{"gene":"CD24","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2009,"finding":"CD24 associates with damage-associated molecular pattern molecules HMGB1, HSP70, and HSP90, negatively regulates their stimulatory activity, and inhibits NF-κB activation. This occurs through CD24 association with Siglec-10 (in humans) or Siglec-G (in mice), selectively suppressing innate immune responses to danger- but not pathogen-associated molecular patterns.","method":"Co-immunoprecipitation, CD24-deficient mouse model with defined phenotypic readout (susceptibility to DAMPs vs PAMPs), genetic epistasis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, knockout mouse phenotype, epistasis with Siglec-G/10, replicated across human and mouse systems in a single rigorous study","pmids":["19264983"],"is_preprint":false},{"year":2019,"finding":"CD24 expressed on tumor cells interacts with the inhibitory receptor Siglec-10 expressed by tumor-associated macrophages to suppress macrophage-mediated phagocytosis, functioning as an innate immune 'don't eat me' checkpoint. Genetic ablation of either CD24 or Siglec-10, or blockade of the CD24-Siglec-10 interaction with monoclonal antibodies, robustly augments phagocytosis of CD24-expressing human tumors and reduces tumor growth in vivo.","method":"Genetic ablation (CRISPR/knockout), monoclonal antibody blockade, phagocytosis assays, in vivo tumor growth and survival assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic ablation + antibody blockade + in vivo models), replicated across multiple tumor types","pmids":["31367043"],"is_preprint":false},{"year":2015,"finding":"Intracellular CD24 competitively inhibits ARF binding to nucleophosmin (NPM), resulting in decreased ARF levels, increased MDM2, and decreased p53 and p21/CDKN1A. This mechanism enables functional inactivation of p53 by both somatic mutation and viral oncogenes (SV40 large T antigen, HPV16 E6). Targeted mutation and shRNA silencing of CD24 retard prostate cancer growth, progression, and metastasis.","method":"shRNA silencing, targeted mutation, co-immunoprecipitation, competitive binding assay, in vivo tumor growth assay","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for ARF-NPM-CD24 interaction, multiple functional readouts (in vitro and in vivo), multiple oncogene contexts tested in one study","pmids":["25600590"],"is_preprint":false},{"year":2012,"finding":"CD24 knockdown reduces STAT3 and FAK phosphorylation, and reduces Src phosphorylation. CD24 overexpression augments Src-Y416 phosphorylation, recruits Src into lipid rafts, and increases expression of STAT3-dependent target genes. Anti-CD24 antibody treatment reduces tumor growth and affects Src phosphorylation in vivo.","method":"siRNA knockdown, overexpression, reporter assays, lipid raft fractionation, xenograft tumor model, antibody treatment","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD, OE, reporter assay, fractionation, in vivo), single lab","pmids":["22760497"],"is_preprint":false},{"year":2011,"finding":"CD24 expression promotes cancer cell invasion through increased generation and transmission of contractile forces. CD24 facilitates localization of β1-integrins in lipid rafts; knockdown of CD24 or β1-integrin reduces invasiveness. Inhibition of Src kinase or STAT3 strongly reduces invasiveness of CD24-high cells. Myosin light chain kinase inhibitor and Rho kinase inhibitor reduce CD24-dependent invasiveness.","method":"Stable transfection and knockdown, Fourier transform traction microscopy, 3D ECM invasion assays, pharmacological inhibitors","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including biophysical measurements (traction microscopy) and genetic/pharmacological perturbations, single lab","pmids":["21828044"],"is_preprint":false},{"year":2016,"finding":"CD24 associates with EGFR and supports EGF/EGFR signaling in gastric cancer cells. CD24 inhibits EGFR internalization and degradation in a RhoA-dependent manner, thereby stabilizing EGFR and sustaining downstream ERK and Akt phosphorylation upon EGF stimulation. Knockdown of CD24 decreases EGFR levels and cell migration.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence, RhoA pulldown assay, Western blotting, wound healing assay","journal":"Journal of Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional assays with multiple readouts, single lab","pmids":["26830684"],"is_preprint":false},{"year":2009,"finding":"CD24 promotes colorectal cancer cell proliferation via activation of ERK, Raf-1, and p38 MAPK. Suppression of ERK and p38 MAPK activity with specific inhibitors (U0126 and SB203580) abrogates CD24-induced proliferation in vitro.","method":"Overexpression, pharmacological inhibition, in vitro proliferation assays, in vivo tumorigenicity assay","journal":"Cancer Science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological pathway dissection with two inhibitors, overexpression and in vivo validation, single lab","pmids":["19860845"],"is_preprint":false},{"year":2022,"finding":"The CD24-Siglec-E axis (not other Siglecs) is a key suppressor of obesity-related metabolic dysfunction. Sialylation-dependent recognition of CD24 by Siglec-E induces SHP-1 recruitment and represses metaflammation. Inactivation of the CD24-Siglec-E pathway exacerbates, while CD24Fc treatment alleviates, diet-induced obesity, dyslipidemia, insulin resistance, and NASH.","method":"Multiple mouse strains with single/combined Cd24 or Siglec gene mutations, CD24Fc treatment, mechanistic studies showing SHP-1 recruitment","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple mouse strains, pharmacological rescue, SHP-1 recruitment mechanism, validated in human clinical trial cohort","pmids":["35921817"],"is_preprint":false},{"year":2014,"finding":"CD24 promotes gastric cancer cell survival and invasion via activation of STAT3. Knockdown of CD24 induces apoptosis through the mitochondrial apoptotic pathway and inhibits STAT3 activation. CD24 also regulates E-cadherin, fibronectin, and vitamin D receptor expression.","method":"siRNA knockdown, in vitro apoptosis and invasion assays, in vivo tumor model, STAT3 pathway analysis","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple cellular phenotype readouts plus in vivo confirmation, single lab","pmids":["24327257"],"is_preprint":false},{"year":2018,"finding":"CD24 regulates sorafenib resistance by activating autophagy in HCC. CD24 overexpression increases PP2A protein production and induces deactivation of the mTOR/AKT pathway, which enhances autophagy. Depletion of CD24 or inhibition of autophagy (pharmacologically or by autophagy gene knockdown) restores sorafenib sensitivity.","method":"siRNA knockdown, overexpression, pharmacological autophagy inhibitors, essential autophagy gene knockdown, Western blotting for mTOR/AKT pathway","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent methods of autophagy inhibition (pharmacological + genetic) plus pathway analysis, single lab","pmids":["29844385"],"is_preprint":false},{"year":2020,"finding":"CD24 recruits PTEN to the lipid raft domain and regulates the PTEN/AKT/mTORC1 pathway to activate autophagy, thereby impairing retinoblastoma cell sensitivity to vincristine. Lipid raft localization of CD24 was essential for this PTEN recruitment function.","method":"Overexpression, siRNA knockdown, lipid raft fractionation, pathway analysis (PTEN/AKT/mTORC1), cell viability assays","journal":"Molecular Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lipid raft fractionation showing PTEN recruitment, pathway analysis with multiple readouts, single lab","pmids":["32394616"],"is_preprint":false},{"year":2014,"finding":"Siglec-G expression on host antigen-presenting cells negatively regulates graft-versus-host disease. The interaction between Siglec-G on host APCs and CD24 on donor T cells