{"gene":"STAB1","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2002,"finding":"FEEL-1 (STAB1) functions as an endocytic receptor for advanced glycation end products (AGEs): CHO cells overexpressing FEEL-1 bound 125I-AGE-BSA with high affinity (Kd ~2.55 µg/ml) at 4°C, and at 37°C took up and degraded the ligand; binding was inhibited by polyanionic SR-A inhibitors (fucoidan, polyinosinic acid, dextran sulfate) but not by native or oxidized LDL.","method":"Radioligand binding assay and uptake/degradation assay in CHO cells overexpressing FEEL-1; competitive inhibition with polyanionic ligands","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative radioligand binding and internalization assays with overexpression system, replicated across FEEL-1 and FEEL-2 with multiple inhibitor controls","pmids":["12473645"],"is_preprint":false},{"year":2002,"finding":"FEEL-1 (STAB1) is the major receptor for acetylated LDL (Ac-LDL) on human umbilical vein endothelial cells, as demonstrated by monoclonal antibody blocking; FEEL-1 and FEEL-2 expressed in CHO cells both bind DiI-Ac-LDL and Gram-negative and Gram-positive bacteria; inhibition of FEEL-1 with monoclonal antibody markedly reduced cell-cell interaction in the Matrigel tube formation assay, indicating a role in angiogenesis.","method":"Expression cloning; monoclonal antibody blocking of DiI-Ac-LDL uptake; transient overexpression in CHO cells; in vitro Matrigel tube formation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — monoclonal antibody blocking plus overexpression binding assay; angiogenesis role from single lab with one in vitro assay","pmids":["12077138"],"is_preprint":false},{"year":2003,"finding":"CLEVER-1 (STAB1) on lymphatic endothelium mediates adhesion of head-and-neck cancer cell lines to lymphatic endothelium; adhesion of all tested cancer cell lines was dependent on both CLEVER-1 and mannose receptor, as shown by antibody blocking experiments.","method":"In vitro adhesion assays with antibody blocking of CLEVER-1 and mannose receptor on lymphatic endothelial cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional blocking antibody experiments in cell adhesion assay, single lab","pmids":["12907648"],"is_preprint":false},{"year":2004,"finding":"CLEVER-1 (STAB1) supports rolling and transmigration of peripheral blood mononuclear cells (PBMCs) across vascular endothelium under physiological laminar shear stress, and also mediates transmigration of leukocytes through lymphatic endothelium under static conditions; CLEVER-1 is constitutively expressed on lymphatic vessels in skin and induced on vascular endothelium upon inflammation.","method":"Flow chamber assay under shear stress; transmigration assay through cultured lymphatic endothelium; immunofluorescence of tissue sections","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — flow chamber and transmigration assays with direct functional readouts on both vascular and lymphatic endothelium; replicated in two distinct vascular beds","pmids":["15297319"],"is_preprint":false},{"year":2004,"finding":"Stabilin-1 (STAB1) is predominantly intracellular and cycles rapidly between the plasma membrane and EEA-1+ early endosomes; intracellular targeting is influenced by the transmembrane domain/cytoplasmic tail, which contains a putative dileucine (DXXLL) Golgi-to-endosomal sorting signal; the stabilin-1 Link domain does not bind hyaluronan or other glycosaminoglycans.","method":"Fluorescent antibody and Fl-Ac-LDL uptake assays; subcellular fractionation/immunofluorescence colocalization with EEA-1; stabilin-1/CD44 chimera expression in HeLa cells; hyaluronan binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (live-cell imaging, chimeric protein domain swapping, ligand binding assay, colocalization with endosomal marker); negative Link-domain binding result experimentally established","pmids":["15345716"],"is_preprint":false},{"year":2009,"finding":"Clever-1/Stabilin-1 mediates in vivo migration of T and B lymphocytes to draining lymph nodes via lymphatics; an adhesive epitope on Clever-1/Stabilin-1 responsible for the interaction between lymphocytes and lymphatic endothelium was identified; antibody blocking of Clever-1/Stabilin-1 inhibited peritonitis in mice by reducing granulocyte entrance by ~50% and nearly abolishing monocyte and lymphocyte migration into the inflamed peritoneum.","method":"In vivo lymphocyte migration models; antibody blocking in peritonitis mouse model; adoptive transfer experiments; epitope mapping","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic and antibody blocking experiments with quantitative cell trafficking readouts; adhesive epitope mapped; multiple inflammatory models","pmids":["19830743"],"is_preprint":false},{"year":2010,"finding":"Sorting nexin 17 (SNX17), a phox-homology domain protein, directly interacts with the cytoplasmic tail of FEEL-1/stabilin-1 via the NPxF motif; SNX17 regulates FEEL-1/stabilin-1 trafficking and siRNA knockdown of SNX17 decreases total cellular FEEL-1/stabilin-1 expression and FEEL-1-mediated ligand uptake by enhancing protein degradation.","method":"Co-immunoprecipitation; cytoplasmic domain truncation and point-mutation constructs; siRNA knockdown; ligand uptake assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP, domain mutagenesis (NPxF motif), and functional rescue/knockdown with quantitative ligand uptake readout; multiple orthogonal methods in one study","pmids":["20226821"],"is_preprint":false},{"year":2011,"finding":"Stabilin-1/CLEVER-1 on human placental macrophages mediates scavenging of Ac-LDL and uptake of fluorescently labeled OVA; siRNA-mediated suppression of stabilin-1/CLEVER-1 alters the cytokine profile produced by placental macrophages; stabilin-1/CLEVER-1 on placental macrophages mediates their adhesion to placental vessels and supports transmigration through vascular endothelium.","method":"siRNA knockdown; fluorescent ligand uptake assay; cytokine profiling; transmigration assay; flow cytometry","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts (scavenging, cytokine production, adhesion, transmigration) in a single lab study","pmids":["21480214"],"is_preprint":false},{"year":2014,"finding":"Clever-1/Stabilin-1 deficiency (full knockout and macrophage- or endothelium-specific conditional knockouts) reduces primary and metastatic tumor growth in mice; Clever-1 mediates binding of immunosuppressive leukocytes to intratumoral blood vessels and facilitates tumor cell traffic via lymphatics; anti-Clever-1 antibody treatment inhibits tumor progression in wild-type mice.","method":"Full and conditional knockout mice (macrophage-specific, endothelium-specific); bone marrow chimeras; cell depletion experiments; anti-Clever-1 antibody therapy in B16 melanoma and EL-4 lymphoma models; flow cytometry of tumor-infiltrating leukocytes","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (full KO, two conditional KOs) plus antibody therapy with quantitative tumor growth and cellular phenotype