{"gene":"ANXA1","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2003,"finding":"Anx-A1 is required for glucocorticoid-mediated inhibition of eicosanoid generation and cell proliferation; Anx-A1-/- lung fibroblasts overexpress COX-2, cytosolic PLA2, and secretory PLA2, and are refractory to dexamethasone inhibition of serum-induced progression from G0/G1 to S phase, despite normal glucocorticoid receptor expression.","method":"Anx-A1(-/-) mouse-derived cell lines; comparative biochemical analysis of COX-2, PLA2 expression; cell cycle analysis; dexamethasone treatment with/without glucocorticoid receptor assessment","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO cell line with multiple orthogonal readouts (eicosanoid release, cell cycle, COX-2, PLA2 expression) in a single focused study","pmids":["12553880"],"is_preprint":false},{"year":2009,"finding":"Glucocorticoids activate PKCα/β, which phosphorylates ANXA1 on Ser27, driving its accumulation at the plasma membrane and subsequent externalization, thereby inhibiting thromboxane B2 generation; cromoglycate drugs enhance this pathway by inhibiting the PP2A phosphatase that otherwise limits ANXA1 release.","method":"Biochemical assays, epifluorescence and electron microscopy in U937 cells; PKC activation assay; PP2A inhibition; thromboxane B2 measurement by RIA","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (biochemistry, epifluorescence, EM, functional assay) in a single focused mechanistic study","pmids":["19428336"],"is_preprint":false},{"year":2014,"finding":"In melanoma cells, externalized full-length ANXA1 is cleaved by a membrane-associated serine protease at a site between Ser28 and Lys29, releasing a pro-invasive N-terminal peptide (ANXA1 2-28) that activates formyl peptide receptors; ANXA1-driven invasion is mediated through MAPK and STAT3 pathways and leads to MMP2 induction.","method":"Proteomic/biochemical characterization of cleavage site; cell invasion assays; pharmacological inhibition of MAPK and STAT3; conditioned medium experiments in melanoma cell lines","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification of cleavage site plus functional pathway inhibition, single lab","pmids":["25362540"],"is_preprint":false},{"year":2016,"finding":"ANXA1 loss-of-function activates ANXA1 expression downstream of ARID1A loss, and ANXA1 then activates AKT signaling to confer resistance to HER2/PI3K/mTOR-targeting drugs including trastuzumab in HER2+ breast cancer cells.","method":"Genome-wide loss-of-function genetic screen; shRNA knockdown; pharmacological rescue with AKT inhibitor MK2206; gene expression analysis; validated in two independent clinical cohorts","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional genetic screen, mechanistic validation with pharmacological rescue, replicated in two independent patient cohorts","pmids":["27172896"],"is_preprint":false},{"year":2016,"finding":"ANXA1 suppresses oncogenic miR-196a biogenesis by stimulating c-Myc and NF-κB expression in breast cancer cells; miR-196a reciprocally targets the ANXA1 3'UTR to directly inhibit ANXA1 expression, forming a negative feedback loop that regulates cell proliferation.","method":"miRNA biogenesis assays; c-Myc/NF-κB expression and activity measurements; luciferase reporter assay for miR-196a targeting of ANXA1; gain/loss-of-function cell proliferation assays; in vivo tumor growth","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus functional gain/loss studies and in vivo validation, single lab","pmids":["27105503"],"is_preprint":false},{"year":2016,"finding":"ANXA1 modulates Th1/Th2 differentiation in CD4+ T cells by regulating GATA-3 expression through the FPR (FPRL-1) downstream ERK and PKB/Akt signaling pathways; conversely, GATA-3 inhibits ANXA1 expression by binding to its promoter.","method":"ANXA1 overexpression and knockdown in T cells; cytokine measurements (IFN-γ, IL-4); western blot for GATA-3/T-bet; pharmacological pathway inhibition; chromatin binding assay for GATA-3 on ANXA1 promoter","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional gain/loss with cytokine readout plus promoter-binding experiment, single lab","pmids":["27833268"],"is_preprint":false},{"year":2018,"finding":"AnxA1 establishes an autocrine signaling loop in triple-negative breast cancer MDA-MB-231 cells via secreted ANXA1 binding to FPR1, which increases cell aggressiveness and survival; pharmacological inhibition of FPR1 (Cyclosporin H or Cyclosporin A) reduces tumor growth and metastasis in nude mice.","method":"FPR1 inhibitor treatment (Cyclosporin H, Cyclosporin A); ANXA1 secretion quantification; cell aggressiveness assays in vitro; in vivo tumor growth and metastasis in nude mice; tissue microarray correlation of ANXA1 and FPR1","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with in vitro and in vivo validation, single lab","pmids":["29932988"],"is_preprint":false},{"year":2019,"finding":"AnxA1 acts directly on platelets via FPR2/ALX, suppressing thrombin-induced Akt activation, intracellular calcium release, and Rap1 expression, thereby decreasing αIIbβ3 integrin activation (without altering surface expression) and reducing platelet aggregation and thrombus formation in cerebral ischemia-reperfusion injury.","method":"AnxA1-/- mice; intravital microscopy; pharmacological treatment with AnxA1 and FPR2/ALX antagonist WRW4; thromboxane B2 measurement; phosphatidylserine expression assay; Akt/calcium/Rap1 signaling assays in human platelets","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice plus pharmacological rescue, multiple orthogonal in vivo and in vitro mechanistic readouts, clinical validation in human samples","pmids":["31154815"],"is_preprint":false},{"year":2019,"finding":"ANXA1 upregulation in colorectal cancer cells in response to hydrodynamic stress promotes cancer cell cluster growth via downstream activation of the PI3K/AKT signaling pathway.","method":"Microarray analysis of stressed cancer tissue-originated spheroids (CTOS); ANXA1 knockdown; PI3K/AKT pathway inhibition; growth assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — knockdown plus pathway inhibition in patient-derived organoid model, single lab","pmids":["31882967"],"is_preprint":false},{"year":2020,"finding":"ANXA1 binds directly to EphA2 (via amino acid residues 20–30 and 28–30 of its N-terminus) and competes with the E3 ubiquitin ligase Cbl, thereby inhibiting Cbl-mediated EphA2 ubiquitination and proteasomal degradation, stabilizing EphA2 and increasing its oncogenic pS897-EphA2 signaling in nasopharyngeal carcinoma.","method":"Co-immunoprecipitation; competitive binding assay with Cbl; ubiquitination assay; mutagenesis mapping of ANXA1 N-terminal binding residues; EphA2 stability assays; in vitro and in vivo tumor growth assays; ANXA1-derived peptide disruption experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, competitive ubiquitination assay, mutagenesis mapping of binding domain, peptide disruption, in vivo validation—multiple orthogonal methods in one study","pmids":["32737118"],"is_preprint":false},{"year":2020,"finding":"ANXA1 interaction with ANXA4 mediates JAK-STAT3 signaling activation in basal-like breast cancer: ANXA4 directly binds ANXA1 (co-IP confirmed), and ANXA1 knockdown reduces JAK1 expression and STAT3 phosphorylation (Y705), impairing ANXA4-induced JAK-STAT3 activation.","method":"Co-immunoprecipitation; ANXA1 knockdown; JAK1 expression and STAT3 phosphorylation western blot; colocalization by immunofluorescence; in vivo tumor model","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP confirmed interaction plus knockdown epistasis, single lab","pmids":["32552056"],"is_preprint":false},{"year":2020,"finding":"ANXA1 directs Schwann cell proliferation and migration after peripheral nerve injury by activating formyl peptide receptor 2 (FPR2) and its downstream AMPK signaling cascade; Schwann cells lacking FPR2 or AMPK show defects in proliferation and migration, and ANXA1 promotes nerve regeneration in vivo.","method":"FPR2/AMPK knockdown in Schwann cells; proliferation and migration assays; facial nerve crush injury model; in vivo remyelination assessment","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor and kinase knockdown epistasis with in vitro and in vivo functional readouts, single lab","pmids":["32856352"],"is_preprint":false},{"year":2021,"finding":"AnxA1Ac2-26 (ANXA1 mimetic peptide) regulates SCD neutrophils through the FPR2/ALX pathway, activating Akt and ERK1/2 to enable resolution of cerebral thromboinflammatory responses in sickle cell disease mice.","method":"Sickle transgenic mice; pharmacological administration of AnxA1Ac2-26; FPR2/ALX pathway modulation; Akt and ERK1/2 signaling analysis; intravital microscopy of cerebral thrombosis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model plus signaling pathway analysis, single lab","pmids":["33512489"],"is_preprint":false},{"year":2021,"finding":"ANXA1 in vascular smooth muscle cells prevents acute aortic dissection by maintaining the contractile phenotype via the JunB/MYL9 pathway; ANXA1 deficiency triggers VSMC synthetic phenotype switch, elevating inflammation and MMP production leading to elastin degradation.","method":"Anxa1-/- global and VSMC-restricted conditional knockout mice; transcriptomic analysis; micro-CT; immunohistochemistry; Ac2-26 rescue experiment; validation in human AAD specimens","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO, transcriptomics, pharmacological rescue, human tissue validation—replicated mechanistic pathway","pmids":["33757117"],"is_preprint":false},{"year":2021,"finding":"ANXA1 directly binds the intracellular domain of Notch1 (NICD) and targets it for degradation, suppressing Notch1-mediated p15 promoter activation and thereby promoting AML cell proliferation.","method":"Co-immunoprecipitation; NICD stability assays; luciferase reporter for p15 promoter; ANXA1 knockdown/overexpression; NICD inhibitory peptide; patient sample correlation analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assay, peptide disruption, loss-of-function, single lab","pmids":["39447086"],"is_preprint":false},{"year":2021,"finding":"A novel homozygous missense variant in ANXA1 causes autosomal recessive parkinsonism; the variant impairs phagocytosis in zebrafish mutant embryos, linking ANXA1 to microglial clearance of aggregated proteins.","method":"Homozygosity mapping; whole genome sequencing; zebrafish morpholino/mutant phagocytosis assay","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mapping plus in vivo functional validation in zebrafish, single