attenuates GVHD. Rescue experiments with CD24 fusion protein and Siglec-G/CD24 knockout chimeric animals demonstrated that enhancing the CD24-Siglec-G interaction mitigates GVHD.","method":"Knockout mouse models (Siglec-G and CD24 KO), chimeric animals, CD24 fusion protein rescue experiments, multiple clinically relevant murine GVHD models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO models, chimeric animals, and pharmacological rescue in multiple disease models","pmids":["24695850"],"is_preprint":false},{"year":2010,"finding":"NFAT5 transcription factor binds to the CD24 promoter in response to hypertonicity, facilitating local chromatin derepression and enhancing CD24 mRNA and protein expression. CD24 is required to sustain T cell expansion under osmostress.","method":"NFAT5 knockout mice, ChIP (NFAT5 binding to Cd24 promoter), ex vivo T cell culture under hypernatremic conditions, chromatin accessibility assay","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, KO phenotype, chromatin derepression analysis, single lab","pmids":["21037089"],"is_preprint":false},{"year":2011,"finding":"NDRG2 negatively regulates CD24 expression in HCC cells; NDRG2 upregulation decreases CD24 expression and reduces cell adhesion, migration, and invasion, while NDRG2 downregulation increases CD24 expression and promotes these processes.","method":"Adenoviral NDRG2 overexpression, siRNA knockdown, cell adhesion/migration/invasion assays, Western blotting","journal":"BMC Cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — bidirectional manipulation (OE and KD) with defined phenotypic readouts and clinical tissue validation, single lab","pmids":["21676268"],"is_preprint":false},{"year":2012,"finding":"CD24 expression in urothelial carcinoma is regulated by androgen receptor; androgen receptor knockdown suppresses CD24 expression and cell proliferation, androgen treatment increases CD24 promoter activity in an AR-dependent manner, and androgen deprivation reduces xenograft growth and CD24 expression, which is rescued by exogenous CD24 overexpression.","method":"AR knockdown, CD24 promoter activity assays, androgen treatment, xenograft mouse model with CD24 rescue","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assay, in vivo rescue experiment, genetic knockdown, single lab","pmids":["23012401"],"is_preprint":false},{"year":2021,"finding":"Nucleophosmin/B23 (NPM) induces CD24 expression in endometrial cancer cells via the Sp1 binding site in the CD24 promoter. NPM/B23 silencing reduces CD24 surface expression and enhances macrophage-mediated phagocytosis; restoration of CD24 in NPM/B23-silenced cells inhibits phagocytosis, confirming that NPM drives immune evasion through CD24.","method":"siRNA knockdown, promoter assays with Sp1 site mutants, oligonucleotide microarray, phagocytosis assays","journal":"Journal of Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis identifying Sp1 site, rescue experiment, phagocytosis functional readout, single lab","pmids":["33954835"],"is_preprint":false},{"year":2021,"finding":"Translocation of CD24 from the cytosol to the cell membrane is a triggering event for phenotype change and drug resistance acquisition in breast cancer cells. Cytosolic-to-membrane translocation of CD24 correlates with strong and continuous p38 MAPK phosphorylation and subsequent Bcl-2 overexpression, enabling cells to enter slow cell cycle and survive drug stress.","method":"Subcellular fractionation/immunofluorescence tracking of CD24 localization, p38 MAPK inhibitor experiments, Western blotting, phenotype switching assays","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments tied to functional consequence (drug resistance), pharmacological validation, single lab","pmids":["34426608"],"is_preprint":false},{"year":2019,"finding":"CD24 in granulosa cells is associated with hCG-induced upregulation of prostaglandin synthase genes (ARK1C1, PTGS2, PTGES, PLA2G4A) and prostaglandin transporters through supporting the EGFR-ERK1/2 pathway, mediating ovulation. The fraction of CD24+ cumulus GCs decreases in PCOS patients compared to controls.","method":"Single-cell RNA sequencing, hCG treatment of cultured GCs, functional pathway analysis of EGFR-ERK1/2 signaling","journal":"Cell Death & Disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway association from transcriptomics and hCG treatment, single lab, limited mechanistic validation","pmids":["31624236"],"is_preprint":false},{"year":2006,"finding":"Knockdown of CD24 in oral epithelial cells reduces E-cadherin expression and upregulates Snail, Twist, and TGF-β3. Anti-CD24 antibody stimulation induces upregulated E-cadherin and downregulated TGF-β3 expression, suggesting CD24 modulates epithelial differentiation gene programs.","method":"RNAi knockdown, anti-CD24 antibody stimulation, real-time RT-PCR","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method approach (RT-PCR readout), single lab, no direct mechanistic pathway identified","pmids":["16930538"],"is_preprint":false},{"year":2025,"finding":"In JAK2V617F MPN, granulocyte-macrophage colony-stimulating factor drives JAK2-STAT5-dependent upregulation of CD24 on neutrophils, enabling them to evade efferocytosis (macrophage clearance). CD24-hi neutrophils invade megakaryocytes (emperipolesis) and increase active TGF-β, promoting myelofibrosis. Chronic CD24 antibody blockade or CD24 genetic loss restores neutrophil clearance, reduces emperipolesis and active TGF-β, and prevents myelofibrosis in mouse models.","method":"JAK2V617F mouse models, CD24 genetic knockout, chronic antibody blockade, mechanistic pathway analysis (GM-CSF-JAK2-STAT5-CD24), in vivo imaging and histology","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological perturbation, defined signaling pathway (GM-CSF-JAK2-STAT5), multiple orthogonal readouts, in vivo rescue","pmids":["40373279"],"is_preprint":false},{"year":2024,"finding":"GPAA1 (GPI anchor attachment 1), identified in a genome-wide CRISPR knockout screen, is required for CD24 cell surface expression; genetic ablation of GPAA1 abolishes CD24 surface expression and enhances macrophage-mediated phagocytosis. Bestatin (an aminopeptidase inhibitor) binds GPAA1, blocks GPI anchor attachment to CD24, reduces CD24 surface expression, and suppresses ovarian tumor growth.","method":"Genome-wide CRISPR KO screen, GPAA1 genetic ablation, bestatin drug treatment, phagocytosis assays, in vivo tumor growth","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — unbiased genome-wide screen, genetic validation, pharmacological drug-target binding, in vivo efficacy, single lab with multiple orthogonal methods","pmids":["38573857"],"is_preprint":false},{"year":2021,"finding":"DNA promoter methylation and ERG regulate CD24 expression in prostate cancer. ERG overexpression via TMPRSS2:ERG fusion strongly induces CD24 mRNA and protein. Luciferase promoter assays with wild-type versus mutated ERG binding site in the CD24 promoter confirmed ERG-dependent transcriptional activation of CD24.","method":"Quantitative methylation-specific PCR, ERG-inducible cell model, luciferase promoter assays with ERG binding site mutation, immunohistochemistry","journal":"The American Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis with reporter assay, inducible ERG model, clinical tissue validation, single lab","pmids":["33485866"],"is_preprint":false},{"year":2019,"finding":"Heparanase consistently upregulates CD24 expression (including via a splice variant devoid of enzymatic activity), and CD24 overexpression stimulates glioma cell migration, invasion, colony formation, and tumor growth in mice. Anti-CD24 neutralizing antibody attenuates glioma tumor growth, and a similar effect is seen with anti-L1CAM antibody (a CD24 ligand), revealing a heparanase-CD24-L1CAM axis.","method":"Inducible (Tet-on) heparanase overexpression, gene array, CD24 overexpression, anti-CD24/anti-L1CAM neutralizing antibody treatment, in vivo tumor growth","journal":"International Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gene array plus functional validation (OE, antibody blockade, in vivo), single lab","pmids":["31032901"],"is_preprint":false},{"year":2023,"finding":"SOX2 transactivates CD24 expression in embryonal carcinoma cells, as demonstrated by luciferase reporter assays. Co-immunoprecipitation followed by mass spectrometry identified direct CD24 interaction partners involved in cell adhesion, ATP binding, phosphoprotein binding, histone acetylation, and ubiquitination.","method":"Luciferase reporter assays, co-immunoprecipitation followed by mass spectrometry, N- and O-glycosylation analysis by enzymatic digestion and mass spectrometry","journal":"The FEBS Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay for SOX2 transactivation, CoIP-MS for interaction partners, multiple biochemical methods, single lab","pmids":["37254618"],"is_preprint":false},{"year":2019,"finding":"Downregulation of CD24 in hippocampal neurons after traumatic brain injury significantly inhibits phosphorylation of SHP2 and reduces the number of DCX-positive newborn neurons in the dentate gyrus, impairing cognitive functions. CD24 expression is required to support post-traumatic neurogenesis via the SHP2 signaling pathway.","method":"RNA interference in vivo, Western blotting, immunofluorescence, Morris water maze behavioral testing","journal":"The Journal of Surgical Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vivo RNAi approach, correlation-based pathway inference (SHP2 phosphorylation), single lab","pmids":["31421380"],"is_preprint":false},{"year":2024,"finding":"CLL cells suppress CAR T-cell function through CD24 (and CD52) expressed on CLL cells interacting with Siglec-10 on T cells. CD40 stimulation of CLL cells downregulates CD24 and CD52 expression, and blocking CD24 and/or CD52 markedly reduces CAR T-cell dysfunction upon coculture with resting CLL cells.","method":"Co-culture of CLL and T cells, CD40 stimulation, CD24/CD52 blocking antibodies, transcriptome profiling, kinase inhibition with dasatinib, flow cytometry","journal":"Blood Advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blockade with defined functional readout (T cell dysfunction), transcriptome profiling, pharmacological validation, single lab","pmids":["39042920"],"is_preprint":false}],"current_model":"CD24 is a GPI-anchored, heavily glycosylated cell surface protein that functions as a context-dependent signaling molecule and innate immune checkpoint: on immune and stromal cells it binds HMGB1/HSP70/HSP90 (DAMPs) and engages Siglec-G/10 (or Siglec-E in metabolic contexts) to recruit SHP-1/SHP-2 and suppress NF-κB-driven inflammatory responses to tissue damage; on tumor cells it delivers a 'don't eat me' signal to macrophages via Siglec-10, evading phagocytosis; intracellularly, CD24 disrupts the ARF-NPM interaction to promote MDM2-mediated p53 inactivation; it also promotes tumor cell proliferation, migration, and drug resistance through activation of Src/STAT3, MAPK, and PTEN/AKT/mTOR pathways, recruits β1-integrins into lipid rafts to enhance contractile force generation and invasion, stabilizes EGFR by inhibiting its degradation via RhoA, and is itself transcriptionally regulated by androgen receptor, ERG, NFAT5, NPM/B23 (via Sp1), and heparanase, while its surface expression requires GPI anchor attachment catalyzed by GPAA1."},"narrative":{"mechanistic_narrative":"CD24 is a GPI-anchored cell-surface glycoprotein that functions as a context-dependent innate immune checkpoint and a pro-oncogenic signaling hub [PMID:19264983, PMID:31367043]. As a regulator of innate immunity, CD24 binds the danger-associated molecular patterns HMGB1, HSP70, and HSP90 and engages the inhibitory receptor Siglec-10 (human) or Siglec-G (mouse) to selectively dampen NF-κB-driven responses to tissue damage without affecting responses to pathogens [PMID:19264983]; this same axis recruits SHP-1 to repress obesity-associated metaflammation through Siglec-E [PMID:35921817] and attenuates graft-versus-host disease via host Siglec-G engaging donor T-cell CD24 [PMID:24695850]. On tumor cells, the CD24–Siglec-10 interaction transmits a 'don't eat me' signal that suppresses macrophage phagocytosis, and its genetic or antibody-mediated blockade restores phagocytosis and limits tumor growth [PMID:31367043]; analogous CD24-dependent evasion of myeloid clearance drives JAK2V617F myelofibrosis and CLL-mediated CAR T-cell dysfunction [PMID:40373279, PMID:39042920]. CD24 also acts as a positive driver of tumor proliferation, survival, invasion, and drug resistance, recruiting Src and β1-integrins into lipid rafts to enhance contractile force generation and invasion [PMID:22760497, PMID:21828044], stabilizing EGFR by blocking its RhoA-dependent internalization to sustain ERK/Akt signaling [PMID:26830684], activating ERK/p38 MAPK and STAT3 to promote proliferation and survival [PMID:19860845, PMID:24327257], and recruiting PTEN to lipid rafts to modulate AKT/mTOR-dependent autophagy and chemoresistance [PMID:29844385, PMID:32394616]. Intracellularly, CD24 competitively disrupts the ARF–nucleophosmin interaction to lower ARF, raise MDM2, and inactivate p53/p21 [PMID:25600590]. CD24 expression is transcriptionally controlled by androgen receptor, ERG, NFAT5, NPM/B23 (via Sp1), SOX2, and heparanase [PMID:21037089, PMID:23012401, PMID:33954835, PMID:33485866, PMID:31032901, PMID:37254618], and its surface display requires GPI-anchor attachment catalyzed by GPAA1 [PMID:38573857].","teleology":[{"year":2009,"claim":"Established CD24 as a selective innate immune checkpoint by showing it discriminates danger from pathogen signals, answering how the immune system avoids excessive inflammation to self-derived tissue damage.","evidence":"Co-IP with HMGB1/HSP70/HSP90, CD24-deficient mouse phenotype, and genetic epistasis with Siglec-G/10 in human and mouse systems","pmids":["19264983"],"confidence":"High","gaps":["Did not resolve whether the same axis operates in tumor immune evasion","Structural basis of CD24 glycan recognition by Siglec-10/G not defined"]},{"year":2011,"claim":"Defined a biophysical mechanism for CD24-driven invasion, showing CD24 organizes β1-integrins and force-generating machinery rather than acting only as a marker.","evidence":"Stable transfection/knockdown, Fourier transform traction microscopy, 3D ECM invasion assays, and Src/STAT3/ROCK/MLCK pharmacological inhibition","pmids":["21828044"],"confidence":"Medium","gaps":["Single lab","Direct CD24–β1-integrin association not biochemically resolved"]},{"year":2012,"claim":"Connected CD24 to canonical oncogenic kinase signaling by linking it to Src/FAK/STAT3 activation within lipid rafts.","evidence":"siRNA knockdown, overexpression, reporter assays, lipid raft fractionation, and xenograft antibody treatment","pmids":["22760497"],"confidence":"Medium","gaps":["Mechanism by which a GPI-anchored protein activates intracellular Src not fully resolved","Single lab"]},{"year":2015,"claim":"Revealed an unexpected intracellular role for CD24 in p53 control, showing it competitively disrupts the ARF–NPM interaction to inactivate p53 across mutational and viral oncogene contexts.","evidence":"shRNA silencing, targeted mutation, reciprocal Co-IP, competitive binding assays, and in vivo prostate cancer models","pmids":["25600590"],"confidence":"High","gaps":["How a predominantly surface/GPI-anchored protein accesses nucleophosmin not mechanistically explained","Stoichiometry of CD24 competition with ARF unquantified"]},{"year":2016,"claim":"Showed CD24 stabilizes EGFR to sustain mitogenic signaling, answering how CD24 amplifies growth-factor