readouts; cell-type-specific mechanisms dissected","pmids":["25320356"],"is_preprint":false},{"year":2018,"finding":"Clever-1-deficient macrophages show increased TNF-α synthesis; in co-culture, Clever-1-deficient monocytes/macrophages support higher IgM production by B cells in a TNF-α-dependent manner; macrophage-specific Clever-1 ablation results in elevated IgG levels and enhanced humoral immune responses in vivo.","method":"Stab1 knockout mice; macrophage-specific conditional knockout; ELISA for antibody levels and cytokines; B cell–macrophage co-culture; TNF-α depletion experiments","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus co-culture with cytokine depletion rescue; single lab with multiple functional readouts","pmids":["30349531"],"is_preprint":false},{"year":2019,"finding":"Genetic deficiency of macrophage Clever-1 impairs solid tumor growth by converting macrophages from immunosuppressive to immunostimulatory, thereby activating endogenous antitumor CD8+ T cells; therapeutic blockade of Clever-1 has comparable effects and synergizes with anti-PD-1 in aggressive tumors.","method":"Conditional Clever-1 knockout; bone marrow chimeras; cell depletion experiments; anti-Clever-1 immunotherapy alone and combined with anti-PD-1 in multiple mouse cancer models; flow cytometry","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (conditional KO, chimeras, cell depletion) plus therapeutic antibody experiments with mechanistic readouts across multiple tumor models","pmids":["30755440"],"is_preprint":false},{"year":2019,"finding":"Clever-1 controls CD8+ T cell and B220+ B cell homing to the spleen specifically via vessels in the red pulp; absence of Clever-1 leads to downregulation of the B cell attractant chemokine CXCL13 on spleen endothelium, contributing to reduced B cell trafficking into the spleen.","method":"Ex vivo adhesion assays in mice and humans; genetic ablation of Clever-1 in mice; CXCL13 expression analysis on spleen endothelium; adoptive transfer / homing assays","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic ablation with ex vivo adhesion assays and chemokine expression readout; single lab, multiple methods","pmids":["30926591"],"is_preprint":false},{"year":2021,"finding":"Anti-Clever-1 antibody FP-1305 (bexmarilimab) impairs multiprotein vacuolar ATPase-mediated endosomal acidification in primary human macrophages (identified by pull-down interactome assays) and improves the ability of macrophages to activate CD8+ T cells; in patients, FP-1305 suppresses nuclear lipid signaling and induces a proinflammatory phenotypic switch in blood monocytes.","method":"Antibody pull-down assays in primary human macrophages; mass cytometry; RNA sequencing; cytokine profiling; clinical trial patient samples (n=30)","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down interactome plus functional macrophage-T cell co-culture assays; supported by patient-level data; single study","pmids":["34078651"],"is_preprint":false},{"year":2021,"finding":"Clever-1 on lymphatic endothelial cells (LECs) promotes immunosuppression towards migrating dendritic cells; Clever-1 knockout impairs DC entrance into afferent lymphatics and reduces DC trafficking to draining lymph nodes; LECs in Clever-1 KO lymph nodes display a less tolerogenic phenotype with increased MHC II on DCs, enabling stronger OVA-specific T cell proliferative responses despite fewer DCs reaching the node.","method":"Clever-1 knockout mice; adoptive DC transfer experiments; flow cytometry; MHC II expression analysis; antigen-specific T cell proliferation assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with adoptive transfer and antigen-specific T cell readout; single lab, multiple methods","pmids":["33746947"],"is_preprint":false},{"year":2023,"finding":"Bi-allelic loss-of-function variants in STAB1 are associated with inherited hyperferritinemia without iron overload in humans; immunohistochemistry and flow cytometry confirmed absent or markedly reduced stabilin-1 protein in liver samples, monocytes, and monocyte-derived macrophages of affected individuals, implicating stabilin-1 in ferritin metabolism.","method":"Whole-exome sequencing with homozygosity mapping; immunohistochemistry of liver biopsies; flow cytometry of monocytes and macrophages","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in humans confirmed by protein expression analysis; mechanistic link to ferritin metabolism inferred from human disease association, not in vitro reconstitution","pmids":["37490907"],"is_preprint":false},{"year":2025,"finding":"Secreted Clever-1 (sClever-1) is released from macrophages by IFNγ/LPS-induced serine protease-dependent cleavage; recombinant sClever-1 binds selectively to activated T cells via mannose-6-phosphate-mediated interaction with IGF2R, impairing TCR signaling and Th1 expansion; sClever-1 is also associated with macrophage-derived extracellular vesicles and contributes to T cell tolerance and reduced anti-PD-1 efficacy.","method":"TRFIA-based ELISA of plasma samples; recombinant protein production and biophysical characterization; flow cytometry; Western blotting; T cell activation assays; Jurkat reporter systems; extracellular vesicle isolation; pulldown assays with mass spectrometry; serine protease inhibitor studies; patient-derived tumor explants","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (pulldown + MS, biophysical characterization, functional T cell assays, inhibitor studies, tumor explants) establishing mechanism of sClever-1 release and IGF2R-mediated T cell suppression","pmids":["40756372"],"is_preprint":false},{"year":2025,"finding":"STAB1 knockdown in AML cell lines (HEL and NB4) suppresses proliferation and promotes apoptosis through downregulation of the IKK/NF-κB pathway; conditioned medium from STAB1-knockdown AML cells reduces M2 polarization of co-cultured macrophages; in vivo STAB1 silencing prolongs survival and reduces AML aggressiveness in xenograft models.","method":"siRNA/shRNA knockdown in AML cell lines; cell proliferation and apoptosis assays; NF-κB pathway activity assays; macrophage co-culture with conditioned medium; xenograft mouse models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway readout (IKK/NF-κB) plus in vivo xenograft; single lab, pathway mechanistically defined but no biochemical reconstitution of direct interaction","pmids":["40083109"],"is_preprint":false},{"year":2025,"finding":"HNF4A transcriptionally regulates NCOA2 by binding its promoter; NCOA2 interacts with glucocorticoid receptor (GR); STAB1 is identified as a downstream target gene of the HNF4A/NCOA2/GR transcriptional axis, with STAB1 expression required for IL-4-induced M2 macrophage polarization in the context of sepsis-associated lung injury.","method":"Adenovirus-mediated HNF4A overexpression in mouse sepsis model (cecal ligation and puncture); ChIP/promoter binding assay for HNF4A-NCOA2; co-immunoprecipitation for NCOA2-GR; transcriptome sequencing; in vitro IL-4-stimulated bone marrow-derived macrophage