study","pmids":["34180078"],"is_preprint":false},{"year":2022,"finding":"FMDV viral protein 3A interacts with ANXA1 and inhibits ANXA1-TBK1 complex formation, thereby blocking ANXA1-promoted IFN-β production; endogenous ANXA1 promotes RNA virus-stimulated IFN-β production through the TBK1-IRF3 axis (not NF-κB), and ANXA1 also interacts with JAK1 and STAT1 to strengthen IFN-β/IFN-γ signal transduction.","method":"Co-immunoprecipitation; ANXA1-/- knockout cells; IFN-β production assays; IRF3 and NF-κB pathway dissection; ANXA1-3A interaction mapping; JAK1/STAT1 co-IP","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO cells, Co-IP of multiple partners, pathway dissection with orthogonal readouts in one focused study","pmids":["35604142"],"is_preprint":false},{"year":2022,"finding":"ANXA1 interacts with GSK3β (confirmed by GST pulldown and Co-IP), negatively regulates GSK3β phosphorylation, and thereby inhibits EMT and suppresses migration and invasion of NSCLC cells.","method":"GST pulldown; co-immunoprecipitation in H1299 and A549 cells; GSK3β phosphorylation assay; functional rescue assay for EMT/migration/invasion","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown/Co-IP plus functional rescue, single lab","pmids":["34002210"],"is_preprint":false},{"year":2022,"finding":"E2F1-transcribed serine protease PRSS22 physically interacts with ANXA1 (confirmed by mass spectrometry and Co-IP), cleaves ANXA1 to generate an N-terminal peptide that activates the FPR2/ERK signaling axis, promoting breast cancer cell invasion and metastasis.","method":"Protein mass spectrometry; co-immunoprecipitation; cleavage assay; FPR2/ERK signaling analysis; ChIP for E2F1 on PRSS22 promoter; in vitro and in vivo metastasis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, protease cleavage assay, signaling pathway validation, single lab","pmids":["36414640"],"is_preprint":false},{"year":2022,"finding":"CYP2J2 upregulates METTL3, which promotes ANXA1 translation via m6A modification of ANXA1 mRNA; ANXA1 is required for maintenance of endothelial tight junction/adherens junction distribution and blood-retinal barrier integrity under oxidative stress.","method":"CYP2J2 overexpression; METTL3 knockdown; MeRIP-qPCR for m6A on ANXA1 mRNA; endothelial ANXA1 conditional deletion; tight junction fractionation; BRB integrity assay in ischemia-reperfusion model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A modification mapped by MeRIP, conditional KO with functional BRB readout, single lab","pmids":["36269280"],"is_preprint":false},{"year":2023,"finding":"ANXA1 acts as a sponge that sequesters PARP1, preventing PARP1 from binding and poly(ADP-ribosyl)ating Stat3; reduced PARP1-Stat3 interaction decreases Stat3 dephosphorylation and thereby increases Stat3 transcriptional activity, leading to upregulated PD-L1 expression and cancer immune evasion.","method":"Co-immunoprecipitation of ANXA1-PARP1 and PARP1-Stat3; ANXA1 knockdown; PARylation assay of Stat3; Stat3 phosphorylation/dephosphorylation analysis; PD-L1 expression; T cell killing assay; in vivo immune-competent mouse tumor model","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, PARylation mechanistic assay, multiple cancer cell lines, in vivo validation, single lab with multiple orthogonal methods","pmids":["37566399"],"is_preprint":false},{"year":2023,"finding":"An ANXA1-derived peptide A11 competes with deubiquitinase USP7 for binding PD-L1, preventing USP7-mediated PD-L1 deubiquitination and thereby promoting PD-L1 proteasomal degradation in breast, lung, and melanoma cancer cells.","method":"Biotin pull-down coupled with mass spectrometry; human deubiquitinase cDNA library screen to identify USP7; competitive binding assay (A11 vs USP7 for PD-L1); ubiquitination/deubiquitination assays; T cell killing assay; in vivo mouse tumor model with immune competent mice","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-identified interaction, library screen, competitive biochemical assay, ubiquitination mechanistic assay, in vivo validation, multiple orthogonal methods","pmids":["37001908"],"is_preprint":false},{"year":2023,"finding":"Tat-NTS peptide shifts ANXA1 subcellular localization in microglia from the nucleus to the cytoplasm after ischemic injury; this shift increases ANXA1 SUMOylation, which mediates IKKα degradation via NBR1-dependent selective autophagy, blocking NF-κB pathway activation and reducing pro-inflammatory cytokine (IL-1β, TNF-α) production.","method":"Confocal imaging with 3D reconstruction; Co-IP; immunoblotting; ELISA; luciferase reporter assay for NF-κB; AAV-mediated Cre-conditional manipulation in Cx3cr1-Cre mice; MCAO stroke model; behavioral tests; TEM","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods (Co-IP, localization, autophagy pathway, conditional AAV KO, behavioral outcomes) in a single mechanistic study","pmids":["37908731"],"is_preprint":false},{"year":2023,"finding":"SBSN interacts with ANXA1, and this interaction promotes Lys63-linked and Met1-linear polyubiquitination of NEMO, activating NF-κB signaling to drive glioma cell aggressiveness.","method":"Co-immunoprecipitation of SBSN-ANXA1-NEMO; ubiquitin-linkage-specific assays; in vivo tumor assay; EV transfer experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with downstream ubiquitination assay and in vivo validation, single lab","pmids":["36316443"],"is_preprint":false},{"year":2021,"finding":"ANXA1 interacts with TNFR1 (confirmed by Co-IP) and promotes glioma cell growth by activating the p65 and Akt signaling pathways downstream of TNF-α stimulation.","method":"Co-immunoprecipitation; ANXA1 knockdown/overexpression; p65 and Akt pathway western blot; CCK-8 proliferation assay; immunofluorescence","journal":"Open life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus functional assay, single lab, limited mechanistic depth","pmids":["35415239"],"is_preprint":false},{"year":2021,"finding":"ANXA1 is required for KIAA1199-mediated extracellular hyaluronic acid degradation on the surface of rheumatoid arthritis fibroblast-like synoviocytes: the G8 domain of KIAA1199 binds ANXA1 on the cell membrane to anchor KIAA1199, and deletion of this domain abolishes HA-degrading activity in vivo.","method":"Co-IP of KIAA1199 G8 domain with ANXA1; G8-deleted KIAA1199 mutant intra-articular injection in kiaa1199-KO mice; HA degradation assays; CIA mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping Co-IP, in vivo rescue with wild-type vs. G8-deleted mutant, single lab","pmids":["33473125"],"is_preprint":false},{"year":2022,"finding":"ANXA1 reduction in macrophages in a diabetic periodontitis environment is associated with activation of the NLRP3/Caspase-1/GSDMD signaling pathway and increased macrophage pyroptosis; the ANXA1 mimetic peptide Ac2-26 reduces macrophage pyroptosis via this pathway.","method":"Western blot for NLRP3/Caspase-1/GSDMD in diabetic periodontitis macrophages; Ac2-26 peptide treatment; in vivo diabetic rat periodontitis model; ROS/pH-responsive hydrogel delivery system","journal":"Biofabrication","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway protein expression plus peptide treatment, limited mechanistic dissection, single lab","pmids":["39773706"],"is_preprint":false},{"year":2017,"finding":"In hepatopulmonary syndrome, endothelin-1 reduces ANXA1 protein levels through carbonylation and proteasomal degradation of ANXA1; ANXA1 in turn decreases nuclear pERK1/2 accumulation and cyclin D1 expression, inhibiting pulmonary artery smooth muscle cell proliferation.","method":"Carbonylation assay of ANXA1 protein; proteasome inhibitor rescue; pERK1/2 nuclear fractionation; cyclin D1 western blot; PASMC proliferation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — carbonylation/degradation mechanistic assay plus downstream signaling and proliferation readout, single lab","pmids":["28414743"],"is_preprint":false},{"year":2015,"finding":"ANXA1 overexpression induced by low-concentration arsenic trioxide activates ERK MAPK signaling, rendering cancer cells resistant to ATO; ANXA1 silencing combined with ATO increases apoptosis, and pharmacological ERK inhibition (PD98059) phenocopies ANXA1 silencing.","method":"siRNA knockdown of ANXA1; ERK inhibitor PD98059; MTT proliferation/apoptosis assay; western blot for ERK activation; proteomics screen identifying ANXA1 as ATO-responsive protein","journal":"Tumori","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteomics-identified target, siRNA KD, pharmacological epistasis with ERK inhibitor, single lab","pmids":["25983101"],"is_preprint":false},{"year":2021,"finding":"ANXA1 enhances the immunosuppressive function of Tregs in triple-negative breast cancer and reduces the expression of granzyme A mRNA in Tregs, as assessed by suppressive assays and RNA sequencing; the ANXA1 blocker Boc1 reduces Treg function and tumor size in vivo.","method":"Suppressive assay of Tregs; RNA sequencing after Boc1 treatment; ELISA for plasma ANXA1; in vivo tumor model with Boc1 treatment in BALB/c mice","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNA-seq plus functional suppressive assay and in vivo pharmacological block, single lab","pmids":["32300050"],"is_preprint":false},{"year":2020,"finding":"ANXA1 promotes Schwann cell proliferation and migration through FPR2-AMPK signaling, acting as an extracellular trigger; endothelial ANXA1 promotes choroidal endothelial cell proliferation, migration, and tube formation via FPR2/SHP2 axis-mediated inhibition of NLRP3 inflammasome and pyroptosis.","method":"(For choroidal angiogenesis) FPR2/SHP2 knockdown; NLRP3 inhibition; pyroptosis markers; ARPE-19 and HCEC co-culture; ANXA1 secretion under hypoxia; in vivo CNV model","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — receptor knockdown epistasis plus in vivo CNV model, single lab","pmids":["34595678"],"is_preprint":false},{"year":2025,"finding":"FBXO32 E3 ubiquitin ligase directly ubiquitinates ANXA1, promoting its proteasomal degradation; loss of ANXA1 inhibits PI3K/AKT signaling and exacerbates LPS-induced cardiac injury and apoptosis.","method":"Co-immunoprecipitation; ubiquitination assay; FBXO32 knockdown; ANXA1 knockdown rescue experiment; PI3K/AKT western blot; in vivo and in vitro LPS cardiac injury models","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-confirmed ubiquitination plus epistatic rescue experiment, single lab","pmids":["40126756"],"is_preprint":false},{"year":2020,"finding":"WISP1 recruits ANXA1 as an interaction partner (identified by Co-IP and mass spectrometry) to regulate TGF-β signaling pathway during muscle-derived satellite cell differentiation; WISP1 cannot