responses.","evidence":"Co-IP, RhoA pulldown, knockdown/overexpression, immunofluorescence trafficking, and wound-healing assays in gastric cancer cells","pmids":["26830684"],"confidence":"Medium","gaps":["RhoA linkage to CD24 mechanistically indirect","Single lab and tumor type"]},{"year":2019,"claim":"Generalized the CD24–Siglec-10 axis into a therapeutically actionable macrophage 'don't eat me' checkpoint on tumor cells.","evidence":"CRISPR/genetic ablation, monoclonal antibody blockade, phagocytosis assays, and in vivo tumor growth/survival across multiple tumor types","pmids":["31367043"],"confidence":"High","gaps":["Did not define glycan determinants required for Siglec-10 engagement","Contribution relative to other phagocytosis checkpoints not delineated"]},{"year":2022,"claim":"Extended CD24–Siglec inhibitory signaling beyond cancer to metabolic disease, identifying Siglec-E and SHP-1 as the relevant effectors in metaflammation.","evidence":"Multiple single/combined Cd24 and Siglec mouse mutants, CD24Fc pharmacological rescue, SHP-1 recruitment analysis, and a human clinical cohort","pmids":["35921817"],"confidence":"High","gaps":["Cell types responsible for Siglec-E-dependent suppression not fully assigned","Sialylation determinants on CD24 not mapped"]},{"year":2018,"claim":"Linked CD24 to chemoresistance through autophagy, showing CD24 raises PP2A and deactivates mTOR/AKT to enhance protective autophagy.","evidence":"Knockdown/overexpression, pharmacological and genetic autophagy inhibition, and mTOR/AKT pathway analysis in sorafenib-resistant HCC","pmids":["29844385"],"confidence":"Medium","gaps":["Mechanism by which CD24 increases PP2A unknown","Single lab"]},{"year":2020,"claim":"Defined a lipid-raft-dependent CD24–PTEN module controlling AKT/mTORC1 and autophagy-mediated drug resistance.","evidence":"Overexpression/knockdown, lipid raft fractionation showing PTEN recruitment, and PTEN/AKT/mTORC1 pathway analysis in retinoblastoma cells","pmids":["32394616"],"confidence":"Medium","gaps":["Direct vs indirect CD24–PTEN association not established","Single lab and tumor type"]},{"year":2021,"claim":"Connected CD24 subcellular localization to phenotypic plasticity, showing cytosol-to-membrane translocation drives p38/Bcl-2-mediated drug-tolerant states.","evidence":"Subcellular fractionation/immunofluorescence localization tracking and p38 inhibitor experiments in breast cancer cells","pmids":["34426608"],"confidence":"Medium","gaps":["Trigger and machinery for translocation not identified","Single lab"]},{"year":2021,"claim":"Identified upstream transcriptional regulators (ERG, NPM/B23 via Sp1) controlling CD24 levels and immune evasion.","evidence":"ERG-inducible models and Sp1-site promoter mutagenesis with luciferase reporters, plus phagocytosis rescue assays","pmids":["33485866","33954835"],"confidence":"Medium","gaps":["Interplay among the multiple regulators in vivo not integrated","Tissue specificity of each regulator not resolved"]},{"year":2024,"claim":"Pinpointed the biosynthetic requirement for CD24 surface display, identifying GPAA1-mediated GPI anchoring as a druggable node.","evidence":"Genome-wide CRISPR KO screen, GPAA1 ablation, bestatin drug-target binding, phagocytosis assays, and in vivo ovarian tumor growth","pmids":["38573857"],"confidence":"High","gaps":["Selectivity of bestatin/GPAA1 inhibition for CD24 over other GPI-anchored proteins not defined"]},{"year":2025,"claim":"Demonstrated CD24-mediated evasion of myeloid clearance in non-solid disease, defining a GM-CSF–JAK2–STAT5–CD24 axis driving myelofibrosis.","evidence":"JAK2V617F mouse models, CD24 knockout, chronic antibody blockade, and in vivo imaging/histology","pmids":["40373279"],"confidence":"High","gaps":["Whether the effector Siglec receptor mirrors the tumor Siglec-10 axis not specified here","Human MPN validation limited"]},{"year":null,"claim":"It remains unresolved how CD24's glycosylation state quantitatively dictates Siglec receptor choice and downstream phosphatase selection (SHP-1 vs SHP-2) across immune, metabolic, and tumor contexts, and how its surface signaling is mechanistically coupled to its reported intracellular ARF/NPM and PTEN functions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CD24 glycan–Siglec recognition","Mechanism connecting GPI-anchored surface CD24 to intracellular p53 and PTEN regulation undefined","Rules governing tissue-specific Siglec partner selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,7,11]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,4,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,7,11,19,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,9,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,10]}],"complexes":["lipid raft"],"partners":["SIGLEC10","SIGLECG","SIGLECE","HMGB1","EGFR","ITGB1","NPM1","L1CAM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25063","full_name":"Signal transducer CD24","aliases":["Small cell lung carcinoma cluster 4 antigen"],"length_aa":80,"mass_kda":8.1,"function":"May have a pivotal role in cell differentiation of different cell types. Signaling could be triggered by the binding of a lectin-like ligand to the CD24 carbohydrates, and transduced by the release of second messengers derived from the GPI-anchor. Modulates B-cell activation responses. Promotes AG-dependent proliferation of B-cells, and prevents their terminal differentiation into antibody-forming cells (PubMed:11313396). In association with SIGLEC10 may be involved in the selective suppression of the immune response to danger-associated molecular patterns (DAMPs) such as HMGB1, HSP70 and HSP90. 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interaction partners.","date":"2023","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/37254618","citation_count":15,"is_preprint":false},{"pmid":"35398668","id":"PMC_35398668","title":"Phenotypic and molecular states of IDH1 mutation-induced CD24-positive glioma stem-like cells.","date":"2022","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35398668","citation_count":15,"is_preprint":false},{"pmid":"31054360","id":"PMC_31054360","title":"Investigation of CD133 and CD24 as candidate azoospermia markers and their relationship with spermatogenesis defects.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/31054360","citation_count":15,"is_preprint":false},{"pmid":"31534632","id":"PMC_31534632","title":"The role of CD24 in multiple myeloma tumorigenicity and effects of the microenvironment on its expression.","date":"2019","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/31534632","citation_count":15,"is_preprint":false},{"pmid":"32622311","id":"PMC_32622311","title":"The neural stem-cell marker CD24 is specifically upregulated in IDH-mutant glioma.","date":"2020","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32622311","citation_count":15,"is_preprint":false},{"pmid":"27374087","id":"PMC_27374087","title":"Characterization of the CD49f+/CD44+/CD24- single-cell derived stem cell population in basal-like DCIS cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27374087","citation_count":15,"is_preprint":false},{"pmid":"38573857","id":"PMC_38573857","title":"Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38573857","citation_count":14,"is_preprint":false},{"pmid":"35289116","id":"PMC_35289116","title":"CD24 is a surrogate for 'immune-cold' phenotype in aggressive large B-cell lymphoma.","date":"2022","source":"The journal of pathology. Clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/35289116","citation_count":14,"is_preprint":false},{"pmid":"33954835","id":"PMC_33954835","title":"Nucleophosmin/B23 promotes endometrial cancer cell escape from macrophage phagocytosis by increasing CD24 expression.","date":"2021","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/33954835","citation_count":14,"is_preprint":false},{"pmid":"27332878","id":"PMC_27332878","title":"CD90 and CD24 Co-Expression Is Associated with Pancreatic Intraepithelial Neoplasias.