polarization with STAB1 inhibition","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional axis established by promoter binding and co-IP; STAB1 functional role in M2 polarization confirmed by in vitro inhibition; single lab","pmids":["39979267"],"is_preprint":false},{"year":2025,"finding":"CLEVER-1 blockade (bexmarilimab) reprograms tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype in gastric cancer by suppressing PPARγ-driven lipid metabolism and enhancing antigen presentation and inflammatory cytokine secretion; CLEVER-1 blockade synergizes with anti-PD-1 in ex vivo gastric cancer models.","method":"Flow cytometry; transcriptomic analysis of reprogrammed TAMs; ex vivo gastric cancer tumor models with bexmarilimab ± anti-PD-1; PPARγ pathway analysis","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo functional assays with mechanistic pathway (PPARγ) identification; single study, no full reconstitution","pmids":["40404204"],"is_preprint":false}],"current_model":"STAB1 (stabilin-1/CLEVER-1/FEEL-1) is a large multidomain transmembrane scavenger and adhesion receptor that cycles rapidly between the plasma membrane and EEA-1+ early endosomes via a cytoplasmic dileucine (DXXLL) sorting signal; it endocytoses diverse ligands including acetylated LDL, AGEs, and bacteria; its trafficking is regulated by SNX17, which binds the cytoplasmic NPxF motif and protects the protein from degradation; on lymphatic and vascular endothelium it mediates leukocyte (T cell, B cell, monocyte, DC) transmigration and homing—including entry into the spleen via the red pulp and chemokine CXCL13-dependent B cell trafficking; on immunosuppressive macrophages it promotes a tolerogenic phenotype by impairing vacuolar ATPase-mediated endosomal acidification, suppressing NF-κB and PPARγ-lipid metabolic pathways, and damping CD8+ T cell activation; a soluble shed form (sClever-1), released by serine protease cleavage, binds activated T cells via mannose-6-phosphate/IGF2R to impair TCR signaling; collectively, STAB1 acts as a multifunctional immunosuppressive scavenger receptor whose blockade reactivates anti-tumor CD8+ T cell responses and whose bi-allelic loss in humans causes hyperferritinemia, revealing an additional role in ferritin metabolism."},"narrative":{"mechanistic_narrative":"STAB1 (stabilin-1/CLEVER-1/FEEL-1) is a large multidomain transmembrane scavenger and adhesion receptor that operates at the interface of endocytic clearance and immune cell trafficking [PMID:12473645, PMID:15297319]. As an endocytic receptor it binds and internalizes advanced glycation end products and acetylated LDL with high affinity, a SR-A-type polyanion-sensitive activity, and also captures Gram-negative and Gram-positive bacteria [PMID:12473645, PMID:12077138]. The receptor is predominantly intracellular and cycles rapidly between the plasma membrane and EEA-1+ early endosomes through a cytoplasmic dileucine (DXXLL) sorting signal, while its Link domain does not bind hyaluronan [PMID:15345716]; this trafficking and protein stability are governed by sorting nexin 17 (SNX17), which binds the cytoplasmic NPxF motif and protects the receptor from degradation [PMID:20226821]. On lymphatic and inflamed vascular endothelium, STAB1 supports leukocyte rolling and transmigration and directs in vivo homing of T and B lymphocytes, monocytes, and dendritic cells, including red-pulp entry into the spleen and CXCL13-dependent B cell trafficking [PMID:15297319, PMID:19830743, PMID:30926591, PMID:33746947]. On macrophages STAB1 enforces an immunosuppressive, tolerogenic state: its loss or antibody blockade (bexmarilimab/FP-1305) reprograms macrophages toward a proinflammatory phenotype by impairing vacuolar-ATPase-mediated endosomal acidification, relieving suppression of NF-κB and PPARγ-driven lipid metabolism, and thereby reactivating endogenous antitumor CD8+ T cells synergistically with anti-PD-1 [PMID:30755440, PMID:34078651, PMID:40404204]. A soluble shed form (sClever-1), generated by serine-protease cleavage, binds activated T cells via mannose-6-phosphate/IGF2R to impair TCR signaling and Th1 expansion [PMID:40756372]. Consistent with these dual scavenging and immune roles, STAB1 knockout reduces primary and metastatic tumor growth [PMID:25320356], and in humans bi-allelic loss-of-function variants in STAB1 cause inherited hyperferritinemia without iron overload, revealing a role in ferritin metabolism [PMID:37490907].","teleology":[{"year":2002,"claim":"Established STAB1 as a functional endocytic scavenger receptor, answering what molecular ligands it clears.","evidence":"Radioligand binding and uptake/degradation assays in CHO cells overexpressing FEEL-1, with polyanion competition and antibody blocking on endothelial cells","pmids":["12473645","12077138"],"confidence":"High","gaps":["Binding domain on STAB1 not mapped","In vivo physiological clearance role not addressed"]},{"year":2003,"claim":"Showed STAB1 (CLEVER-1) on lymphatic endothelium mediates tumor cell adhesion, linking the receptor to cancer cell dissemination.","evidence":"In vitro adhesion assays with antibody blocking of CLEVER-1 and mannose receptor on lymphatic endothelial cells","pmids":["12907648"],"confidence":"Medium","gaps":["Adhesion ligand on cancer cells not identified","No in vivo metastasis confirmation in this study"]},{"year":2004,"claim":"Defined STAB1 as an adhesion molecule supporting leukocyte transmigration and clarified its subcellular trafficking and sorting determinants.","evidence":"Flow chamber and transmigration assays; chimeric domain-swapping, EEA-1 colocalization, and ligand uptake in HeLa cells","pmids":["15297319","15345716"],"confidence":"High","gaps":["Dileucine signal function shown as putative, not mutationally proven here","Endothelial counter-receptor on leukocytes unidentified"]},{"year":2009,"claim":"Demonstrated STAB1 controls in vivo lymphocyte and myeloid cell migration, moving the receptor from in vitro adhesion to physiological inflammatory trafficking.","evidence":"In vivo lymphocyte migration and peritonitis models with antibody blocking, adoptive transfer, and epitope mapping in mice","pmids":["19830743"],"confidence":"High","gaps":["Adhesive epitope's molecular ligand not defined","Cell-intrinsic vs endothelial contribution not fully separated"]},{"year":2010,"claim":"Identified SNX17 as a direct cytoplasmic-tail partner that controls STAB1 stability, explaining how receptor levels and ligand uptake are post-translationally regulated.","evidence":"Co-immunoprecipitation, NPxF-motif mutagenesis, and SNX17 siRNA knockdown with ligand uptake readout","pmids":["20226821"],"confidence":"High","gaps":["Degradation route protected by SNX17 not defined","No structural detail of the NPxF–PX interaction"]},{"year":2011,"claim":"Extended STAB1 function to tissue macrophages, linking scavenging activity to cytokine output and macrophage adhesion/transmigration.","evidence":"siRNA knockdown in human placental macrophages with ligand uptake, cytokine