AAV overexpression, pharmacological HMGB1 inhibition, cardiac histology\",\n      \"pmids\": [\"26715748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which TLRs mediate HMGB1 signaling independently of RAGE in the heart was not specified\", \"Relative contribution of RAGE vs. TLRs in human myocarditis is unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovering RAGE's function as a nucleic acid co-receptor and a metabolic signaling hub: RAGE was shown to bind RNA in a sequence-independent manner and shuttle it to endosomal TLR7/8/13, while separately activating the hexosamine biosynthetic pathway to O-GlcNAcylate c-Jun at Ser73, creating a positive transcriptional feedback loop.\",\n      \"evidence\": \"RNA binding and endosomal uptake assays with gain/loss-of-function TLR signaling readouts; siRNA, mutagenesis, and O-GlcNAcylation assays in HCC cells\",\n      \"pmids\": [\"27798148\", \"26825459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAGE-bound RNA is handed off to endosomal TLRs mechanistically was not resolved\", \"Whether the hexosamine-c-Jun loop operates in non-hepatic cells was not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealing that RAGE forms ligand-independent heteromeric complexes with GPCRs: β1AR-RAGE co-immunoprecipitated, and activation of either receptor required the other for CaMKII-dependent cardiomyocyte death; simultaneously, AT1R-RAGE complexes were shown to transactivate NF-κB independently of RAGE's ectodomain, demonstrating that RAGE functions as a signal amplifier for GPCR pathways.\",\n      \"evidence\": \"Co-immunoprecipitation, genetic KO and pharmacological blockade of β1AR and AT1R, CaMKII assays, S391A-RAGE peptide inhibitor, atherosclerosis and cardiomyopathy models\",\n      \"pmids\": [\"26966719\", \"30530993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural interface of GPCR-RAGE heteromers remain undefined\", \"Whether other GPCRs form similar complexes with RAGE is unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining post-translational control of RAGE activity and its constitutive role in lung biology: H2S-mediated S-sulfhydration at C259/C301 was shown to inhibit RAGE dimerization, reduce membrane abundance, and accelerate degradation; separately, RAGE-KO mice developed emphysema-like changes, demonstrating RAGE is required for alveolar epithelial differentiation and barrier integrity.\",\n      \"evidence\": \"Tag-switch S-sulfhydration assay with Cys→Ser mutagenesis, split-GFP dimerization; RAGE-KO mice with lung mechanics and alveolar cell phenotyping\",\n      \"pmids\": [\"28108276\", \"28678851\", \"28642238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological source of H2S that modulates RAGE in vivo is not defined\", \"Whether S-sulfhydration affects GPCR-RAGE heteromeric complexes was not tested\", \"Mechanism by which RAGE drives AT1 cell differentiation is molecularly unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending RAGE ligand biology to damage-associated decorin and the STING1 pathway: decorin released during ferroptosis and HMGB1 released during alkaliptosis were both shown to activate RAGE on macrophages, with HMGB1 specifically engaging a RAGE-STING1 axis for cytokine production, revealing context-dependent downstream pathway selection.\",\n      \"evidence\": \"Co-IP/binding of DCN-RAGE, genetic/pharmacological AGER inhibition in pancreatitis model; STING1 pathway epistasis analysis\",\n      \"pmids\": [\"34964698\", \"33992959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how RAGE engages STING1 vs. NF-κB downstream is not known\", \"Whether DCN signals through the same V-domain site as other ligands is not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Closing the DIAPH1-RAC1 pathway to a defined metabolic output: AGER-DIAPH1 interaction was shown to drive RAC1-dependent macropinocytosis in pancreatic cancer, with internalized albumin fueling glutathione synthesis to resist KRAS-G12D inhibitor-induced apoptosis, establishing a complete receptor-to-metabolic-resistance axis.