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27332878","citation_count":14,"is_preprint":false},{"pmid":"39129256","id":"PMC_39129256","title":"Unravelling CD24-Siglec-10 pathway: Cancer immunotherapy from basic science to clinical studies.","date":"2024","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39129256","citation_count":13,"is_preprint":false},{"pmid":"36056698","id":"PMC_36056698","title":"CD24 blockade promotes anti-tumor immunity in oral squamous cell carcinoma.","date":"2022","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/36056698","citation_count":13,"is_preprint":false},{"pmid":"37894750","id":"PMC_37894750","title":"Emerging Immune Checkpoint Molecules on Cancer Cells: CD24 and CD200.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37894750","citation_count":13,"is_preprint":false},{"pmid":"33485866","id":"PMC_33485866","title":"DNA Promoter Methylation and ERG Regulate the Expression of CD24 in Prostate Cancer.","date":"2021","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33485866","citation_count":13,"is_preprint":false},{"pmid":"38203250","id":"PMC_38203250","title":"Inhaled CD24-Enriched Exosomes (EXO-CD24) as a Novel Immune Modulator in Respiratory Disease.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38203250","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49092,"output_tokens":6610,"usd":0.123213,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15754,"output_tokens":4482,"usd":0.09541,"stage2_stop_reason":"end_turn"},"total_usd":0.218623,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"CD24 associates with damage-associated molecular pattern molecules HMGB1, HSP70, and HSP90, negatively regulates their stimulatory activity, and inhibits NF-κB activation. This occurs through CD24 association with Siglec-10 (in humans) or Siglec-G (in mice), selectively suppressing innate immune responses to danger- but not pathogen-associated molecular patterns.\",\n      \"method\": \"Co-immunoprecipitation, CD24-deficient mouse model with defined phenotypic readout (susceptibility to DAMPs vs PAMPs), genetic epistasis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, knockout mouse phenotype, epistasis with Siglec-G/10, replicated across human and mouse systems in a single rigorous study\",\n      \"pmids\": [\"19264983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD24 expressed on tumor cells interacts with the inhibitory receptor Siglec-10 expressed by tumor-associated macrophages to suppress macrophage-mediated phagocytosis, functioning as an innate immune 'don't eat me' checkpoint. Genetic ablation of either CD24 or Siglec-10, or blockade of the CD24-Siglec-10 interaction with monoclonal antibodies, robustly augments phagocytosis of CD24-expressing human tumors and reduces tumor growth in vivo.\",\n      \"method\": \"Genetic ablation (CRISPR/knockout), monoclonal antibody blockade, phagocytosis assays, in vivo tumor growth and survival assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic ablation + antibody blockade + in vivo models), replicated across multiple tumor types\",\n      \"pmids\": [\"31367043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Intracellular CD24 competitively inhibits ARF binding to nucleophosmin (NPM), resulting in decreased ARF levels, increased MDM2, and decreased p53 and p21/CDKN1A. This mechanism enables functional inactivation of p53 by both somatic mutation and viral oncogenes (SV40 large T antigen, HPV16 E6). Targeted mutation and shRNA silencing of CD24 retard prostate cancer growth, progression, and metastasis.\",\n      \"method\": \"shRNA silencing, targeted mutation, co-immunoprecipitation, competitive binding assay, in vivo tumor growth assay\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for ARF-NPM-CD24 interaction, multiple functional readouts (in vitro and in vivo), multiple oncogene contexts tested in one study\",\n      \"pmids\": [\"25600590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD24 knockdown reduces STAT3 and FAK phosphorylation, and reduces Src phosphorylation. CD24 overexpression augments Src-Y416 phosphorylation, recruits Src into lipid rafts, and increases expression of STAT3-dependent target genes. Anti-CD24 antibody treatment reduces tumor growth and affects Src phosphorylation in vivo.\",\n      \"method\": \"siRNA knockdown, overexpression, reporter assays, lipid raft fractionation, xenograft tumor model, antibody treatment\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD, OE, reporter assay, fractionation, in vivo), single lab\",\n      \"pmids\": [\"22760497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD24 expression promotes cancer cell invasion through increased generation and transmission of contractile forces. CD24 facilitates localization of β1-integrins in lipid rafts; knockdown of CD24 or β1-integrin reduces invasiveness. Inhibition of Src kinase or STAT3 strongly reduces invasiveness of CD24-high cells. Myosin light chain kinase inhibitor and Rho kinase inhibitor reduce CD24-dependent invasiveness.\",\n      \"method\": \"Stable transfection and knockdown, Fourier transform traction microscopy, 3D ECM invasion assays, pharmacological inhibitors\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including biophysical measurements (traction microscopy) and genetic/pharmacological perturbations, single lab\",\n      \"pmids\": [\"21828044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD24 associates with EGFR and supports EGF/EGFR signaling in gastric cancer cells. CD24 inhibits EGFR internalization and degradation in a RhoA-dependent manner, thereby stabilizing EGFR and sustaining downstream ERK and Akt phosphorylation upon EGF stimulation. Knockdown of CD24 decreases EGFR levels and cell migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence, RhoA pulldown assay, Western blotting, wound healing assay\",\n      \"journal\": \"Journal of Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional assays with multiple readouts, single lab\",\n      \"pmids\": [\"26830684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD24 promotes colorectal cancer cell proliferation via activation of ERK, Raf-1, and p38 MAPK. Suppression of ERK and p38 MAPK activity with specific inhibitors (U0126 and SB203580) abrogates CD24-induced proliferation in vitro.\",\n      \"method\": \"Overexpression, pharmacological inhibition, in vitro proliferation assays, in vivo tumorigenicity assay\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological pathway dissection with two inhibitors, overexpression and in vivo validation, single lab\",\n      \"pmids\": [\"19860845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CD24-Siglec-E axis (not other Siglecs) is a key suppressor of obesity-related metabolic dysfunction. Sialylation-dependent recognition of CD24 by Siglec-E induces SHP-1 recruitment and represses metaflammation. Inactivation of the CD24-Siglec-E pathway exacerbates, while CD24Fc treatment alleviates, diet-induced obesity, dyslipidemia, insulin resistance, and NASH.\",\n      \"method\": \"Multiple mouse strains with single/combined Cd24 or Siglec gene mutations, CD24Fc treatment, mechanistic studies showing SHP-1 recruitment\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple mouse strains, pharmacological rescue, SHP-1 recruitment mechanism, validated in human clinical trial cohort\",\n      \"pmids\": [\"35921817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD24 promotes gastric cancer cell survival and invasion via activation of STAT3. Knockdown of CD24 induces apoptosis through the mitochondrial apoptotic pathway and inhibits STAT3 activation. CD24 also regulates E-cadherin, fibronectin, and vitamin D receptor expression.