affect TGF-β signaling markers when ANXA1 is knocked down.","method":"Co-immunoprecipitation; mass spectrometry; ANXA1 knockdown with WISP1 activation; western blot for TGF-β pathway proteins; immunofluorescence","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — Co-IP/MS interaction plus epistatic knockdown, but TGF-β pathway mechanistic detail limited, single lab","pmids":["32458119"],"is_preprint":false},{"year":2010,"finding":"α-MSH inhibits TNF-α-induced maturation of human monocyte-derived dendritic cells through upregulation of ANXA1; specific siRNA knockdown of ANXA1 abolishes the α-MSH inhibitory effect on DC maturation markers (CD83, CD86), IL-12 production, and phagocytic activity.","method":"siRNA knockdown of ANXA1; flow cytometry for CD83/CD86; ELISA for IL-12/IL-10; phagocytosis assay; α-MSH treatment","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — specific siRNA epistasis with multiple functional readouts, single lab","pmids":["21131366"],"is_preprint":false},{"year":2013,"finding":"FoxM1 transcription factor directly transcriptionally activates ANXA1 expression in glioma cells; overexpression of FoxM1 upregulates ANXA1, and FoxM1-driven proliferation, migration, and angiogenesis occur in an ANXA1-dependent manner.","method":"FoxM1 overexpression/knockdown; ChIP or promoter assay for FoxM1 on ANXA1; ANXA1 knockdown rescue; proliferation, migration, angiogenesis assays in vitro and in vivo","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — transcriptional regulation confirmed plus epistatic rescue, single lab","pmids":["23991102"],"is_preprint":false},{"year":2021,"finding":"RRM2 stabilizes ANXA1 protein and activates the AKT pathway independent of its ribonucleotide reductase activity, promoting sunitinib resistance in renal cell carcinoma.","method":"RRM2 knockdown/overexpression; ANXA1 protein stability assays; AKT pathway western blot; sunitinib resistance assays in vitro and in vivo; RRM2 enzymatic-dead mutant","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — enzymatic-dead mutant control plus protein stability and signaling assays, single lab","pmids":["34319001"],"is_preprint":false},{"year":2024,"finding":"The ANXA1-FPR2 axis protects against obesity-associated atrial fibrillation by activating AMPK in cardiomyocytes to enhance fatty acid oxidation and reduce lipid accumulation; AAV9-mediated AMPK knockdown in myocardium reverses the protective effect of Ac2-26 on AF susceptibility in obese mice.","method":"High-fat diet obese mice; AAV9-shAMPK myocardial-specific knockdown; FPR2 inhibitor (Boc-2, WRW4); Ac2-26 peptide administration; fatty acid oxidation assays; in vitro palmitic acid cardiomyocyte model","journal":"Cardiovascular diabetology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic knockdown in vivo plus pharmacological epistasis with in vitro validation, single lab","pmids":["39709478"],"is_preprint":false},{"year":2024,"finding":"CAM-A-induced nuclear aggregation of HBV core protein (HBc) upregulates ANXA1 expression, and ANXA1 directly mediates apoptosis in HBV-infected cells; ANXA1 silencing delays cell death and apoptosis in CAM-A-treated cells.","method":"siRNA knockdown of ANXA1 in HBV-infected differentiated HepaRG cells and HBc-overexpressing HepG2-NTCP cells; transcriptomic analysis; apoptosis markers; primary human hepatocytes","journal":"JHEP reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA epistasis in multiple cell models with apoptosis phenotypic readout plus transcriptomic mechanistic link, single lab","pmids":["39386256"],"is_preprint":false},{"year":2022,"finding":"YTHDC1 (m6A reader) inhibits ANXA1 expression in ccRCC via RNA binding (RIP-qPCR/MeRIP-qPCR), and ANXA1 activates the MAPK pathway downstream; the YY1/HDAC2 epigenetic complex downregulates YTHDC1, which de-represses ANXA1/MAPK signaling and promotes sunitinib resistance.","method":"RIP-qPCR; MeRIP-qPCR; RNA-seq; western blot; HDAC2 inhibitor treatment; xenograft assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — m6A-RIP mechanistic assay plus pharmacological and genetic epistasis, single lab","pmids":["35974388"],"is_preprint":false},{"year":2021,"finding":"ANXA1 from intestinal epithelial cells (IECs) stimulates NKG2A expression on natural killer cells during colitis; NKG2A upregulation on NK cells inhibits neutrophil recruitment and activity, alleviating DSS-induced colitis.","method":"DSS colitis mouse model; ANXA1 overexpression in IECs; NK-IEC co-culture; NKG2A expression measurement; neutrophil infiltration assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-culture and overexpression with NKG2A/neutrophil readout, limited mechanistic dissection of direct ANXA1-NK cell interaction, single lab","pmids":["27435504"],"is_preprint":false},{"year":2023,"finding":"ANXA1 drives glioma immunosuppression via FPR1 signaling: tumor-derived ANXA1 induces M2-like macrophage/microglia polarization through FPR1, establishing a Treg-driven immunosuppressive tumor microenvironment and suppressing the anti-tumor immune response to TLR3 ligand poly(I:C).","method":"In vitro macrophage/microglia polarization assays; FPR1 pharmacological inhibition; in vivo glioma model; clinical trial patient sample analysis (RNA-seq and protein validation)","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological FPR1 inhibition plus in vivo model and clinical sample validation, single lab","pmids":["38049523"],"is_preprint":false}],"current_model":"ANXA1 (Annexin A1) is a calcium- and phospholipid-binding protein that functions as a key mediator of glucocorticoid anti-inflammatory signaling: upon glucocorticoid stimulation, PKCα/β phosphorylates ANXA1 at Ser27, driving its membrane translocation and externalization to suppress eicosanoid (PGE2, TxB2) production via PLA2 inhibition; extracellularly, ANXA1 and its N-terminal-derived peptides (e.g., Ac2-26, generated by membrane serine protease cleavage between Ser28 and Lys29) signal through formyl peptide receptors (FPR1/FPR2/ALX) to suppress platelet activation (via reducing Akt, calcium, Rap1, and αIIbβ3 activation), regulate neutrophil and macrophage phenotype, promote Schwann cell proliferation and nerve regeneration via FPR2/AMPK, and drive inflammation resolution; intracellularly, ANXA1 interacts with multiple proteins including EphA2 (inhibiting Cbl-mediated ubiquitination/degradation), PARP1 (sequestering it from Stat3 to upregulate PD-L1), Notch1 NICD (targeting it for degradation), GSK3β (inhibiting its phosphorylation to block EMT), TBK1 (promoting IRF3-mediated IFN-β production against RNA viruses), and TNFR1, with its own stability regulated by FBXO32-mediated ubiquitination and by RRM2-dependent stabilization; subcellular localization—nuclear vs. cytoplasmic/membrane—is dynamically regulated by SUMOylation and determines its function in microglia during neuroinflammation."},"narrative":{"mechanistic_narrative":"ANXA1 (Annexin A1) is a calcium- and phospholipid-binding protein that serves as a central effector of glucocorticoid anti-inflammatory action and inflammation resolution, with broad additional roles in tumor signaling and tissue protection [PMID:12553880, PMID:19428336]. In its canonical anti-inflammatory mode, ANXA1 is required for glucocorticoid-mediated suppression of eicosanoid generation, since cells lacking it overexpress COX-2 and PLA2 and resist dexamethasone [PMID:12553880]; glucocorticoids drive this through PKCα/β phosphorylation of ANXA1 at Ser27, promoting plasma-membrane accumulation and externalization, a step opposed by PP2A [PMID:19428336]. Externalized ANXA1 is cleaved by membrane-associated serine proteases—including PRSS22—near its N-terminus to release bioactive peptides that signal through formyl peptide receptors (FPR1, FPR2/ALX) [PMID:25362540, PMID:36414640]. Through FPR2/ALX, ANXA1 suppresses platelet activation by blunting thrombin-induced Akt, calcium, Rap1 and αIIbβ3 integrin activation [PMID:31154815], drives Schwann cell proliferation and nerve regeneration via FPR2-AMPK [PMID:32856352], and promotes neutrophil-mediated resolution [PMID:33512489]; via the FPR2-AMPK axis it also protects cardiomyocytes by enhancing fatty acid oxidation [PMID:39709478]. ANXA1 additionally preserves vascular smooth muscle contractile phenotype through JunB/MYL9, guarding against aortic dissection [PMID:33757117]. Intracellularly, ANXA1 acts as a protein-stability and signaling hub: it binds EphA2 to block Cbl-mediated ubiquitination and stabilize oncogenic EphA2 [PMID:32737118], sequesters PARP1 away from STAT3 to raise STAT3 activity and PD-L1 expression [PMID:37566399], binds Notch1 NICD to target it for degradation [PMID:39447086], binds GSK3β to inhibit its phosphorylation and block EMT [PMID:34002210], and promotes TBK1-IRF3-dependent IFN-β production against RNA viruses while reinforcing JAK1/STAT1 signaling [PMID:35604142]. ANXA1 frequently converges on PI3K/AKT signaling to confer therapy resistance and survival across cancers [PMID:27172896, PMID:31882967, PMID:40126756]. Its own abundance is controlled by ubiquitin-dependent turnover (FBXO32) [PMID:40126756], stabilization (RRM2) [PMID:34319001], and m6A-dependent translational regulation (METTL3/YTHDC1) [PMID:36269280, PMID:35974388], while SUMOylation-linked nuclear-to-cytoplasmic shifts govern its inflammatory output in microglia [PMID:37908731]. A homozygous missense ANXA1 variant causes autosomal recessive parkinsonism and impairs microglial phagocytosis [PMID:34180078].","teleology":[{"year":2003,"claim":"Established that ANXA1 is genetically required for glucocorticoid suppression of eicosanoid production and proliferation, moving it from correlate to obligate mediator of glucocorticoid action.","evidence":"Anx-A1 knockout fibroblast lines with COX-2/PLA2 expression and cell-cycle readouts under dexamethasone","pmids":["12553880"],"confidence":"High","gaps":["Did not resolve how ANXA1 mechanistically inhibits PLA2","Receptor/effector mediating the externalized signal not defined here"]},{"year":2009,"claim":"Defined the upstream control of ANXA1 externalization, showing glucocorticoid-driven PKCα/β phosphorylation at Ser27 triggers membrane translocation and release, opposed by PP2A.","evidence":"Biochemistry, epifluorescence and EM in U937 cells with PKC activation, PP2A inhibition, thromboxane B2 assay","pmids":["19428336"],"confidence":"High","gaps":["Mechanism of physical translocation across the membrane not defined","Identity of the externalization machinery unresolved"]},{"year":2014,"claim":"Identified the proteolytic event that converts full-length ANXA1 into a receptor-active peptide, linking