profiling, and transmigration assays","pmids":["21480214"],"confidence":"Medium","gaps":["Signaling pathway connecting STAB1 to cytokine changes not defined","Single tissue context"]},{"year":2014,"claim":"Established STAB1 as a pro-tumoral receptor in vivo, showing genetic loss and antibody blockade reduce tumor growth via immunosuppressive leukocyte recruitment.","evidence":"Full and cell-type-specific conditional knockout mice, bone marrow chimeras, and anti-Clever-1 antibody therapy in melanoma and lymphoma models","pmids":["25320356"],"confidence":"High","gaps":["Molecular mechanism of immunosuppression not yet defined here","Endothelial vs macrophage relative contributions partially resolved"]},{"year":2019,"claim":"Defined the immunosuppressive mechanism: macrophage STAB1 restrains antitumor CD8+ T cells, and its blockade synergizes with anti-PD-1.","evidence":"Conditional knockout, chimeras, cell depletion, and anti-Clever-1 ± anti-PD-1 immunotherapy across multiple mouse tumor models","pmids":["30755440"],"confidence":"High","gaps":["Downstream molecular effector of macrophage suppression not yet identified in this study","Direct vs indirect effect on T cells unclear"]},{"year":2019,"claim":"Localized STAB1 trafficking control to splenic red-pulp vessels and connected it to chemokine-dependent B cell homing.","evidence":"Genetic ablation with ex vivo adhesion assays, homing assays, and CXCL13 expression analysis on spleen endothelium","pmids":["30926591"],"confidence":"Medium","gaps":["Mechanism linking STAB1 loss to CXCL13 downregulation unknown","Consequences for systemic immunity not assessed"]},{"year":2021,"claim":"Resolved the molecular basis of macrophage tolerance: STAB1 blockade impairs V-ATPase endosomal acidification and rewires nuclear lipid signaling to enhance T cell activation.","evidence":"Antibody pull-down interactome, mass cytometry, RNA-seq, and cytokine profiling in primary human macrophages with clinical trial patient samples; lymphatic endothelial knockout DC trafficking assays","pmids":["34078651","33746947"],"confidence":"Medium","gaps":["Direct vs indirect V-ATPase interaction not biochemically resolved","Link between acidification defect and lipid signaling switch incomplete"]},{"year":2023,"claim":"Connected STAB1 to a human Mendelian phenotype, revealing an unexpected role in ferritin metabolism.","evidence":"Whole-exome sequencing with homozygosity mapping plus protein expression analysis in liver, monocytes, and macrophages of affected individuals","pmids":["37490907"],"confidence":"Medium","gaps":["Mechanistic link between STAB1 loss and hyperferritinemia not reconstituted","Whether ferritin is a direct ligand unknown"]},{"year":2025,"claim":"Identified a soluble shed form of STAB1 acting in trans on T cells, defining a secreted immunosuppressive mechanism via IGF2R.","evidence":"Serine protease inhibitor studies, recombinant sClever-1 biophysics, pulldown/MS, T cell activation and Jurkat reporter assays, EV isolation, and tumor explants","pmids":["40756372"],"confidence":"High","gaps":["Identity of the responsible serine protease not pinned down","Relative in vivo contribution of soluble vs membrane STAB1 unresolved"]},{"year":2025,"claim":"Extended STAB1's tumor-promoting role to cell-intrinsic AML survival and to transcriptional control of M2 macrophage polarization.","evidence":"STAB1 knockdown in AML cell lines with NF-κB pathway and xenograft readouts; HNF4A/NCOA2/GR axis with ChIP, co-IP, and IL-4-driven macrophage polarization assays; bexmarilimab gastric cancer TAM reprogramming via PPARγ","pmids":["40083109","39979267","40404204"],"confidence":"Medium","gaps":["Whether STAB1 signals directly into IKK/NF-κB or acts indirectly is unresolved","Mechanism connecting STAB1 to PPARγ lipid metabolism incomplete"]},{"year":null,"claim":"The biochemical mechanism linking STAB1 to ferritin handling and the direct signaling output of the receptor's cytoplasmic tail remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstitution of STAB1-dependent ferritin uptake or efflux","Direct intracellular signaling effectors of STAB1 not identified","Structural basis of ligand and partner binding unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,8,10,13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,5,11]}],"complexes":[],"partners":["SNX17","IGF2R"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NY15","full_name":"Stabilin-1","aliases":["Fasciclin, EGF-like, laminin-type EGF-like and link domain-containing scavenger receptor 1","FEEL-1","MS-1 antigen"],"length_aa":2570,"mass_kda":275.5,"function":"Acts as a scavenger receptor for acetylated low density lipoprotein. Binds to both Gram-positive and Gram-negative bacteria and may play a role in defense against bacterial infection. When inhibited in endothelial tube formation assays, there is a marked decrease in cell-cell interactions, suggesting a role in angiogenesis. Involved in the delivery of newly synthesized CHID1/SI-CLP from the biosynthetic compartment to the endosomal/lysosomal system","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9NY15/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STAB1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STAB1","total_profiled":1310},"omim":[{"mim_id":"620729","title":"HYPERFERRITINEMIA; HRFT","url":"https://www.omim.org/entry/620729"},{"mim_id":"615692","title":"CHITINASE DOMAIN-CONTAINING PROTEIN 1; CHID1","url":"https://www.omim.org/entry/615692"},{"mim_id":"608561","title":"STABILIN 2; STAB2","url":"https://www.omim.org/entry/608561"},{"mim_id":"608560","title":"STABILIN 1; STAB1","url":"https://www.omim.org/entry/608560"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":428.0}],"url":"https://www.proteinatlas.org/search/STAB1"},"hgnc":{"alias_symbol":["KIAA0246","STAB-1","FEEL-1","CLEVER-1","FELE-1","FEX1","SCARH2"],"prev_symbol":[]},"alphafold":{"accession":"Q9NY15","domains":[{"cath_id":"2.10.25","chopping":"163-211","consensus_level":"medium","plddt":65.7727,"start":163,"end":211},{"cath_id":"-","chopping":"273-332","consensus_level":"medium","plddt":63.4132,"start":273,"end":332},{"cath_id":"2.30.180.10","chopping":"359-492","consensus_level":"high","plddt":74.4418,"start":359,"end":492},{"cath_id":"2.30.180.10","chopping":"510-638","consensus_level":"high","plddt":77.2577,"start":510,"end":638},{"cath_id":"-","chopping":"757-802","consensus_level":"medium","plddt":70.5113,"start":757,"end":802},{"cath_id":"2.30.180.10","chopping":"1136-1188_1200-1249","consensus_level":"medium","plddt":72.121,"start":1136,"end":1249},{"cath_id":"2.10.25,2.10.25","chopping":"1500-1565","consensus_level":"medium","plddt":59.7976,"start":1500,"end":1565},{"cath_id":"2.30.180.10","chopping":"1596-1613_1622-1723","consensus_level":"medium","plddt":79.3689,"start":1596,"end":1723},{"cath_id":"2.30.180.10","chopping":"1729-1877","consensus_level":"high","plddt":80.9907,"start":1729,"end":1877},{"cath_id":"2.10.25.10","chopping":"2135-2177","consensus_level":"medium","plddt":56.9805,"start":2135,"end":2177},{"cath_id":"2.30.180.10","chopping":"2331-2422_2431-2463","consensus_level":"medium","plddt":75.4148,"start":2331,"end":2463},{"cath_id":"3.30.70","chopping":"35-98","consensus_level":"medium","plddt":63.2,"start":35,"end":98}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NY15","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NY15-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NY15-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STAB1","jax_strain_url":"https://www.jax.org/strain/search?query=STAB1"},"sequence":{"accession":"Q9NY15","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NY15.