\",\n      \"method\": \"siRNA knockdown, in vitro apoptosis and invasion assays, in vivo tumor model, STAT3 pathway analysis\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple cellular phenotype readouts plus in vivo confirmation, single lab\",\n      \"pmids\": [\"24327257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD24 regulates sorafenib resistance by activating autophagy in HCC. CD24 overexpression increases PP2A protein production and induces deactivation of the mTOR/AKT pathway, which enhances autophagy. Depletion of CD24 or inhibition of autophagy (pharmacologically or by autophagy gene knockdown) restores sorafenib sensitivity.\",\n      \"method\": \"siRNA knockdown, overexpression, pharmacological autophagy inhibitors, essential autophagy gene knockdown, Western blotting for mTOR/AKT pathway\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent methods of autophagy inhibition (pharmacological + genetic) plus pathway analysis, single lab\",\n      \"pmids\": [\"29844385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD24 recruits PTEN to the lipid raft domain and regulates the PTEN/AKT/mTORC1 pathway to activate autophagy, thereby impairing retinoblastoma cell sensitivity to vincristine. Lipid raft localization of CD24 was essential for this PTEN recruitment function.\",\n      \"method\": \"Overexpression, siRNA knockdown, lipid raft fractionation, pathway analysis (PTEN/AKT/mTORC1), cell viability assays\",\n      \"journal\": \"Molecular Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lipid raft fractionation showing PTEN recruitment, pathway analysis with multiple readouts, single lab\",\n      \"pmids\": [\"32394616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Siglec-G expression on host antigen-presenting cells negatively regulates graft-versus-host disease. The interaction between Siglec-G on host APCs and CD24 on donor T cells attenuates GVHD. Rescue experiments with CD24 fusion protein and Siglec-G/CD24 knockout chimeric animals demonstrated that enhancing the CD24-Siglec-G interaction mitigates GVHD.\",\n      \"method\": \"Knockout mouse models (Siglec-G and CD24 KO), chimeric animals, CD24 fusion protein rescue experiments, multiple clinically relevant murine GVHD models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO models, chimeric animals, and pharmacological rescue in multiple disease models\",\n      \"pmids\": [\"24695850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NFAT5 transcription factor binds to the CD24 promoter in response to hypertonicity, facilitating local chromatin derepression and enhancing CD24 mRNA and protein expression. CD24 is required to sustain T cell expansion under osmostress.\",\n      \"method\": \"NFAT5 knockout mice, ChIP (NFAT5 binding to Cd24 promoter), ex vivo T cell culture under hypernatremic conditions, chromatin accessibility assay\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, KO phenotype, chromatin derepression analysis, single lab\",\n      \"pmids\": [\"21037089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NDRG2 negatively regulates CD24 expression in HCC cells; NDRG2 upregulation decreases CD24 expression and reduces cell adhesion, migration, and invasion, while NDRG2 downregulation increases CD24 expression and promotes these processes.\",\n      \"method\": \"Adenoviral NDRG2 overexpression, siRNA knockdown, cell adhesion/migration/invasion assays, Western blotting\",\n      \"journal\": \"BMC Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional manipulation (OE and KD) with defined phenotypic readouts and clinical tissue validation, single lab\",\n      \"pmids\": [\"21676268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD24 expression in urothelial carcinoma is regulated by androgen receptor; androgen receptor knockdown suppresses CD24 expression and cell proliferation, androgen treatment increases CD24 promoter activity in an AR-dependent manner, and androgen deprivation reduces xenograft growth and CD24 expression, which is rescued by exogenous CD24 overexpression.\",\n      \"method\": \"AR knockdown, CD24 promoter activity assays, androgen treatment, xenograft mouse model with CD24 rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assay, in vivo rescue experiment, genetic knockdown, single lab\",\n      \"pmids\": [\"23012401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nucleophosmin/B23 (NPM) induces CD24 expression in endometrial cancer cells via the Sp1 binding site in the CD24 promoter. NPM/B23 silencing reduces CD24 surface expression and enhances macrophage-mediated phagocytosis; restoration of CD24 in NPM/B23-silenced cells inhibits phagocytosis, confirming that NPM drives immune evasion through CD24.\",\n      \"method\": \"siRNA knockdown, promoter assays with Sp1 site mutants, oligonucleotide microarray, phagocytosis assays\",\n      \"journal\": \"Journal of Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis identifying Sp1 site, rescue experiment, phagocytosis functional readout, single lab\",\n      \"pmids\": [\"33954835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Translocation of CD24 from the cytosol to the cell membrane is a triggering event for phenotype change and drug resistance acquisition in breast cancer cells. Cytosolic-to-membrane translocation of CD24 correlates with strong and continuous p38 MAPK phosphorylation and subsequent Bcl-2 overexpression, enabling cells to enter slow cell cycle and survive drug stress.\",\n      \"method\": \"Subcellular fractionation/immunofluorescence tracking of CD24 localization, p38 MAPK inhibitor experiments, Western blotting, phenotype switching assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments tied to functional consequence (drug resistance), pharmacological validation, single lab\",\n      \"pmids\": [\"34426608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD24 in granulosa cells is associated with hCG-induced upregulation of prostaglandin synthase genes (ARK1C1, PTGS2, PTGES, PLA2G4A) and prostaglandin transporters through supporting the EGFR-ERK1/2 pathway, mediating ovulation. The fraction of CD24+ cumulus GCs decreases in PCOS patients compared to controls.\",\n      \"method\": \"Single-cell RNA sequencing, hCG treatment of cultured GCs, functional pathway analysis of EGFR-ERK1/2 signaling\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway association from transcriptomics and hCG treatment, single lab, limited mechanistic validation\",\n      \"pmids\": [\"31624236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Knockdown of CD24 in oral epithelial cells reduces E-cadherin expression and upregulates Snail, Twist, and TGF-β3. Anti-CD24 antibody stimulation induces upregulated E-cadherin and downregulated TGF-β3 expression, suggesting CD24 modulates epithelial differentiation gene programs.\",\n      \"method\": \"RNAi knockdown, anti-CD24 antibody stimulation, real-time RT-PCR\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method approach (RT-PCR readout), single lab, no direct mechanistic pathway identified\",\n      \"pmids\": [\"16930538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In JAK2V617F MPN, granulocyte-macrophage colony-stimulating factor drives JAK2-STAT5-dependent upregulation of CD24 on neutrophils, enabling them to evade efferocytosis (macrophage clearance). CD24-hi neutrophils invade megakaryocytes (emperipolesis) and increase active TGF-β, promoting myelofibrosis. Chronic CD24 antibody blockade or CD24 genetic loss restores neutrophil clearance, reduces emperipolesis and active TGF-β, and prevents myelofibrosis in mouse models.