externalization to FPR signaling and tumor invasion.","evidence":"Proteomic cleavage-site mapping (Ser28/Lys29) and invasion assays with MAPK/STAT3 inhibition in melanoma cells","pmids":["25362540"],"confidence":"Medium","gaps":["Protease identity not established in this study","In vivo relevance of the peptide not tested"]},{"year":2016,"claim":"Showed ANXA1 drives PI3K/AKT-dependent therapy resistance downstream of ARID1A loss, establishing an oncogenic survival axis in HER2+ breast cancer.","evidence":"Genome-wide loss-of-function screen, shRNA, AKT-inhibitor rescue, two clinical cohorts","pmids":["27172896"],"confidence":"High","gaps":["Direct molecular link from ANXA1 to AKT activation not defined","Whether secreted or intracellular ANXA1 mediates this is unclear"]},{"year":2016,"claim":"Extended ANXA1 immunoregulation to adaptive immunity and microRNA circuits, revealing reciprocal feedback loops controlling its own expression.","evidence":"T-cell GATA-3/FPR signaling assays and a miR-196a/ANXA1 3'UTR luciferase feedback loop in breast cancer cells","pmids":["27833268","27105503"],"confidence":"Medium","gaps":["Direct vs indirect promoter regulation not fully resolved","In vivo contribution of the feedback loop limited"]},{"year":2019,"claim":"Demonstrated direct ANXA1 action on platelets via FPR2/ALX, defining its anti-thrombotic mechanism through suppression of Akt/calcium/Rap1 and integrin inside-out activation.","evidence":"AnxA1-/- mice, intravital microscopy, WRW4 antagonism, human platelet signaling assays in cerebral ischemia-reperfusion","pmids":["31154815"],"confidence":"High","gaps":["Whether full-length or cleaved peptide is the active ligand on platelets not separated","Structural basis of FPR2 engagement unresolved"]},{"year":2020,"claim":"Revealed ANXA1 as an intracellular stability regulator, mapping its N-terminal binding to EphA2 and competition with Cbl that stabilizes oncogenic EphA2 signaling.","evidence":"Co-IP, competitive Cbl/ubiquitination assays, mutagenesis mapping, peptide disruption, in vivo tumor assays","pmids":["32737118"],"confidence":"High","gaps":["Calcium-dependence of the EphA2 interaction not addressed","Generalizability beyond nasopharyngeal carcinoma untested here"]},{"year":2020,"claim":"Expanded ANXA1's FPR2-AMPK signaling role beyond inflammation to Schwann cell-driven nerve regeneration and endothelial angiogenesis.","evidence":"FPR2/AMPK knockdown, proliferation/migration assays, nerve crush model; FPR2/SHP2 axis in choroidal endothelium","pmids":["32856352","34595678"],"confidence":"Medium","gaps":["Source and processing of ANXA1 ligand in these tissues not defined","Direct receptor binding not biochemically demonstrated"]},{"year":2021,"claim":"Established ANXA1 as a tissue-protective factor in vascular smooth muscle, defining the JunB/MYL9 contractile-phenotype pathway preventing aortic dissection.","evidence":"Global and VSMC-conditional Anxa1 knockouts, transcriptomics, Ac2-26 rescue, human AAD specimens","pmids":["33757117"],"confidence":"High","gaps":["Receptor mediating intracellular vs extracellular ANXA1 effect not separated","Upstream trigger of phenotype switch unresolved"]},{"year":2021,"claim":"Linked ANXA1 to a Mendelian neurodegenerative disease, implicating it in microglial phagocytic clearance.","evidence":"Homozygosity mapping, whole-genome sequencing, zebrafish phagocytosis assay","pmids":["34180078"],"confidence":"Medium","gaps":["Molecular mechanism connecting variant to phagocytosis defect not defined","Human neuronal/microglial validation absent"]},{"year":2021,"claim":"Identified post-translational control of ANXA1 abundance via RRM2-dependent stabilization driving AKT-dependent drug resistance.","evidence":"RRM2 enzymatic-dead mutant, protein stability and AKT assays, sunitinib resistance in vitro and in vivo","pmids":["34319001"],"confidence":"Medium","gaps":["Mechanism by which RRM2 stabilizes ANXA1 not defined","Single-lab finding in renal carcinoma"]},{"year":2022,"claim":"Defined ANXA1 as a positive regulator of antiviral interferon, acting through TBK1-IRF3 and reinforcing JAK1/STAT1 signaling, and a target of viral antagonism.","evidence":"ANXA1-/- cells, Co-IP of TBK1/JAK1/STAT1, IFN-β assays, FMDV 3A interaction mapping","pmids":["35604142"],"confidence":"High","gaps":["Whether ANXA1 directly activates TBK1 kinase activity not shown","Structural basis of complex formation undefined"]},{"year":2022,"claim":"Showed ANXA1 binds GSK3β to suppress EMT and identified the protease PRSS22 that cleaves ANXA1 to drive FPR2/ERK metastatic signaling, expanding both intracellular and extracellular tumor mechanisms.","evidence":"GST pulldown/Co-IP with GSK3β functional rescue; MS/Co-IP and cleavage assays for PRSS22 with E2F1 ChIP","pmids":["34002210","36414640"],"confidence":"Medium","gaps":["Reconciliation of ANXA1's opposing pro- and anti-tumor roles unresolved","Direct enzymatic kinetics of PRSS22 cleavage not quantified"]},{"year":2023,"claim":"Revealed an ANXA1-PARP1-STAT3 axis controlling immune evasion, defining ANXA1 as a PARP1 sponge that elevates STAT3 activity and PD-L1.","evidence":"Co-IP of ANXA1-PARP1 and PARP1-STAT3, STAT3 PARylation/phosphorylation assays, PD-L1 and T-cell killing, in vivo immunocompetent tumor model","pmids":["37566399"],"confidence":"High","gaps":["Stoichiometry of sequestration not defined","Whether nuclear ANXA1 mediates this not directly shown"]},{"year":2023,"claim":"Demonstrated SUMOylation-coupled nuclear-to-cytoplasmic relocalization of ANXA1 controls NF-κB-driven microglial neuroinflammation through NBR1-dependent IKKα autophagy.","evidence":"Confocal localization, Co-IP, NF-κB reporter, conditional AAV manipulation in Cx3cr1-Cre mice, MCAO stroke model","pmids":["37908731"],"confidence":"High","gaps":["SUMO sites on ANXA1 not mapped","Trigger of nuclear-cytoplasmic shift in physiological injury unresolved"]},{"year":2025,"claim":"Identified FBXO32 as the E3 ligase that ubiquitinates ANXA1 for degradation, completing a picture of bidirectional control of ANXA1 protein levels.","evidence":"Co-IP, ubiquitination assay, FBXO32 knockdown, ANXA1-rescue with PI3K/AKT readout in LPS cardiac injury models","pmids":["40126756"],"confidence":"Medium","gaps":["Degron on ANXA1 not mapped","Signal regulating FBXO32-ANXA1 engagement unknown"]},{"year":null,"claim":"How ANXA1's opposing roles—anti-inflammatory resolution agent versus context-dependent oncogenic survival/immunosuppressive factor—are determined by localization, processing, and receptor usage remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified framework distinguishing intracellular vs externalized/cleaved functions","Structural basis of FPR1 vs FPR2 selectivity undefined","In vivo physiological control of nuclear vs cytoplasmic ANXA1 incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,14,20,17]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,7,11,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[20,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,16,20,40]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,9,17]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,14,31]}],"complexes":[],"partners":["EPHA2","PARP1","NOTCH1","GSK3B","TBK1","JAK1","FBXO32","RRM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04083","full_name":"Annexin A1","aliases":["Annexin I","Annexin-1","Calpactin II","Calpactin-2","Chromobindin-9","Lipocortin I","Phospholipase A2 inhibitory protein","p35"],"length_aa":346,"mass_kda":38.7,"function":"Plays important roles in the innate immune response as effector of glucocorticoid-mediated responses and regulator of the inflammatory process. Has anti-inflammatory activity (PubMed:8425544). Plays a role in glucocorticoid-mediated down-regulation of the early phase of the inflammatory response (By similarity). Contributes to the adaptive immune response by enhancing signaling cascades that are triggered by T-cell activation, regulates differentiation and proliferation of activated T cells (PubMed:17008549). Promotes the differentiation of T cells into Th1 cells and negatively regulates differentiation into Th2 cells (PubMed:17008549). Has no effect on unstimulated T cells (PubMed:17008549). Negatively regulates hormone exocytosis via activation of the formyl peptide receptors and reorganization of the actin cytoskeleton (PubMed:19625660). Has high affinity for Ca(2+) and can bind up to eight Ca(2+) ions (By similarity). Displays Ca(2+)-dependent binding to phospholipid membranes (PubMed:2532504, PubMed:8557678). Plays a role in the formation of phagocytic cups and phagosomes. Plays a role in phagocytosis by mediating the Ca(2+)-dependent interaction between phagosomes and the actin cytoskeleton (By similarity). In the context of antitumor immunity, interacts with FPR1 on dendritic cells allowing for tumor-associated antigens uptake and cross-presentation to T cells to mount an antitumor specific T cell response Functions at least in part by activating the formyl peptide receptors and downstream signaling cascades (PubMed:15187149, PubMed:22879591, PubMed:25664854). Promotes chemotaxis of granulocytes and monocytes via activation of the formyl peptide receptors (PubMed:15187149). Promotes rearrangement of the actin cytoskeleton, cell polarization and cell migration (PubMed:15187149). Promotes resolution of inflammation and wound healing (PubMed:25664854). Acts via neutrophil N-formyl peptide receptors to enhance the release of CXCL2 (PubMed:22879591)","subcellular_location":"Nucleus; Cytoplasm; Cell projection, cilium; Cell membrane; Membrane; Endosome membrane; Basolateral cell membrane; Apical cell membrane; Lateral cell membrane; Secreted; Secreted, extracellular space; Cell membrane; Secreted, extracellular exosome; Cytoplasmic vesicle, secretory vesicle lumen; Cell projection, phagocytic cup; Early endosome; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/P04083/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANXA1","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":[{"gene":"INPPL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANXA1","total_profiled":1310},"omim":[{"mim_id":"621505","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 35; ANKRD35","url":"https://www.omim.org/entry/621505"},{"mim_id":"621486","title":"MICROTUBULE-INTERACTING AND TRAFFICKING DOMAIN-CONTAINING PROTEIN 1; MITD1","url":"https://www.omim.org/entry/621486"},{"mim_id":"610924","title":"RANBP-TYPE AND C3HC4-TYPE ZINC FINGER-CONTAINING 1; RBCK1","url":"https://www.omim.org/entry/610924"},{"mim_id":"602573","title":"ANNEXIN A13; ANXA13","url":"https://www.omim.org/entry/602573"},{"mim_id":"186360","title":"ANNEXIN A7; ANXA7","url":"https://www.omim.org/entry/186360"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":7699.2}],"url":"https://www.proteinatlas.org/search/ANXA1"},"hgnc":{"alias_symbol":[],"prev_symbol":["ANX1","LPC1"]},"alphafold":{"accession":"P04083","domains":[{"cath_id":"1.10.220.10","chopping":"43-111","consensus_level":"medium","plddt":98.2351,"start":43,"end":111},{"cath_id":"1.10.220.10","chopping":"273-342","consensus_level":"medium","plddt":96.9309,"start":273,"end":342}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04083","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04083-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04083-F1-predicted_aligned_error_v6.png","plddt_mean":95.