\",\n      \"evidence\": \"Co-IP of AGER-DIAPH1, RAC1 activity assays, macropinocytosis/glutathione quantification, combination therapy in PDX/orthotopic/GEM mouse models\",\n      \"pmids\": [\"39879317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DIAPH1-dependent macropinocytosis operates in non-pancreatic RAGE-high cancers is untested\", \"Structural details of the AGER-DIAPH1 interface that would enable rational drug design are lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of full-length RAGE oligomerization and GPCR heteromerization, how ligand identity determines selection among divergent downstream pathways (NF-κB, STING1, Rac1, CaMKII), and the physiological regulation of the balance between membrane-bound and soluble RAGE isoforms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length RAGE structure in complex with any ligand or GPCR partner\", \"Mechanism of soluble RAGE shedding and its regulation in vivo remain poorly defined\", \"Integrated signaling model explaining ligand-specific pathway selection is lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 4, 9, 17]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 6, 10, 11, 14, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4, 7, 9, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 8, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 15]}\n    ],\n    \"complexes\": [\n      \"RAGE-DIAPH1\",\n      \"RAGE-AT1R\",\n      \"RAGE-β1AR\",\n      \"RAGE-Mac-1\"\n    ],\n    \"partners\": [\n      \"DIAPH1\",\n      \"AGTR1\",\n      \"ADRB1\",\n      \"HMGB1\",\n      \"ITGAM\",\n      \"RAC1\",\n      \"S100B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"AGER (RAGE) is a multiligand pattern-recognition receptor of the immunoglobulin superfamily that transduces danger signals from advanced glycation end products (AGEs), HMGB1, S100/calgranulins, amyloid-β, complement C1q, decorin, and extracellular RNA into NF-κB, MAPK, Rac1/Cdc42, and CaMKII signaling cascades, thereby orchestrating inflammatory, neurodegenerative, and metabolic responses [PMID:1378843, PMID:8751438, PMID:10399917, PMID:22386596, PMID:27798148, PMID:34964698]. Ligand engagement at the extracellular V-type Ig domain requires an intact 43-residue cytoplasmic tail, which bifurcates signaling: Ras-dependent NF-κB activation versus Rac1/Cdc42-dependent cytoskeletal remodeling and neurite outgrowth; additionally, RAGE undergoes ligand-independent transactivation through preformed heterocomplexes with AT1R and β1AR [PMID:10391939, PMID:30530993, PMID:26966719]. Soluble decoy isoforms arise by ADAM10-mediated ectodomain shedding (cRAGE) or alternative splicing (esRAGE) and competitively antagonize RAGE signaling, while RAGE dimerization—stabilized by transmembrane cysteines C259/C301—is required for full signaling activity [PMID:18603587, PMID:12495433, PMID:28108276]. Intracellularly, RAGE engages DIAPH1 to activate RAC1-dependent macropinocytosis, conferring amino acid scavenging and therapy resistance in pancreatic cancer [PMID:39879317].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing that a novel immunoglobulin-superfamily receptor specifically binds AGEs answered the fundamental question of how cells sense glycation damage, founding the RAGE field.\",\n      \"evidence\": \"cDNA cloning from bovine lung, recombinant expression in HEK293 cells with radioligand binding (Kd ~100 nM) and antibody blockade\",\n      \"pmids\": [\"1378843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No downstream signaling pathway yet identified\", \"Endogenous ligand specificity beyond AGE-albumin unknown\", \"Physiological relevance in vivo not demonstrated\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of amyloid-β as a second RAGE ligand on neurons and microglia recast RAGE from a metabolic receptor to a broader pattern-recognition receptor implicated in neurodegeneration.\",\n      \"evidence\": \"Direct RAGE–Aβ binding assays, antibody blockade, cell-based neurotoxicity assays, immunohistochemistry in Alzheimer's disease brain\",\n      \"pmids\": [\"8751438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Aβ–RAGE interaction undefined\", \"In vivo causality in AD not yet tested with genetic tools\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Discovery of NF-κB-responsive elements in the RAGE promoter established a positive-feedback transcriptional loop whereby RAGE-driven NF-κB amplifies RAGE expression itself.\",\n      \"evidence\": \"Deletion-reporter constructs, DNase I footprinting, EMSA, and site-directed mutagenesis in vascular cells\",\n      \"pmids\": [\"9195959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other transcription factors cooperate at the RAGE promoter remained unknown\", \"Epigenetic regulation not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that soluble RAGE (sRAGE) administration suppressed diabetic atherosclerosis independent of glycemia proved in vivo causal relevance and introduced the decoy-receptor therapeutic concept.