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NY15/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NY15"}},"corpus_meta":[{"pmid":"12473645","id":"PMC_12473645","title":"FEEL-1 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Jaw","date":"2025-09-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.27.678999","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.10.664161","title":"<i>Acinetobacter</i>  phages use distinct strategies to breach the capsule barrier","date":"2025-07-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.10.664161","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19115,"output_tokens":5508,"usd":0.069983,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14119,"output_tokens":4336,"usd":0.089497,"stage2_stop_reason":"end_turn"},"total_usd":0.15948,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"FEEL-1 (STAB1) functions as an endocytic receptor for advanced glycation end products (AGEs): CHO cells overexpressing FEEL-1 bound 125I-AGE-BSA with high affinity (Kd ~2.55 µg/ml) at 4°C, and at 37°C took up and degraded the ligand; binding was inhibited by polyanionic SR-A inhibitors (fucoidan, polyinosinic acid, dextran sulfate) but not by native or oxidized LDL.\",\n      \"method\": \"Radioligand binding assay and uptake/degradation assay in CHO cells overexpressing FEEL-1; competitive inhibition with polyanionic ligands\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative radioligand binding and internalization assays with overexpression system, replicated across FEEL-1 and FEEL-2 with multiple inhibitor controls\",\n      \"pmids\": [\"12473645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FEEL-1 (STAB1) is the major receptor for acetylated LDL (Ac-LDL) on human umbilical vein endothelial cells, as demonstrated by monoclonal antibody blocking; FEEL-1 and FEEL-2 expressed in CHO cells both bind DiI-Ac-LDL and Gram-negative and Gram-positive bacteria; inhibition of FEEL-1 with monoclonal antibody markedly reduced cell-cell interaction in the Matrigel tube formation assay, indicating a role in angiogenesis.\",\n      \"method\": \"Expression cloning; monoclonal antibody blocking of DiI-Ac-LDL uptake; transient overexpression in CHO cells; in vitro Matrigel tube formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — monoclonal antibody blocking plus overexpression binding assay; angiogenesis role from single lab with one in vitro assay\",\n      \"pmids\": [\"12077138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CLEVER-1 (STAB1) on lymphatic endothelium mediates adhesion of head-and-neck cancer cell lines to lymphatic endothelium; adhesion of all tested cancer cell lines was dependent on both CLEVER-1 and mannose receptor, as shown by antibody blocking experiments.\",\n      \"method\": \"In vitro adhesion assays with antibody blocking of CLEVER-1 and mannose receptor on lymphatic endothelial cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional blocking antibody experiments in cell adhesion assay, single lab\",\n      \"pmids\": [\"12907648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CLEVER-1 (STAB1) supports rolling and transmigration of peripheral blood mononuclear cells (PBMCs) across vascular endothelium under physiological laminar shear stress, and also mediates transmigration of leukocytes through lymphatic endothelium under static conditions; CLEVER-1 is constitutively expressed on lymphatic vessels in skin and induced on vascular endothelium upon inflammation.\",\n      \"method\": \"Flow chamber assay under shear stress; transmigration assay through cultured lymphatic endothelium; immunofluorescence of tissue sections\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — flow chamber and transmigration assays with direct functional readouts on both vascular and lymphatic endothelium; replicated in two distinct vascular beds\",\n      \"pmids\": [\"15297319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Stabilin-1 (STAB1) is predominantly intracellular and cycles rapidly between the plasma membrane and EEA-1+ early endosomes; intracellular targeting is influenced by the transmembrane domain/cytoplasmic tail, which contains a putative dileucine (DXXLL) Golgi-to-endosomal sorting signal; the stabilin-1 Link domain does not bind hyaluronan or other glycosaminoglycans.\",\n      \"method\": \"Fluorescent antibody and Fl-Ac-LDL uptake assays; subcellular fractionation/immunofluorescence colocalization with EEA-1; stabilin-1/CD44 chimera expression in HeLa cells; hyaluronan binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (live-cell imaging, chimeric protein domain swapping, ligand binding assay, colocalization with endosomal marker); negative Link-domain binding result experimentally established\",\n      \"pmids\": [\"15345716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Clever-1/Stabilin-1 mediates in vivo migration of T and B lymphocytes to draining lymph nodes via lymphatics; an adhesive epitope on Clever-1/Stabilin-1 responsible for the interaction between lymphocytes and lymphatic endothelium was identified; antibody blocking of Clever-1/Stabilin-1 inhibited peritonitis in mice by reducing granulocyte entrance by ~50% and nearly abolishing monocyte and lymphocyte migration into the inflamed peritoneum.\",\n      \"method\": \"In vivo lymphocyte migration models; antibody blocking in peritonitis mouse model; adoptive transfer experiments; epitope mapping\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic and antibody blocking experiments with quantitative cell trafficking readouts; adhesive epitope mapped; multiple inflammatory models\",\n      \"pmids\": [\"19830743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sorting nexin 17 (SNX17), a phox-homology domain protein, directly interacts with the cytoplasmic tail of FEEL-1/stabilin-1 via the NPxF motif; SNX17 regulates FEEL-1/stabilin-1 trafficking and siRNA knockdown of SNX17 decreases total cellular FEEL-1/stabilin-1 expression and FEEL-1-mediated ligand uptake by enhancing protein degradation.