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANXA1","jax_strain_url":"https://www.jax.org/strain/search?query=ANXA1"},"sequence":{"accession":"P04083","fasta_url":"https://rest.uniprot.org/uniprotkb/P04083.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04083/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04083"}},"corpus_meta":[{"pmid":"15183626","id":"PMC_15183626","title":"Simple diagnostic assay for hairy cell leukaemia by immunocytochemical detection of annexin A1 (ANXA1).","date":"2004","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15183626","citation_count":160,"is_preprint":false},{"pmid":"34319001","id":"PMC_34319001","title":"RRM2 Regulates Sensitivity to Sunitinib and PD-1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway.","date":"2021","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/34319001","citation_count":139,"is_preprint":false},{"pmid":"31154815","id":"PMC_31154815","title":"Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation.","date":"2019","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/31154815","citation_count":126,"is_preprint":false},{"pmid":"32300050","id":"PMC_32300050","title":"Targeting ANXA1 abrogates Treg-mediated immune suppression 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phase, despite normal glucocorticoid receptor expression.\",\n      \"method\": \"Anx-A1(-/-) mouse-derived cell lines; comparative biochemical analysis of COX-2, PLA2 expression; cell cycle analysis; dexamethasone treatment with/without glucocorticoid receptor assessment\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO cell line with multiple orthogonal readouts (eicosanoid release, cell cycle, COX-2, PLA2 expression) in a single focused study\",\n      \"pmids\": [\"12553880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Glucocorticoids activate PKCα/β, which phosphorylates ANXA1 on Ser27, driving its accumulation at the plasma membrane and subsequent externalization, thereby inhibiting thromboxane B2 generation; cromoglycate drugs enhance this pathway by inhibiting the PP2A phosphatase that otherwise limits ANXA1 release.\",\n      \"method\": \"Biochemical assays, epifluorescence and electron microscopy in U937 cells; PKC activation assay; PP2A inhibition; thromboxane B2 measurement by RIA\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (biochemistry, epifluorescence, EM, functional assay) in a single focused mechanistic study\",\n      \"pmids\": [\"19428336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In melanoma cells, externalized full-length ANXA1 is cleaved by a membrane-associated serine protease at a site between Ser28 and Lys29, releasing a pro-invasive N-terminal peptide (ANXA1 2-28) that activates formyl peptide receptors; ANXA1-driven invasion is mediated through MAPK and STAT3 pathways and leads to MMP2 induction.\",\n      \"method\": \"Proteomic/biochemical characterization of cleavage site; cell invasion assays; pharmacological inhibition of MAPK and STAT3; conditioned medium experiments in melanoma cell lines\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification of cleavage site plus functional pathway inhibition, single lab\",\n      \"pmids\": [\"25362540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANXA1 loss-of-function activates ANXA1 expression downstream of ARID1A loss, and ANXA1 then activates AKT signaling to confer resistance to HER2/PI3K/mTOR-targeting drugs including trastuzumab in HER2+ breast cancer cells.\",\n      \"method\": \"Genome-wide loss-of-function genetic screen; shRNA knockdown; pharmacological rescue with AKT inhibitor MK2206; gene expression analysis; validated in two independent clinical cohorts\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional genetic screen, mechanistic validation with pharmacological rescue, replicated in two independent patient cohorts\",\n      \"pmids\": [\"27172896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANXA1 suppresses oncogenic miR-196a biogenesis by stimulating c-Myc and NF-κB expression in breast cancer cells; miR-196a reciprocally targets the ANXA1 3'UTR to directly inhibit ANXA1 expression, forming a negative feedback loop that regulates cell proliferation.\",\n      \"method\": \"miRNA biogenesis assays; c-Myc/NF-κB expression and activity measurements; luciferase reporter assay for miR-196a targeting of ANXA1; gain/loss-of-function cell proliferation assays; in vivo tumor growth\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus functional gain/loss studies and in vivo validation, single lab\",\n      \"pmids\": [\"27105503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANXA1 modulates Th1/Th2 differentiation in CD4+ T cells by regulating GATA-3 expression through the FPR (FPRL-1) downstream ERK and PKB/Akt signaling pathways; conversely, GATA-3 inhibits ANXA1 expression by binding to its promoter.\",\n      \"method\": \"ANXA1 overexpression and knockdown in T cells; cytokine measurements (IFN-γ, IL-4); western blot for GATA-3/T-bet; pharmacological pathway inhibition; chromatin binding assay for GATA-3 on ANXA1 promoter\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional gain/loss with cytokine readout plus promoter-binding experiment, single lab\",\n      \"pmids\": [\"27833268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AnxA1 establishes an autocrine signaling loop in triple-negative breast cancer MDA-MB-231 cells via secreted ANXA1 binding to FPR1, which increases cell aggressiveness and survival; pharmacological inhibition of FPR1 (Cyclosporin H or Cyclosporin A) reduces tumor growth and metastasis in nude mice.\",\n      \"method\": \"FPR1 inhibitor treatment (Cyclosporin H, Cyclosporin A); ANXA1 secretion quantification; cell aggressiveness assays in vitro; in vivo tumor growth and metastasis in nude mice; tissue microarray correlation of ANXA1 and FPR1\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"29932988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AnxA1 acts directly on platelets via FPR2/ALX, suppressing thrombin-induced Akt activation, intracellular calcium release, and Rap1 expression, thereby decreasing αIIbβ3 integrin activation (without altering surface expression) and reducing platelet aggregation and thrombus formation in cerebral ischemia-reperfusion injury.\",\n      \"method\": \"AnxA1-/- mice; intravital microscopy; pharmacological treatment with AnxA1 and FPR2/ALX antagonist WRW4; thromboxane B2 measurement; phosphatidylserine expression assay; Akt/calcium/Rap1 signaling assays in human platelets\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice plus pharmacological rescue, multiple orthogonal in vivo and in vitro mechanistic readouts, clinical validation in human samples\",\n      \"pmids\": [\"31154815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANXA1 upregulation in colorectal cancer cells in response to hydrodynamic stress promotes cancer cell cluster growth via downstream activation of the PI3K/AKT signaling pathway.\",\n      \"method\": \"Microarray analysis of stressed cancer tissue-originated spheroids (CTOS); ANXA1 knockdown; PI3K/AKT pathway inhibition; growth assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — knockdown plus pathway inhibition in patient-derived organoid model, single lab\",\n      \"pmids\": [\"31882967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA1 binds directly to EphA2 (via amino acid residues 20–30 and 28–30 of its N-terminus) and competes with the E3 ubiquitin ligase Cbl, thereby inhibiting Cbl-mediated EphA2 ubiquitination and proteasomal degradation, stabilizing EphA2 and increasing its oncogenic pS897-EphA2 signaling in nasopharyngeal carcinoma.\",\n      \"method\": \"Co-immunoprecipitation; competitive binding assay with Cbl; ubiquitination assay; mutagenesis mapping of ANXA1 N-terminal binding residues; EphA2 stability assays; in vitro and in vivo tumor growth assays; ANXA1-derived peptide disruption experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, competitive ubiquitination assay, mutagenesis mapping of binding domain, peptide disruption, in vivo validation—multiple orthogonal methods in one study\",\n      \"pmids\": [\"32737118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA1 interaction with ANXA4 mediates JAK-STAT3 signaling activation in basal-like breast cancer: ANXA4 directly binds ANXA1 (co-IP confirmed), and ANXA1 knockdown reduces JAK1 expression and STAT3 phosphorylation (Y705), impairing ANXA4-induced JAK-STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation; ANXA1 knockdown; JAK1 expression and STAT3 phosphorylation western blot; colocalization by immunofluorescence; in vivo tumor model\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP confirmed interaction plus knockdown epistasis, single lab\",\n      \"pmids\": [\"32552056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA1 directs Schwann cell proliferation and migration after peripheral nerve injury by activating formyl peptide receptor 2 (FPR2) and its downstream AMPK signaling cascade; Schwann cells lacking FPR2 or AMPK show defects in proliferation and migration, and ANXA1 promotes nerve regeneration in vivo.\",\n      \"method\": \"FPR2/AMPK knockdown in Schwann cells; proliferation and migration assays; facial nerve crush injury model; in vivo remyelination assessment\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor and kinase knockdown epistasis with in vitro and in vivo functional readouts, single lab\",\n      \"pmids\": [\"32856352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AnxA1Ac2-26 (ANXA1 mimetic peptide) regulates SCD neutrophils through the FPR2/ALX pathway, activating Akt and ERK1/2 to enable resolution of cerebral thromboinflammatory responses in sickle cell disease mice.