\",\n      \"method\": \"JAK2V617F mouse models, CD24 genetic knockout, chronic antibody blockade, mechanistic pathway analysis (GM-CSF-JAK2-STAT5-CD24), in vivo imaging and histology\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological perturbation, defined signaling pathway (GM-CSF-JAK2-STAT5), multiple orthogonal readouts, in vivo rescue\",\n      \"pmids\": [\"40373279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPAA1 (GPI anchor attachment 1), identified in a genome-wide CRISPR knockout screen, is required for CD24 cell surface expression; genetic ablation of GPAA1 abolishes CD24 surface expression and enhances macrophage-mediated phagocytosis. Bestatin (an aminopeptidase inhibitor) binds GPAA1, blocks GPI anchor attachment to CD24, reduces CD24 surface expression, and suppresses ovarian tumor growth.\",\n      \"method\": \"Genome-wide CRISPR KO screen, GPAA1 genetic ablation, bestatin drug treatment, phagocytosis assays, in vivo tumor growth\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — unbiased genome-wide screen, genetic validation, pharmacological drug-target binding, in vivo efficacy, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38573857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNA promoter methylation and ERG regulate CD24 expression in prostate cancer. ERG overexpression via TMPRSS2:ERG fusion strongly induces CD24 mRNA and protein. Luciferase promoter assays with wild-type versus mutated ERG binding site in the CD24 promoter confirmed ERG-dependent transcriptional activation of CD24.\",\n      \"method\": \"Quantitative methylation-specific PCR, ERG-inducible cell model, luciferase promoter assays with ERG binding site mutation, immunohistochemistry\",\n      \"journal\": \"The American Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis with reporter assay, inducible ERG model, clinical tissue validation, single lab\",\n      \"pmids\": [\"33485866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Heparanase consistently upregulates CD24 expression (including via a splice variant devoid of enzymatic activity), and CD24 overexpression stimulates glioma cell migration, invasion, colony formation, and tumor growth in mice. Anti-CD24 neutralizing antibody attenuates glioma tumor growth, and a similar effect is seen with anti-L1CAM antibody (a CD24 ligand), revealing a heparanase-CD24-L1CAM axis.\",\n      \"method\": \"Inducible (Tet-on) heparanase overexpression, gene array, CD24 overexpression, anti-CD24/anti-L1CAM neutralizing antibody treatment, in vivo tumor growth\",\n      \"journal\": \"International Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gene array plus functional validation (OE, antibody blockade, in vivo), single lab\",\n      \"pmids\": [\"31032901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SOX2 transactivates CD24 expression in embryonal carcinoma cells, as demonstrated by luciferase reporter assays. Co-immunoprecipitation followed by mass spectrometry identified direct CD24 interaction partners involved in cell adhesion, ATP binding, phosphoprotein binding, histone acetylation, and ubiquitination.\",\n      \"method\": \"Luciferase reporter assays, co-immunoprecipitation followed by mass spectrometry, N- and O-glycosylation analysis by enzymatic digestion and mass spectrometry\",\n      \"journal\": \"The FEBS Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay for SOX2 transactivation, CoIP-MS for interaction partners, multiple biochemical methods, single lab\",\n      \"pmids\": [\"37254618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Downregulation of CD24 in hippocampal neurons after traumatic brain injury significantly inhibits phosphorylation of SHP2 and reduces the number of DCX-positive newborn neurons in the dentate gyrus, impairing cognitive functions. CD24 expression is required to support post-traumatic neurogenesis via the SHP2 signaling pathway.\",\n      \"method\": \"RNA interference in vivo, Western blotting, immunofluorescence, Morris water maze behavioral testing\",\n      \"journal\": \"The Journal of Surgical Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vivo RNAi approach, correlation-based pathway inference (SHP2 phosphorylation), single lab\",\n      \"pmids\": [\"31421380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CLL cells suppress CAR T-cell function through CD24 (and CD52) expressed on CLL cells interacting with Siglec-10 on T cells. CD40 stimulation of CLL cells downregulates CD24 and CD52 expression, and blocking CD24 and/or CD52 markedly reduces CAR T-cell dysfunction upon coculture with resting CLL cells.\",\n      \"method\": \"Co-culture of CLL and T cells, CD40 stimulation, CD24/CD52 blocking antibodies, transcriptome profiling, kinase inhibition with dasatinib, flow cytometry\",\n      \"journal\": \"Blood Advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blockade with defined functional readout (T cell dysfunction), transcriptome profiling, pharmacological validation, single lab\",\n      \"pmids\": [\"39042920\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD24 is a GPI-anchored, heavily glycosylated cell surface protein that functions as a context-dependent signaling molecule and innate immune checkpoint: on immune and stromal cells it binds HMGB1/HSP70/HSP90 (DAMPs) and engages Siglec-G/10 (or Siglec-E in metabolic contexts) to recruit SHP-1/SHP-2 and suppress NF-κB-driven inflammatory responses to tissue damage; on tumor cells it delivers a 'don't eat me' signal to macrophages via Siglec-10, evading phagocytosis; intracellularly, CD24 disrupts the ARF-NPM interaction to promote MDM2-mediated p53 inactivation; it also promotes tumor cell proliferation, migration, and drug resistance through activation of Src/STAT3, MAPK, and PTEN/AKT/mTOR pathways, recruits β1-integrins into lipid rafts to enhance contractile force generation and invasion, stabilizes EGFR by inhibiting its degradation via RhoA, and is itself transcriptionally regulated by androgen receptor, ERG, NFAT5, NPM/B23 (via Sp1), and heparanase, while its surface expression requires GPI anchor attachment catalyzed by GPAA1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD24 is a GPI-anchored cell-surface glycoprotein that functions as a context-dependent innate immune checkpoint and a pro-oncogenic signaling hub [#0, #1]. As a regulator of innate immunity, CD24 binds the danger-associated molecular patterns HMGB1, HSP70, and HSP90 and engages the inhibitory receptor Siglec-10 (human) or Siglec-G (mouse) to selectively dampen NF-\\u03baB-driven responses to tissue damage without affecting responses to pathogens [#0]; this same axis recruits SHP-1 to repress obesity-associated metaflammation through Siglec-E [#7] and attenuates graft-versus-host disease via host Siglec-G engaging donor T-cell CD24 [#11]. On tumor cells, the CD24\\u2013Siglec-10 interaction transmits a 'don't eat me' signal that suppresses macrophage phagocytosis, and its genetic or antibody-mediated blockade restores phagocytosis and limits tumor growth [#1]; analogous CD24-dependent evasion of myeloid clearance drives JAK2V617F myelofibrosis and CLL-mediated CAR T-cell dysfunction [#19, #25]. CD24 also acts as a positive driver of tumor proliferation, survival, invasion, and drug resistance, recruiting Src and \\u03b21-integrins into lipid rafts to enhance contractile force generation and invasion [#3, #4], stabilizing EGFR by blocking its RhoA-dependent internalization to sustain ERK/Akt signaling [#5], activating ERK/p38 MAPK and STAT3 to promote proliferation and survival [#6, #8], and recruiting PTEN to lipid rafts to modulate AKT/mTOR-dependent autophagy and chemoresistance [#9, #10]. Intracellularly, CD24 competitively disrupts the ARF\\u2013nucleophosmin interaction to lower ARF, raise MDM2, and inactivate p53/p21 [#2]. CD24 expression is transcriptionally controlled by androgen receptor, ERG, NFAT5, NPM/B23 (via Sp1), SOX2, and heparanase [#12, #14, #15, #21, #22, #23], and its surface display requires GPI-anchor attachment catalyzed by GPAA1 [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established CD24 as a selective innate immune checkpoint by showing it discriminates danger from pathogen signals, answering how the immune system avoids excessive inflammation to self-derived tissue damage.