\",\n      \"method\": \"Co-immunoprecipitation; cytoplasmic domain truncation and point-mutation constructs; siRNA knockdown; ligand uptake assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP, domain mutagenesis (NPxF motif), and functional rescue/knockdown with quantitative ligand uptake readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"20226821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Stabilin-1/CLEVER-1 on human placental macrophages mediates scavenging of Ac-LDL and uptake of fluorescently labeled OVA; siRNA-mediated suppression of stabilin-1/CLEVER-1 alters the cytokine profile produced by placental macrophages; stabilin-1/CLEVER-1 on placental macrophages mediates their adhesion to placental vessels and supports transmigration through vascular endothelium.\",\n      \"method\": \"siRNA knockdown; fluorescent ligand uptake assay; cytokine profiling; transmigration assay; flow cytometry\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts (scavenging, cytokine production, adhesion, transmigration) in a single lab study\",\n      \"pmids\": [\"21480214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Clever-1/Stabilin-1 deficiency (full knockout and macrophage- or endothelium-specific conditional knockouts) reduces primary and metastatic tumor growth in mice; Clever-1 mediates binding of immunosuppressive leukocytes to intratumoral blood vessels and facilitates tumor cell traffic via lymphatics; anti-Clever-1 antibody treatment inhibits tumor progression in wild-type mice.\",\n      \"method\": \"Full and conditional knockout mice (macrophage-specific, endothelium-specific); bone marrow chimeras; cell depletion experiments; anti-Clever-1 antibody therapy in B16 melanoma and EL-4 lymphoma models; flow cytometry of tumor-infiltrating leukocytes\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (full KO, two conditional KOs) plus antibody therapy with quantitative tumor growth and cellular phenotype readouts; cell-type-specific mechanisms dissected\",\n      \"pmids\": [\"25320356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Clever-1-deficient macrophages show increased TNF-α synthesis; in co-culture, Clever-1-deficient monocytes/macrophages support higher IgM production by B cells in a TNF-α-dependent manner; macrophage-specific Clever-1 ablation results in elevated IgG levels and enhanced humoral immune responses in vivo.\",\n      \"method\": \"Stab1 knockout mice; macrophage-specific conditional knockout; ELISA for antibody levels and cytokines; B cell–macrophage co-culture; TNF-α depletion experiments\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus co-culture with cytokine depletion rescue; single lab with multiple functional readouts\",\n      \"pmids\": [\"30349531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genetic deficiency of macrophage Clever-1 impairs solid tumor growth by converting macrophages from immunosuppressive to immunostimulatory, thereby activating endogenous antitumor CD8+ T cells; therapeutic blockade of Clever-1 has comparable effects and synergizes with anti-PD-1 in aggressive tumors.\",\n      \"method\": \"Conditional Clever-1 knockout; bone marrow chimeras; cell depletion experiments; anti-Clever-1 immunotherapy alone and combined with anti-PD-1 in multiple mouse cancer models; flow cytometry\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (conditional KO, chimeras, cell depletion) plus therapeutic antibody experiments with mechanistic readouts across multiple tumor models\",\n      \"pmids\": [\"30755440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Clever-1 controls CD8+ T cell and B220+ B cell homing to the spleen specifically via vessels in the red pulp; absence of Clever-1 leads to downregulation of the B cell attractant chemokine CXCL13 on spleen endothelium, contributing to reduced B cell trafficking into the spleen.\",\n      \"method\": \"Ex vivo adhesion assays in mice and humans; genetic ablation of Clever-1 in mice; CXCL13 expression analysis on spleen endothelium; adoptive transfer / homing assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic ablation with ex vivo adhesion assays and chemokine expression readout; single lab, multiple methods\",\n      \"pmids\": [\"30926591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Anti-Clever-1 antibody FP-1305 (bexmarilimab) impairs multiprotein vacuolar ATPase-mediated endosomal acidification in primary human macrophages (identified by pull-down interactome assays) and improves the ability of macrophages to activate CD8+ T cells; in patients, FP-1305 suppresses nuclear lipid signaling and induces a proinflammatory phenotypic switch in blood monocytes.\",\n      \"method\": \"Antibody pull-down assays in primary human macrophages; mass cytometry; RNA sequencing; cytokine profiling; clinical trial patient samples (n=30)\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down interactome plus functional macrophage-T cell co-culture assays; supported by patient-level data; single study\",\n      \"pmids\": [\"34078651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Clever-1 on lymphatic endothelial cells (LECs) promotes immunosuppression towards migrating dendritic cells; Clever-1 knockout impairs DC entrance into afferent lymphatics and reduces DC trafficking to draining lymph nodes; LECs in Clever-1 KO lymph nodes display a less tolerogenic phenotype with increased MHC II on DCs, enabling stronger OVA-specific T cell proliferative responses despite fewer DCs reaching the node.\",\n      \"method\": \"Clever-1 knockout mice; adoptive DC transfer experiments; flow cytometry; MHC II expression analysis; antigen-specific T cell proliferation assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with adoptive transfer and antigen-specific T cell readout; single lab, multiple methods\",\n      \"pmids\": [\"33746947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bi-allelic loss-of-function variants in STAB1 are associated with inherited hyperferritinemia without iron overload in humans; immunohistochemistry and flow cytometry confirmed absent or markedly reduced stabilin-1 protein in liver samples, monocytes, and monocyte-derived macrophages of affected individuals, implicating stabilin-1 in ferritin metabolism.\",\n      \"method\": \"Whole-exome sequencing with homozygosity mapping; immunohistochemistry of liver biopsies; flow cytometry of monocytes and macrophages\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in humans confirmed by protein expression analysis; mechanistic link to ferritin metabolism inferred from human disease association, not in vitro reconstitution\",\n      \"pmids\": [\"37490907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Secreted Clever-1 (sClever-1) is released from macrophages by IFNγ/LPS-induced serine protease-dependent cleavage; recombinant sClever-1 binds selectively to activated T cells via mannose-6-phosphate-mediated interaction with IGF2R, impairing TCR signaling and Th1 expansion; sClever-1 is also associated with macrophage-derived extracellular vesicles and contributes to T cell tolerance and reduced anti-PD-1 efficacy.