\",\n      \"method\": \"Sickle transgenic mice; pharmacological administration of AnxA1Ac2-26; FPR2/ALX pathway modulation; Akt and ERK1/2 signaling analysis; intravital microscopy of cerebral thrombosis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model plus signaling pathway analysis, single lab\",\n      \"pmids\": [\"33512489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA1 in vascular smooth muscle cells prevents acute aortic dissection by maintaining the contractile phenotype via the JunB/MYL9 pathway; ANXA1 deficiency triggers VSMC synthetic phenotype switch, elevating inflammation and MMP production leading to elastin degradation.\",\n      \"method\": \"Anxa1-/- global and VSMC-restricted conditional knockout mice; transcriptomic analysis; micro-CT; immunohistochemistry; Ac2-26 rescue experiment; validation in human AAD specimens\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO, transcriptomics, pharmacological rescue, human tissue validation—replicated mechanistic pathway\",\n      \"pmids\": [\"33757117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA1 directly binds the intracellular domain of Notch1 (NICD) and targets it for degradation, suppressing Notch1-mediated p15 promoter activation and thereby promoting AML cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation; NICD stability assays; luciferase reporter for p15 promoter; ANXA1 knockdown/overexpression; NICD inhibitory peptide; patient sample correlation analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assay, peptide disruption, loss-of-function, single lab\",\n      \"pmids\": [\"39447086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A novel homozygous missense variant in ANXA1 causes autosomal recessive parkinsonism; the variant impairs phagocytosis in zebrafish mutant embryos, linking ANXA1 to microglial clearance of aggregated proteins.\",\n      \"method\": \"Homozygosity mapping; whole genome sequencing; zebrafish morpholino/mutant phagocytosis assay\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mapping plus in vivo functional validation in zebrafish, single study\",\n      \"pmids\": [\"34180078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FMDV viral protein 3A interacts with ANXA1 and inhibits ANXA1-TBK1 complex formation, thereby blocking ANXA1-promoted IFN-β production; endogenous ANXA1 promotes RNA virus-stimulated IFN-β production through the TBK1-IRF3 axis (not NF-κB), and ANXA1 also interacts with JAK1 and STAT1 to strengthen IFN-β/IFN-γ signal transduction.\",\n      \"method\": \"Co-immunoprecipitation; ANXA1-/- knockout cells; IFN-β production assays; IRF3 and NF-κB pathway dissection; ANXA1-3A interaction mapping; JAK1/STAT1 co-IP\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells, Co-IP of multiple partners, pathway dissection with orthogonal readouts in one focused study\",\n      \"pmids\": [\"35604142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANXA1 interacts with GSK3β (confirmed by GST pulldown and Co-IP), negatively regulates GSK3β phosphorylation, and thereby inhibits EMT and suppresses migration and invasion of NSCLC cells.\",\n      \"method\": \"GST pulldown; co-immunoprecipitation in H1299 and A549 cells; GSK3β phosphorylation assay; functional rescue assay for EMT/migration/invasion\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown/Co-IP plus functional rescue, single lab\",\n      \"pmids\": [\"34002210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"E2F1-transcribed serine protease PRSS22 physically interacts with ANXA1 (confirmed by mass spectrometry and Co-IP), cleaves ANXA1 to generate an N-terminal peptide that activates the FPR2/ERK signaling axis, promoting breast cancer cell invasion and metastasis.\",\n      \"method\": \"Protein mass spectrometry; co-immunoprecipitation; cleavage assay; FPR2/ERK signaling analysis; ChIP for E2F1 on PRSS22 promoter; in vitro and in vivo metastasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, protease cleavage assay, signaling pathway validation, single lab\",\n      \"pmids\": [\"36414640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CYP2J2 upregulates METTL3, which promotes ANXA1 translation via m6A modification of ANXA1 mRNA; ANXA1 is required for maintenance of endothelial tight junction/adherens junction distribution and blood-retinal barrier integrity under oxidative stress.\",\n      \"method\": \"CYP2J2 overexpression; METTL3 knockdown; MeRIP-qPCR for m6A on ANXA1 mRNA; endothelial ANXA1 conditional deletion; tight junction fractionation; BRB integrity assay in ischemia-reperfusion model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A modification mapped by MeRIP, conditional KO with functional BRB readout, single lab\",\n      \"pmids\": [\"36269280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANXA1 acts as a sponge that sequesters PARP1, preventing PARP1 from binding and poly(ADP-ribosyl)ating Stat3; reduced PARP1-Stat3 interaction decreases Stat3 dephosphorylation and thereby increases Stat3 transcriptional activity, leading to upregulated PD-L1 expression and cancer immune evasion.\",\n      \"method\": \"Co-immunoprecipitation of ANXA1-PARP1 and PARP1-Stat3; ANXA1 knockdown; PARylation assay of Stat3; Stat3 phosphorylation/dephosphorylation analysis; PD-L1 expression; T cell killing assay; in vivo immune-competent mouse tumor model\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, PARylation mechanistic assay, multiple cancer cell lines, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37566399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"An ANXA1-derived peptide A11 competes with deubiquitinase USP7 for binding PD-L1, preventing USP7-mediated PD-L1 deubiquitination and thereby promoting PD-L1 proteasomal degradation in breast, lung, and melanoma cancer cells.\",\n      \"method\": \"Biotin pull-down coupled with mass spectrometry; human deubiquitinase cDNA library screen to identify USP7; competitive binding assay (A11 vs USP7 for PD-L1); ubiquitination/deubiquitination assays; T cell killing assay; in vivo mouse tumor model with immune competent mice\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-identified interaction, library screen, competitive biochemical assay, ubiquitination mechanistic assay, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"37001908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tat-NTS peptide shifts ANXA1 subcellular localization in microglia from the nucleus to the cytoplasm after ischemic injury; this shift increases ANXA1 SUMOylation, which mediates IKKα degradation via NBR1-dependent selective autophagy, blocking NF-κB pathway activation and reducing pro-inflammatory cytokine (IL-1β, TNF-α) production.\",\n      \"method\": \"Confocal imaging with 3D reconstruction; Co-IP; immunoblotting; ELISA; luciferase reporter assay for NF-κB; AAV-mediated Cre-conditional manipulation in Cx3cr1-Cre mice; MCAO stroke model; behavioral tests; TEM\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods (Co-IP, localization, autophagy pathway, conditional AAV KO, behavioral outcomes) in a single mechanistic study\",\n      \"pmids\": [\"37908731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SBSN interacts with ANXA1, and this interaction promotes Lys63-linked and Met1-linear polyubiquitination of NEMO, activating NF-κB signaling to drive glioma cell aggressiveness.\",\n      \"method\": \"Co-immunoprecipitation of SBSN-ANXA1-NEMO; ubiquitin-linkage-specific assays; in vivo tumor assay; EV transfer experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with downstream ubiquitination assay and in vivo validation, single lab\",\n      \"pmids\": [\"36316443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA1 interacts with TNFR1 (confirmed by Co-IP) and promotes glioma cell growth by activating the p65 and Akt signaling pathways downstream of TNF-α stimulation.\",\n      \"method\": \"Co-immunoprecipitation; ANXA1 knockdown/overexpression; p65 and Akt pathway western blot; CCK-8 proliferation assay; immunofluorescence\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus functional assay, single lab, limited mechanistic depth\",\n      \"pmids\": [\"35415239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA1 is required for KIAA1199-mediated extracellular hyaluronic acid degradation on the surface of rheumatoid arthritis fibroblast-like synoviocytes: the G8 domain of KIAA1199 binds ANXA1 on the cell membrane to anchor KIAA1199, and deletion of this domain abolishes HA-degrading activity in vivo.\",\n      \"method\": \"Co-IP of KIAA1199 G8 domain with ANXA1; G8-deleted KIAA1199 mutant intra-articular injection in kiaa1199-KO mice; HA degradation assays; CIA mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping Co-IP, in vivo rescue with wild-type vs. G8-deleted mutant, single lab\",\n      \"pmids\": [\"33473125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANXA1 reduction in macrophages in a diabetic periodontitis environment is associated with activation of the NLRP3/Caspase-1/GSDMD signaling pathway and increased macrophage pyroptosis; the ANXA1 mimetic peptide Ac2-26 reduces macrophage pyroptosis via this pathway.\",\n      \"method\": \"Western blot for NLRP3/Caspase-1/GSDMD in diabetic periodontitis macrophages; Ac2-26 peptide treatment; in vivo diabetic rat periodontitis model; ROS/pH-responsive hydrogel delivery system\",\n      \"journal\": \"Biofabrication\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway protein expression plus peptide treatment, limited mechanistic dissection, single lab\",\n      \"pmids\": [\"39773706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In hepatopulmonary syndrome, endothelin-1 reduces ANXA1 protein levels through carbonylation and proteasomal degradation of ANXA1; ANXA1 in turn decreases nuclear pERK1/2 accumulation and cyclin D1 expression, inhibiting pulmonary artery smooth muscle cell proliferation.\",\n      \"method\": \"Carbonylation assay of ANXA1 protein; proteasome inhibitor rescue; pERK1/2 nuclear fractionation; cyclin D1 western blot; PASMC proliferation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — carbonylation/degradation mechanistic assay plus downstream signaling and proliferation readout, single lab\",\n      \"pmids\": [\"28414743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ANXA1 overexpression induced by low-concentration arsenic trioxide activates ERK MAPK signaling, rendering cancer cells resistant to ATO; ANXA1 silencing combined with ATO increases apoptosis, and pharmacological ERK inhibition (PD98059) phenocopies ANXA1 silencing.