\",\n      \"evidence\": \"Pharmacological sRAGE in streptozotocin-diabetic ApoE-KO mice with lesion quantification\",\n      \"pmids\": [\"9734395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"sRAGE source (shedding vs. splice variant) not yet distinguished\", \"Whether sRAGE blocks all RAGE ligands equally was untested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"S100/calgranulin family members were identified as proinflammatory RAGE ligands, and the cytoplasmic domain was shown to bifurcate signaling into Ras→NF-κB versus Rac1/Cdc42→cytoskeletal remodeling branches, defining RAGE as a multi-pathway signaling hub.\",\n      \"evidence\": \"Receptor binding assays, in vivo DTH/colitis blockade models, dominant-negative GTPase epistasis with domain-deletion mutants in neuroblastoma cells\",\n      \"pmids\": [\"10399917\", \"10391939\", \"10531386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cytoplasmic interactors mediating Ras or Rac activation unknown\", \"Whether CML is the sole AGE species relevant in vivo undetermined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Parallel discoveries that RAGE mediates Aβ transcytosis across the blood–brain barrier and that alternative splicing produces secreted esRAGE as an endogenous decoy defined two critical functional dimensions: RAGE as a transporter of pathogenic cargo and endogenous soluble isoforms as built-in negative regulators.\",\n      \"evidence\": \"In vivo BBB transport assays in APPsw mice with RAGE blockade; RT-PCR cloning of splice variants with ERK/VEGF pathway assays in COS-7 and endothelial cells\",\n      \"pmids\": [\"12808450\", \"12495433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural difference between esRAGE and later-discovered cRAGE unresolved\", \"Quantitative contribution of each sRAGE species in vivo unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that HMGB1–RAGE signaling in dendritic cells drives maturation and T cell polarization positioned RAGE as a key innate-to-adaptive immune bridge.\",\n      \"evidence\": \"RAGE−/− DCs, neutralizing antibodies, DC maturation markers by FACS, IL-12 production, T cell proliferation assays\",\n      \"pmids\": [\"15944249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAGE cooperates with TLR4 for HMGB1 sensing on DCs not fully resolved\", \"Relevance to human DC biology not confirmed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Crystallographic and biophysical analysis of multimeric S100B–RAGE V-domain interaction revealed that RAGE activation involves receptor oligomerization driven by multivalent ligand assemblies.\",\n      \"evidence\": \"1.9 Å X-ray crystal structure of S100B, SPR, analytical ultracentrifugation showing tetrameric S100B binds two RAGE molecules\",\n      \"pmids\": [\"17660747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length RAGE oligomeric structure unresolved\", \"Whether all RAGE ligands promote similar receptor clustering untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Three convergent advances resolved RAGE's injury-sensing role and its regulation: HMGB1–RAGE on macrophages mediates post-ischemic neuroinflammation (with cell-type specificity via bone marrow chimeras), ADAM10 was identified as the sheddase generating circulating cRAGE, and RAGE/Rac1/Cdc42 drives neuronal differentiation.\",\n      \"evidence\": \"MCAO ischemia model with bone marrow chimeras; ADAM10-KO MEFs and protease inhibitor screening; RNAi in P19 cells and primary neurons with constitutively active Rac1/Cdc42 rescue\",\n      \"pmids\": [\"19005067\", \"18603587\", \"18058943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM10 shedding is regulated by all RAGE ligands not tested\", \"Downstream adaptor linking RAGE cytoplasmic tail to Rac1 still unidentified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of C1q as a RAGE ligand (forming a ternary complex with Mac-1) and development of the V-domain inhibitor FPS-ZM1 provided a new innate immune axis and a pharmacological proof-of-concept tool.\",\n      \"evidence\": \"SPR binding (Kd ~5.6 µM), pull-down of RAGE–Mac-1 complex; FPS-ZM1 multi-readout analysis in aged APPsw mice\",\n      \"pmids\": [\"22386596\", \"22406537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RAGE–Mac-1 cooperation unknown\", \"FPS-ZM1 selectivity profile across all RAGE ligands incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that AT1R transactivates RAGE independently of RAGE ligands via a preformed receptor heterocomplex revealed a ligand-independent mode of RAGE signaling that selectively drives NF-κB inflammation downstream of Ang II.