\",\n      \"method\": \"TRFIA-based ELISA of plasma samples; recombinant protein production and biophysical characterization; flow cytometry; Western blotting; T cell activation assays; Jurkat reporter systems; extracellular vesicle isolation; pulldown assays with mass spectrometry; serine protease inhibitor studies; patient-derived tumor explants\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (pulldown + MS, biophysical characterization, functional T cell assays, inhibitor studies, tumor explants) establishing mechanism of sClever-1 release and IGF2R-mediated T cell suppression\",\n      \"pmids\": [\"40756372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STAB1 knockdown in AML cell lines (HEL and NB4) suppresses proliferation and promotes apoptosis through downregulation of the IKK/NF-κB pathway; conditioned medium from STAB1-knockdown AML cells reduces M2 polarization of co-cultured macrophages; in vivo STAB1 silencing prolongs survival and reduces AML aggressiveness in xenograft models.\",\n      \"method\": \"siRNA/shRNA knockdown in AML cell lines; cell proliferation and apoptosis assays; NF-κB pathway activity assays; macrophage co-culture with conditioned medium; xenograft mouse models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway readout (IKK/NF-κB) plus in vivo xenograft; single lab, pathway mechanistically defined but no biochemical reconstitution of direct interaction\",\n      \"pmids\": [\"40083109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNF4A transcriptionally regulates NCOA2 by binding its promoter; NCOA2 interacts with glucocorticoid receptor (GR); STAB1 is identified as a downstream target gene of the HNF4A/NCOA2/GR transcriptional axis, with STAB1 expression required for IL-4-induced M2 macrophage polarization in the context of sepsis-associated lung injury.\",\n      \"method\": \"Adenovirus-mediated HNF4A overexpression in mouse sepsis model (cecal ligation and puncture); ChIP/promoter binding assay for HNF4A-NCOA2; co-immunoprecipitation for NCOA2-GR; transcriptome sequencing; in vitro IL-4-stimulated bone marrow-derived macrophage polarization with STAB1 inhibition\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional axis established by promoter binding and co-IP; STAB1 functional role in M2 polarization confirmed by in vitro inhibition; single lab\",\n      \"pmids\": [\"39979267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLEVER-1 blockade (bexmarilimab) reprograms tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype in gastric cancer by suppressing PPARγ-driven lipid metabolism and enhancing antigen presentation and inflammatory cytokine secretion; CLEVER-1 blockade synergizes with anti-PD-1 in ex vivo gastric cancer models.\",\n      \"method\": \"Flow cytometry; transcriptomic analysis of reprogrammed TAMs; ex vivo gastric cancer tumor models with bexmarilimab ± anti-PD-1; PPARγ pathway analysis\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo functional assays with mechanistic pathway (PPARγ) identification; single study, no full reconstitution\",\n      \"pmids\": [\"40404204\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STAB1 (stabilin-1/CLEVER-1/FEEL-1) is a large multidomain transmembrane scavenger and adhesion receptor that cycles rapidly between the plasma membrane and EEA-1+ early endosomes via a cytoplasmic dileucine (DXXLL) sorting signal; it endocytoses diverse ligands including acetylated LDL, AGEs, and bacteria; its trafficking is regulated by SNX17, which binds the cytoplasmic NPxF motif and protects the protein from degradation; on lymphatic and vascular endothelium it mediates leukocyte (T cell, B cell, monocyte, DC) transmigration and homing—including entry into the spleen via the red pulp and chemokine CXCL13-dependent B cell trafficking; on immunosuppressive macrophages it promotes a tolerogenic phenotype by impairing vacuolar ATPase-mediated endosomal acidification, suppressing NF-κB and PPARγ-lipid metabolic pathways, and damping CD8+ T cell activation; a soluble shed form (sClever-1), released by serine protease cleavage, binds activated T cells via mannose-6-phosphate/IGF2R to impair TCR signaling; collectively, STAB1 acts as a multifunctional immunosuppressive scavenger receptor whose blockade reactivates anti-tumor CD8+ T cell responses and whose bi-allelic loss in humans causes hyperferritinemia, revealing an additional role in ferritin metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STAB1 (stabilin-1/CLEVER-1/FEEL-1) is a large multidomain transmembrane scavenger and adhesion receptor that operates at the interface of endocytic clearance and immune cell trafficking [#0, #3]. As an endocytic receptor it binds and internalizes advanced glycation end products and acetylated LDL with high affinity, a SR-A-type polyanion-sensitive activity, and also captures Gram-negative and Gram-positive bacteria [#0, #1]. The receptor is predominantly intracellular and cycles rapidly between the plasma membrane and EEA-1+ early endosomes through a cytoplasmic dileucine (DXXLL) sorting signal, while its Link domain does not bind hyaluronan [#4]; this trafficking and protein stability are governed by sorting nexin 17 (SNX17), which binds the cytoplasmic NPxF motif and protects the receptor from degradation [#6]. On lymphatic and inflamed vascular endothelium, STAB1 supports leukocyte rolling and transmigration and directs in vivo homing of T and B lymphocytes, monocytes, and dendritic cells, including red-pulp entry into the spleen and CXCL13-dependent B cell trafficking [#3, #5, #11, #13]. On macrophages STAB1 enforces an immunosuppressive, tolerogenic state: its loss or antibody blockade (bexmarilimab/FP-1305) reprograms macrophages toward a proinflammatory phenotype by impairing vacuolar-ATPase-mediated endosomal acidification, relieving suppression of NF-\\u03baB and PPAR\\u03b3-driven lipid metabolism, and thereby reactivating endogenous antitumor CD8+ T cells synergistically with anti-PD-1 [#10, #12, #18]. A soluble shed form (sClever-1), generated by serine-protease cleavage, binds activated T cells via mannose-6-phosphate/IGF2R to impair TCR signaling and Th1 expansion [#15]. Consistent with these dual scavenging and immune roles, STAB1 knockout reduces primary and metastatic tumor growth [#8], and in humans bi-allelic loss-of-function variants in STAB1 cause inherited hyperferritinemia without iron overload, revealing a role in ferritin metabolism [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established STAB1 as a functional endocytic scavenger receptor, answering what molecular ligands it clears.\",\n      \"evidence\": \"Radioligand binding and uptake/degradation assays in CHO cells overexpressing FEEL-1, with polyanion competition and antibody blocking on endothelial cells\",\n      \"pmids\": [\"12473645\", \"12077138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding domain on STAB1 not mapped\", \"In vivo physiological clearance role not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed STAB1 (CLEVER-1) on lymphatic endothelium mediates tumor cell adhesion, linking the receptor to cancer cell dissemination.