\",\n      \"method\": \"siRNA knockdown of ANXA1; ERK inhibitor PD98059; MTT proliferation/apoptosis assay; western blot for ERK activation; proteomics screen identifying ANXA1 as ATO-responsive protein\",\n      \"journal\": \"Tumori\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteomics-identified target, siRNA KD, pharmacological epistasis with ERK inhibitor, single lab\",\n      \"pmids\": [\"25983101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA1 enhances the immunosuppressive function of Tregs in triple-negative breast cancer and reduces the expression of granzyme A mRNA in Tregs, as assessed by suppressive assays and RNA sequencing; the ANXA1 blocker Boc1 reduces Treg function and tumor size in vivo.\",\n      \"method\": \"Suppressive assay of Tregs; RNA sequencing after Boc1 treatment; ELISA for plasma ANXA1; in vivo tumor model with Boc1 treatment in BALB/c mice\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNA-seq plus functional suppressive assay and in vivo pharmacological block, single lab\",\n      \"pmids\": [\"32300050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA1 promotes Schwann cell proliferation and migration through FPR2-AMPK signaling, acting as an extracellular trigger; endothelial ANXA1 promotes choroidal endothelial cell proliferation, migration, and tube formation via FPR2/SHP2 axis-mediated inhibition of NLRP3 inflammasome and pyroptosis.\",\n      \"method\": \"(For choroidal angiogenesis) FPR2/SHP2 knockdown; NLRP3 inhibition; pyroptosis markers; ARPE-19 and HCEC co-culture; ANXA1 secretion under hypoxia; in vivo CNV model\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — receptor knockdown epistasis plus in vivo CNV model, single lab\",\n      \"pmids\": [\"34595678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO32 E3 ubiquitin ligase directly ubiquitinates ANXA1, promoting its proteasomal degradation; loss of ANXA1 inhibits PI3K/AKT signaling and exacerbates LPS-induced cardiac injury and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; FBXO32 knockdown; ANXA1 knockdown rescue experiment; PI3K/AKT western blot; in vivo and in vitro LPS cardiac injury models\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-confirmed ubiquitination plus epistatic rescue experiment, single lab\",\n      \"pmids\": [\"40126756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WISP1 recruits ANXA1 as an interaction partner (identified by Co-IP and mass spectrometry) to regulate TGF-β signaling pathway during muscle-derived satellite cell differentiation; WISP1 cannot affect TGF-β signaling markers when ANXA1 is knocked down.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry; ANXA1 knockdown with WISP1 activation; western blot for TGF-β pathway proteins; immunofluorescence\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/MS interaction plus epistatic knockdown, but TGF-β pathway mechanistic detail limited, single lab\",\n      \"pmids\": [\"32458119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"α-MSH inhibits TNF-α-induced maturation of human monocyte-derived dendritic cells through upregulation of ANXA1; specific siRNA knockdown of ANXA1 abolishes the α-MSH inhibitory effect on DC maturation markers (CD83, CD86), IL-12 production, and phagocytic activity.\",\n      \"method\": \"siRNA knockdown of ANXA1; flow cytometry for CD83/CD86; ELISA for IL-12/IL-10; phagocytosis assay; α-MSH treatment\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — specific siRNA epistasis with multiple functional readouts, single lab\",\n      \"pmids\": [\"21131366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FoxM1 transcription factor directly transcriptionally activates ANXA1 expression in glioma cells; overexpression of FoxM1 upregulates ANXA1, and FoxM1-driven proliferation, migration, and angiogenesis occur in an ANXA1-dependent manner.\",\n      \"method\": \"FoxM1 overexpression/knockdown; ChIP or promoter assay for FoxM1 on ANXA1; ANXA1 knockdown rescue; proliferation, migration, angiogenesis assays in vitro and in vivo\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — transcriptional regulation confirmed plus epistatic rescue, single lab\",\n      \"pmids\": [\"23991102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRM2 stabilizes ANXA1 protein and activates the AKT pathway independent of its ribonucleotide reductase activity, promoting sunitinib resistance in renal cell carcinoma.\",\n      \"method\": \"RRM2 knockdown/overexpression; ANXA1 protein stability assays; AKT pathway western blot; sunitinib resistance assays in vitro and in vivo; RRM2 enzymatic-dead mutant\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — enzymatic-dead mutant control plus protein stability and signaling assays, single lab\",\n      \"pmids\": [\"34319001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The ANXA1-FPR2 axis protects against obesity-associated atrial fibrillation by activating AMPK in cardiomyocytes to enhance fatty acid oxidation and reduce lipid accumulation; AAV9-mediated AMPK knockdown in myocardium reverses the protective effect of Ac2-26 on AF susceptibility in obese mice.\",\n      \"method\": \"High-fat diet obese mice; AAV9-shAMPK myocardial-specific knockdown; FPR2 inhibitor (Boc-2, WRW4); Ac2-26 peptide administration; fatty acid oxidation assays; in vitro palmitic acid cardiomyocyte model\",\n      \"journal\": \"Cardiovascular diabetology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic knockdown in vivo plus pharmacological epistasis with in vitro validation, single lab\",\n      \"pmids\": [\"39709478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAM-A-induced nuclear aggregation of HBV core protein (HBc) upregulates ANXA1 expression, and ANXA1 directly mediates apoptosis in HBV-infected cells; ANXA1 silencing delays cell death and apoptosis in CAM-A-treated cells.\",\n      \"method\": \"siRNA knockdown of ANXA1 in HBV-infected differentiated HepaRG cells and HBc-overexpressing HepG2-NTCP cells; transcriptomic analysis; apoptosis markers; primary human hepatocytes\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA epistasis in multiple cell models with apoptosis phenotypic readout plus transcriptomic mechanistic link, single lab\",\n      \"pmids\": [\"39386256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDC1 (m6A reader) inhibits ANXA1 expression in ccRCC via RNA binding (RIP-qPCR/MeRIP-qPCR), and ANXA1 activates the MAPK pathway downstream; the YY1/HDAC2 epigenetic complex downregulates YTHDC1, which de-represses ANXA1/MAPK signaling and promotes sunitinib resistance.\",\n      \"method\": \"RIP-qPCR; MeRIP-qPCR; RNA-seq; western blot; HDAC2 inhibitor treatment; xenograft assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — m6A-RIP mechanistic assay plus pharmacological and genetic epistasis, single lab\",\n      \"pmids\": [\"35974388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA1 from intestinal epithelial cells (IECs) stimulates NKG2A expression on natural killer cells during colitis; NKG2A upregulation on NK cells inhibits neutrophil recruitment and activity, alleviating DSS-induced colitis.\",\n      \"method\": \"DSS colitis mouse model; ANXA1 overexpression in IECs; NK-IEC co-culture; NKG2A expression measurement; neutrophil infiltration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-culture and overexpression with NKG2A/neutrophil readout, limited mechanistic dissection of direct ANXA1-NK cell interaction, single lab\",\n      \"pmids\": [\"27435504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANXA1 drives glioma immunosuppression via FPR1 signaling: tumor-derived ANXA1 induces M2-like macrophage/microglia polarization through FPR1, establishing a Treg-driven immunosuppressive tumor microenvironment and suppressing the anti-tumor immune response to TLR3 ligand poly(I:C).\",\n      \"method\": \"In vitro macrophage/microglia polarization assays; FPR1 pharmacological inhibition; in vivo glioma model; clinical trial patient sample analysis (RNA-seq and protein validation)\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological FPR1 inhibition plus in vivo model and clinical sample validation, single lab\",\n      \"pmids\": [\"38049523\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANXA1 (Annexin A1) is a calcium- and phospholipid-binding protein that functions as a key mediator of glucocorticoid anti-inflammatory signaling: upon glucocorticoid stimulation, PKCα/β phosphorylates ANXA1 at Ser27, driving its membrane translocation and externalization to suppress eicosanoid (PGE2, TxB2) production via PLA2 inhibition; extracellularly, ANXA1 and its N-terminal-derived peptides (e.g., Ac2-26, generated by membrane serine protease cleavage between Ser28 and Lys29) signal through formyl peptide receptors (FPR1/FPR2/ALX) to suppress platelet activation (via reducing Akt, calcium, Rap1, and αIIbβ3 activation), regulate neutrophil and macrophage phenotype, promote Schwann cell proliferation and nerve regeneration via FPR2/AMPK, and drive inflammation resolution; intracellularly, ANXA1 interacts with multiple proteins including EphA2 (inhibiting Cbl-mediated ubiquitination/degradation), PARP1 (sequestering it from Stat3 to upregulate PD-L1), Notch1 NICD (targeting it for degradation), GSK3β (inhibiting its phosphorylation to block EMT), TBK1 (promoting IRF3-mediated IFN-β production against RNA viruses), and TNFR1, with its own stability regulated by FBXO32-mediated ubiquitination and by RRM2-dependent stabilization; subcellular localization—nuclear vs. cytoplasmic/membrane—is dynamically regulated by SUMOylation and determines its function in microglia during neuroinflammation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANXA1 (Annexin A1) is a calcium- and phospholipid-binding protein that serves as a central effector of glucocorticoid anti-inflammatory action and inflammation resolution, with broad additional roles in tumor signaling and tissue protection [#0, #1]. In its canonical anti-inflammatory mode, ANXA1 is required for glucocorticoid-mediated suppression of eicosanoid generation, since cells lacking it overexpress COX-2 and PLA2 and resist dexamethasone [#0]; glucocorticoids drive this through PKCα/β phosphorylation of ANXA1 at Ser27, promoting plasma-membrane accumulation and externalization, a step opposed by PP2A [#1]. Externalized ANXA1 is cleaved by membrane-associated serine proteases—including PRSS22—near its N-terminus to release bioactive peptides that signal through formyl peptide receptors (FPR1, FPR2/ALX) [#2, #18]. Through FPR2/ALX, ANXA1 suppresses platelet activation by blunting thrombin-induced Akt, calcium, Rap1 and αIIbβ3 integrin activation [#7], drives Schwann cell proliferation and nerve regeneration via FPR2-AMPK [#11], and promotes neutrophil-mediated resolution [#12]; via the FPR2-AMPK axis it also protects cardiomyocytes by enhancing fatty acid oxidation [#36]. ANXA1 additionally preserves vascular smooth muscle contractile phenotype through JunB/MYL9, guarding against aortic dissection [#13]. Intracellularly, ANXA1 acts as a protein-stability and signaling hub: it binds EphA2 to block Cbl-mediated ubiquitination and stabilize oncogenic EphA2 [#9], sequesters PARP1 away from STAT3 to raise STAT3 activity and PD-L1 expression [#20], binds Notch1 NICD to target it for degradation [#14], binds GSK3β to inhibit its phosphorylation and block EMT [#17], and promotes TBK1-IRF3-dependent IFN-β production against RNA viruses while reinforcing JAK1/STAT1 signaling [#16]. ANXA1 frequently converges on PI3K/AKT signaling to confer therapy resistance and survival across cancers [#3, #8, #31]. Its own abundance is controlled by ubiquitin-dependent turnover (FBXO32) [#31], stabilization (RRM2) [#35], and m6A-dependent translational regulation (METTL3/YTHDC1) [#19, #38], while SUMOylation-linked nuclear-to-cytoplasmic shifts govern its inflammatory output in microglia [#22]. A homozygous missense ANXA1 variant causes autosomal recessive parkinsonism and impairs microglial phagocytosis [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that ANXA1 is genetically required for glucocorticoid suppression of eicosanoid production and proliferation, moving it from correlate to obligate mediator of glucocorticoid action.