\",\n      \"evidence\": \"Co-IP of AT1R–RAGE complex, RAGE-KO and ectodomain-deletion mouse models, rescue with WT vs. S391A mutant RAGE peptide in Ager/ApoE-KO atherosclerosis model\",\n      \"pmids\": [\"30530993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other GPCRs transactivate RAGE untested beyond β1AR\", \"Structural interface of AT1R–RAGE heterocomplex undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Three studies expanded RAGE's signaling repertoire: β1AR–RAGE heterocomplexes drive CaMKII-dependent cardiomyocyte death; RAGE acts as a co-receptor delivering RNA to endosomal TLR7/8/13; and RAGE feeds a hexosamine/O-GlcNAcylation/c-Jun positive feedback loop in HCC.\",\n      \"evidence\": \"Co-IP of β1AR–RAGE, double KO epistasis, CaMKII activity; RNA binding/uptake assays with RAGE KO/overexpression in TLR reporter systems; O-GlcNAc mass spectrometry and c-Jun S73 mutagenesis with AGER promoter reporter\",\n      \"pmids\": [\"26966719\", \"27798148\", \"26825459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAGE–nucleic acid sensing extends to dsDNA innate pathways beyond TLR9 not settled\", \"Structural basis of β1AR–RAGE interaction undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of C259 and C301 as dimerization-critical cysteines modified by H2S (S-sulfhydration) established the molecular basis for RAGE oligomeric assembly and introduced a redox-based regulatory mechanism controlling receptor surface stability.\",\n      \"evidence\": \"Split-GFP dimerization assay, C259S/C301S mutagenesis, tag-switch S-sulfhydration detection, cycloheximide chase for half-life\",\n      \"pmids\": [\"28108276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous H2S levels regulate RAGE dimerization in vivo unproven\", \"Role of other cysteine residues untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Decorin released from ferroptotic cells was identified as a novel RAGE ligand on macrophages, linking ferroptosis to NF-κB-dependent sterile inflammation; separately, HMGB1–RAGE was shown to activate STING1 during alkaliptosis.\",\n      \"evidence\": \"Co-IP of DCN–AGER, AGER KO macrophages, NF-κB reporter, acute pancreatitis model; FANCD2 genetic perturbation, AGER KO macrophages, STING1/TBK1/IRF3 pathway readout\",\n      \"pmids\": [\"34964698\", \"33992959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether decorin–RAGE axis operates during physiological wound healing unknown\", \"STING1 activation mechanism downstream of RAGE unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RAGE was shown to drive macropinocytosis via DIAPH1→RAC1 to scavenge amino acids for glutathione synthesis, conferring resistance to KRAS-G12D inhibitor MRTX1133 in pancreatic cancer—identifying the first direct cytoplasmic adaptor (DIAPH1) for RAGE.\",\n      \"evidence\": \"Co-IP of AGER–DIAPH1, RAC1 activity assay, fluorescent albumin uptake, GSH measurement, patient-derived xenografts, orthotopic and genetically engineered mouse PDAC models\",\n      \"pmids\": [\"39879317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DIAPH1 is the universal cytoplasmic adaptor for all RAGE signaling arms is untested\", \"Structural basis of AGER–DIAPH1 interaction unresolved\", \"Whether RAGE-driven macropinocytosis occurs in non-cancer contexts unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length RAGE signaling complex structure—including the cytoplasmic tail bound to DIAPH1 and/or other adaptors—has not been solved; how a single 43-residue cytoplasmic tail activates at least four distinct downstream cascades (NF-κB, Rac1/Cdc42, CaMKII, STING1) remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of full-length RAGE or RAGE–adaptor complex\", \"Mechanism of pathway selectivity by a short cytoplasmic tail undefined\", \"Relative physiological importance of >8 different ligands unranked\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 4, 6, 7, 18, 28]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [10, 22]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [14, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4, 8, 13, 20, 25]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 11, 15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 12, 14, 22, 28, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 7, 20, 21, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 10, 19, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 17, 32]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17, 26]}\n    ],\n    \"complexes\": [\n      \"AT1R–RAGE heterocomplex\",\n      \"β1AR–RAGE heterocomplex\",\n      \"RAGE–Mac-1 (CD11b/CD18) complex\",\n      \"RAGE–DIAPH1 complex\"\n    ],\n    \"partners\": [\n      \"HMGB1\",\n      \"DIAPH1\",\n      \"ADAM10\",\n      \"RAC1\",\n      \"AGTR1\",\n      \"ADRB1\",\n      \"ITGAM\",\n      \"CDC42\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}