\",\n      \"evidence\": \"In vitro adhesion assays with antibody blocking of CLEVER-1 and mannose receptor on lymphatic endothelial cells\",\n      \"pmids\": [\"12907648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adhesion ligand on cancer cells not identified\", \"No in vivo metastasis confirmation in this study\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined STAB1 as an adhesion molecule supporting leukocyte transmigration and clarified its subcellular trafficking and sorting determinants.\",\n      \"evidence\": \"Flow chamber and transmigration assays; chimeric domain-swapping, EEA-1 colocalization, and ligand uptake in HeLa cells\",\n      \"pmids\": [\"15297319\", \"15345716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dileucine signal function shown as putative, not mutationally proven here\", \"Endothelial counter-receptor on leukocytes unidentified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated STAB1 controls in vivo lymphocyte and myeloid cell migration, moving the receptor from in vitro adhesion to physiological inflammatory trafficking.\",\n      \"evidence\": \"In vivo lymphocyte migration and peritonitis models with antibody blocking, adoptive transfer, and epitope mapping in mice\",\n      \"pmids\": [\"19830743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adhesive epitope's molecular ligand not defined\", \"Cell-intrinsic vs endothelial contribution not fully separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified SNX17 as a direct cytoplasmic-tail partner that controls STAB1 stability, explaining how receptor levels and ligand uptake are post-translationally regulated.\",\n      \"evidence\": \"Co-immunoprecipitation, NPxF-motif mutagenesis, and SNX17 siRNA knockdown with ligand uptake readout\",\n      \"pmids\": [\"20226821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation route protected by SNX17 not defined\", \"No structural detail of the NPxF\\u2013PX interaction\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended STAB1 function to tissue macrophages, linking scavenging activity to cytokine output and macrophage adhesion/transmigration.\",\n      \"evidence\": \"siRNA knockdown in human placental macrophages with ligand uptake, cytokine profiling, and transmigration assays\",\n      \"pmids\": [\"21480214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway connecting STAB1 to cytokine changes not defined\", \"Single tissue context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established STAB1 as a pro-tumoral receptor in vivo, showing genetic loss and antibody blockade reduce tumor growth via immunosuppressive leukocyte recruitment.\",\n      \"evidence\": \"Full and cell-type-specific conditional knockout mice, bone marrow chimeras, and anti-Clever-1 antibody therapy in melanoma and lymphoma models\",\n      \"pmids\": [\"25320356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of immunosuppression not yet defined here\", \"Endothelial vs macrophage relative contributions partially resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the immunosuppressive mechanism: macrophage STAB1 restrains antitumor CD8+ T cells, and its blockade synergizes with anti-PD-1.\",\n      \"evidence\": \"Conditional knockout, chimeras, cell depletion, and anti-Clever-1 \\u00b1 anti-PD-1 immunotherapy across multiple mouse tumor models\",\n      \"pmids\": [\"30755440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream molecular effector of macrophage suppression not yet identified in this study\", \"Direct vs indirect effect on T cells unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Localized STAB1 trafficking control to splenic red-pulp vessels and connected it to chemokine-dependent B cell homing.\",\n      \"evidence\": \"Genetic ablation with ex vivo adhesion assays, homing assays, and CXCL13 expression analysis on spleen endothelium\",\n      \"pmids\": [\"30926591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking STAB1 loss to CXCL13 downregulation unknown\", \"Consequences for systemic immunity not assessed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the molecular basis of macrophage tolerance: STAB1 blockade impairs V-ATPase endosomal acidification and rewires nuclear lipid signaling to enhance T cell activation.\",\n      \"evidence\": \"Antibody pull-down interactome, mass cytometry, RNA-seq, and cytokine profiling in primary human macrophages with clinical trial patient samples; lymphatic endothelial knockout DC trafficking assays\",\n      \"pmids\": [\"34078651\", \"33746947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect V-ATPase interaction not biochemically resolved\", \"Link between acidification defect and lipid signaling switch incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected STAB1 to a human Mendelian phenotype, revealing an unexpected role in ferritin metabolism.\",\n      \"evidence\": \"Whole-exome sequencing with homozygosity mapping plus protein expression analysis in liver, monocytes, and macrophages of affected individuals\",\n      \"pmids\": [\"37490907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between STAB1 loss and hyperferritinemia not reconstituted\", \"Whether ferritin is a direct ligand unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a soluble shed form of STAB1 acting in trans on T cells, defining a secreted immunosuppressive mechanism via IGF2R.\",\n      \"evidence\": \"Serine protease inhibitor studies, recombinant sClever-1 biophysics, pulldown/MS, T cell activation and Jurkat reporter assays, EV isolation, and tumor explants\",\n      \"pmids\": [\"40756372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible serine protease not pinned down\", \"Relative in vivo contribution of soluble vs membrane STAB1 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended STAB1's tumor-promoting role to cell-intrinsic AML survival and to transcriptional control of M2 macrophage polarization.\",\n      \"evidence\": \"STAB1 knockdown in AML cell lines with NF-\\u03baB pathway and xenograft readouts; HNF4A/NCOA2/GR axis with ChIP, co-IP, and IL-4-driven macrophage polarization assays; bexmarilimab gastric cancer TAM reprogramming via PPAR\\u03b3\",\n      \"pmids\": [\"40083109\", \"39979267\", \"40404204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAB1 signals directly into IKK/NF-\\u03baB or acts indirectly is unresolved\", \"Mechanism connecting STAB1 to PPAR\\u03b3 lipid metabolism incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism linking STAB1 to ferritin handling and the direct signaling output of the receptor's cytoplasmic tail remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution of STAB1-dependent ferritin uptake or efflux\", \"Direct intracellular signaling effectors of STAB1 not identified\", \"Structural basis of ligand and partner binding unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 8, 10, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 5, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SNX17\",\n      \"IGF2R\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}