\",\n      \"evidence\": \"Anx-A1 knockout fibroblast lines with COX-2/PLA2 expression and cell-cycle readouts under dexamethasone\",\n      \"pmids\": [\"12553880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how ANXA1 mechanistically inhibits PLA2\", \"Receptor/effector mediating the externalized signal not defined here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the upstream control of ANXA1 externalization, showing glucocorticoid-driven PKCα/β phosphorylation at Ser27 triggers membrane translocation and release, opposed by PP2A.\",\n      \"evidence\": \"Biochemistry, epifluorescence and EM in U937 cells with PKC activation, PP2A inhibition, thromboxane B2 assay\",\n      \"pmids\": [\"19428336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of physical translocation across the membrane not defined\", \"Identity of the externalization machinery unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the proteolytic event that converts full-length ANXA1 into a receptor-active peptide, linking externalization to FPR signaling and tumor invasion.\",\n      \"evidence\": \"Proteomic cleavage-site mapping (Ser28/Lys29) and invasion assays with MAPK/STAT3 inhibition in melanoma cells\",\n      \"pmids\": [\"25362540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease identity not established in this study\", \"In vivo relevance of the peptide not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed ANXA1 drives PI3K/AKT-dependent therapy resistance downstream of ARID1A loss, establishing an oncogenic survival axis in HER2+ breast cancer.\",\n      \"evidence\": \"Genome-wide loss-of-function screen, shRNA, AKT-inhibitor rescue, two clinical cohorts\",\n      \"pmids\": [\"27172896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from ANXA1 to AKT activation not defined\", \"Whether secreted or intracellular ANXA1 mediates this is unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended ANXA1 immunoregulation to adaptive immunity and microRNA circuits, revealing reciprocal feedback loops controlling its own expression.\",\n      \"evidence\": \"T-cell GATA-3/FPR signaling assays and a miR-196a/ANXA1 3'UTR luciferase feedback loop in breast cancer cells\",\n      \"pmids\": [\"27833268\", \"27105503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect promoter regulation not fully resolved\", \"In vivo contribution of the feedback loop limited\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated direct ANXA1 action on platelets via FPR2/ALX, defining its anti-thrombotic mechanism through suppression of Akt/calcium/Rap1 and integrin inside-out activation.\",\n      \"evidence\": \"AnxA1-/- mice, intravital microscopy, WRW4 antagonism, human platelet signaling assays in cerebral ischemia-reperfusion\",\n      \"pmids\": [\"31154815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether full-length or cleaved peptide is the active ligand on platelets not separated\", \"Structural basis of FPR2 engagement unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed ANXA1 as an intracellular stability regulator, mapping its N-terminal binding to EphA2 and competition with Cbl that stabilizes oncogenic EphA2 signaling.\",\n      \"evidence\": \"Co-IP, competitive Cbl/ubiquitination assays, mutagenesis mapping, peptide disruption, in vivo tumor assays\",\n      \"pmids\": [\"32737118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calcium-dependence of the EphA2 interaction not addressed\", \"Generalizability beyond nasopharyngeal carcinoma untested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded ANXA1's FPR2-AMPK signaling role beyond inflammation to Schwann cell-driven nerve regeneration and endothelial angiogenesis.\",\n      \"evidence\": \"FPR2/AMPK knockdown, proliferation/migration assays, nerve crush model; FPR2/SHP2 axis in choroidal endothelium\",\n      \"pmids\": [\"32856352\", \"34595678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source and processing of ANXA1 ligand in these tissues not defined\", \"Direct receptor binding not biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established ANXA1 as a tissue-protective factor in vascular smooth muscle, defining the JunB/MYL9 contractile-phenotype pathway preventing aortic dissection.\",\n      \"evidence\": \"Global and VSMC-conditional Anxa1 knockouts, transcriptomics, Ac2-26 rescue, human AAD specimens\",\n      \"pmids\": [\"33757117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating intracellular vs extracellular ANXA1 effect not separated\", \"Upstream trigger of phenotype switch unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked ANXA1 to a Mendelian neurodegenerative disease, implicating it in microglial phagocytic clearance.\",\n      \"evidence\": \"Homozygosity mapping, whole-genome sequencing, zebrafish phagocytosis assay\",\n      \"pmids\": [\"34180078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting variant to phagocytosis defect not defined\", \"Human neuronal/microglial validation absent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified post-translational control of ANXA1 abundance via RRM2-dependent stabilization driving AKT-dependent drug resistance.\",\n      \"evidence\": \"RRM2 enzymatic-dead mutant, protein stability and AKT assays, sunitinib resistance in vitro and in vivo\",\n      \"pmids\": [\"34319001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which RRM2 stabilizes ANXA1 not defined\", \"Single-lab finding in renal carcinoma\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined ANXA1 as a positive regulator of antiviral interferon, acting through TBK1-IRF3 and reinforcing JAK1/STAT1 signaling, and a target of viral antagonism.\",\n      \"evidence\": \"ANXA1-/- cells, Co-IP of TBK1/JAK1/STAT1, IFN-β assays, FMDV 3A interaction mapping\",\n      \"pmids\": [\"35604142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ANXA1 directly activates TBK1 kinase activity not shown\", \"Structural basis of complex formation undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed ANXA1 binds GSK3β to suppress EMT and identified the protease PRSS22 that cleaves ANXA1 to drive FPR2/ERK metastatic signaling, expanding both intracellular and extracellular tumor mechanisms.\",\n      \"evidence\": \"GST pulldown/Co-IP with GSK3β functional rescue; MS/Co-IP and cleavage assays for PRSS22 with E2F1 ChIP\",\n      \"pmids\": [\"34002210\", \"36414640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of ANXA1's opposing pro- and anti-tumor roles unresolved\", \"Direct enzymatic kinetics of PRSS22 cleavage not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an ANXA1-PARP1-STAT3 axis controlling immune evasion, defining ANXA1 as a PARP1 sponge that elevates STAT3 activity and PD-L1.\",\n      \"evidence\": \"Co-IP of ANXA1-PARP1 and PARP1-STAT3, STAT3 PARylation/phosphorylation assays, PD-L1 and T-cell killing, in vivo immunocompetent tumor model\",\n      \"pmids\": [\"37566399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of sequestration not defined\", \"Whether nuclear ANXA1 mediates this not directly shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated SUMOylation-coupled nuclear-to-cytoplasmic relocalization of ANXA1 controls NF-κB-driven microglial neuroinflammation through NBR1-dependent IKKα autophagy.\",\n      \"evidence\": \"Confocal localization, Co-IP, NF-κB reporter, conditional AAV manipulation in Cx3cr1-Cre mice, MCAO stroke model\",\n      \"pmids\": [\"37908731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO sites on ANXA1 not mapped\", \"Trigger of nuclear-cytoplasmic shift in physiological injury unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified FBXO32 as the E3 ligase that ubiquitinates ANXA1 for degradation, completing a picture of bidirectional control of ANXA1 protein levels.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, FBXO32 knockdown, ANXA1-rescue with PI3K/AKT readout in LPS cardiac injury models\",\n      \"pmids\": [\"40126756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron on ANXA1 not mapped\", \"Signal regulating FBXO32-ANXA1 engagement unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANXA1's opposing roles—anti-inflammatory resolution agent versus context-dependent oncogenic survival/immunosuppressive factor—are determined by localization, processing, and receptor usage remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified framework distinguishing intracellular vs externalized/cleaved functions\", \"Structural basis of FPR1 vs FPR2 selectivity undefined\", \"In vivo physiological control of nuclear vs cytoplasmic ANXA1 incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 14, 20, 17]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 7, 11, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [20, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 16, 20, 40]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 9, 17]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 14, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EphA2\", \"PARP1\", \"Notch1\", \"GSK3B\", \"TBK1\", \"JAK1\", \"FBXO32\", \"RRM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}