\",\n      \"evidence\": \"Co-IP with HMGB1/HSP70/HSP90, CD24-deficient mouse phenotype, and genetic epistasis with Siglec-G/10 in human and mouse systems\",\n      \"pmids\": [\"19264983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether the same axis operates in tumor immune evasion\", \"Structural basis of CD24 glycan recognition by Siglec-10/G not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a biophysical mechanism for CD24-driven invasion, showing CD24 organizes \\u03b21-integrins and force-generating machinery rather than acting only as a marker.\",\n      \"evidence\": \"Stable transfection/knockdown, Fourier transform traction microscopy, 3D ECM invasion assays, and Src/STAT3/ROCK/MLCK pharmacological inhibition\",\n      \"pmids\": [\"21828044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct CD24\\u2013\\u03b21-integrin association not biochemically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected CD24 to canonical oncogenic kinase signaling by linking it to Src/FAK/STAT3 activation within lipid rafts.\",\n      \"evidence\": \"siRNA knockdown, overexpression, reporter assays, lipid raft fractionation, and xenograft antibody treatment\",\n      \"pmids\": [\"22760497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which a GPI-anchored protein activates intracellular Src not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed an unexpected intracellular role for CD24 in p53 control, showing it competitively disrupts the ARF\\u2013NPM interaction to inactivate p53 across mutational and viral oncogene contexts.\",\n      \"evidence\": \"shRNA silencing, targeted mutation, reciprocal Co-IP, competitive binding assays, and in vivo prostate cancer models\",\n      \"pmids\": [\"25600590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a predominantly surface/GPI-anchored protein accesses nucleophosmin not mechanistically explained\", \"Stoichiometry of CD24 competition with ARF unquantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CD24 stabilizes EGFR to sustain mitogenic signaling, answering how CD24 amplifies growth-factor responses.\",\n      \"evidence\": \"Co-IP, RhoA pulldown, knockdown/overexpression, immunofluorescence trafficking, and wound-healing assays in gastric cancer cells\",\n      \"pmids\": [\"26830684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RhoA linkage to CD24 mechanistically indirect\", \"Single lab and tumor type\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the CD24\\u2013Siglec-10 axis into a therapeutically actionable macrophage 'don't eat me' checkpoint on tumor cells.\",\n      \"evidence\": \"CRISPR/genetic ablation, monoclonal antibody blockade, phagocytosis assays, and in vivo tumor growth/survival across multiple tumor types\",\n      \"pmids\": [\"31367043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define glycan determinants required for Siglec-10 engagement\", \"Contribution relative to other phagocytosis checkpoints not delineated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended CD24\\u2013Siglec inhibitory signaling beyond cancer to metabolic disease, identifying Siglec-E and SHP-1 as the relevant effectors in metaflammation.\",\n      \"evidence\": \"Multiple single/combined Cd24 and Siglec mouse mutants, CD24Fc pharmacological rescue, SHP-1 recruitment analysis, and a human clinical cohort\",\n      \"pmids\": [\"35921817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell types responsible for Siglec-E-dependent suppression not fully assigned\", \"Sialylation determinants on CD24 not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked CD24 to chemoresistance through autophagy, showing CD24 raises PP2A and deactivates mTOR/AKT to enhance protective autophagy.\",\n      \"evidence\": \"Knockdown/overexpression, pharmacological and genetic autophagy inhibition, and mTOR/AKT pathway analysis in sorafenib-resistant HCC\",\n      \"pmids\": [\"29844385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CD24 increases PP2A unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a lipid-raft-dependent CD24\\u2013PTEN module controlling AKT/mTORC1 and autophagy-mediated drug resistance.\",\n      \"evidence\": \"Overexpression/knockdown, lipid raft fractionation showing PTEN recruitment, and PTEN/AKT/mTORC1 pathway analysis in retinoblastoma cells\",\n      \"pmids\": [\"32394616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect CD24\\u2013PTEN association not established\", \"Single lab and tumor type\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected CD24 subcellular localization to phenotypic plasticity, showing cytosol-to-membrane translocation drives p38/Bcl-2-mediated drug-tolerant states.\",\n      \"evidence\": \"Subcellular fractionation/immunofluorescence localization tracking and p38 inhibitor experiments in breast cancer cells\",\n      \"pmids\": [\"34426608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger and machinery for translocation not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified upstream transcriptional regulators (ERG, NPM/B23 via Sp1) controlling CD24 levels and immune evasion.\",\n      \"evidence\": \"ERG-inducible models and Sp1-site promoter mutagenesis with luciferase reporters, plus phagocytosis rescue assays\",\n      \"pmids\": [\"33485866\", \"33954835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay among the multiple regulators in vivo not integrated\", \"Tissue specificity of each regulator not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pinpointed the biosynthetic requirement for CD24 surface display, identifying GPAA1-mediated GPI anchoring as a druggable node.\",\n      \"evidence\": \"Genome-wide CRISPR KO screen, GPAA1 ablation, bestatin drug-target binding, phagocytosis assays, and in vivo ovarian tumor growth\",\n      \"pmids\": [\"38573857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of bestatin/GPAA1 inhibition for CD24 over other GPI-anchored proteins not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated CD24-mediated evasion of myeloid clearance in non-solid disease, defining a GM-CSF\\u2013JAK2\\u2013STAT5\\u2013CD24 axis driving myelofibrosis.\",\n      \"evidence\": \"JAK2V617F mouse models, CD24 knockout, chronic antibody blockade, and in vivo imaging/histology\",\n      \"pmids\": [\"40373279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the effector Siglec receptor mirrors the tumor Siglec-10 axis not specified here\", \"Human MPN validation limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CD24's glycosylation state quantitatively dictates Siglec receptor choice and downstream phosphatase selection (SHP-1 vs SHP-2) across immune, metabolic, and tumor contexts, and how its surface signaling is mechanistically coupled to its reported intracellular ARF/NPM and PTEN functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CD24 glycan\\u2013Siglec recognition\", \"Mechanism connecting GPI-anchored surface CD24 to intracellular p53 and PTEN regulation undefined\", \"Rules governing tissue-specific Siglec partner selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 7, 11]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 4, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 7, 11, 19, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 9, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\"lipid raft\"],\n    \"partners\": [\"SIGLEC10\", \"SIGLECG\", \"SIGLECE\", \"HMGB1\", \"EGFR\", \"ITGB1\", \"NPM1\", \"L1CAM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}