{"gene":"SCARA5","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2009,"finding":"SCARA5 is a ferritin receptor that binds serum ferritin at the cell surface and mediates its endocytosis, resulting in intracellular iron delivery independent of the transferrin/TfR1 pathway. This was demonstrated in kidney capsule cells during organogenesis.","method":"Chimeric embryo model (TfR1-/- fluorescence-tagged cells), cell-based ferritin binding and endocytosis assays, in vivo iron delivery assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-based binding and endocytosis assays combined with in vivo chimeric embryo model; foundational paper replicated by subsequent studies","pmids":["19154717"],"is_preprint":false},{"year":2006,"finding":"SCARA5 is a type II transmembrane protein that assembles as a homotrimer at the plasma membrane. It contains C-terminal intracellular, transmembrane, extracellular spacer, collagenous, and N-terminal scavenger receptor cysteine-rich (SRCR) domains. SCARA5-transfected cells bound E. coli and S. aureus in a polyanionic-inhibitable manner but could not endocytose acetylated or oxidized LDL, distinguishing it from SR-A1/II and MARCO.","method":"cDNA cloning, CHO cell transfection, plasma membrane localization assay, bacterial binding assay, modified LDL uptake assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct expression in CHO cells with functional assays for ligand binding, oligomerization, and localization; multiple orthogonal readouts in single study","pmids":["16407294"],"is_preprint":false},{"year":2009,"finding":"SCARA5 physically associates with focal adhesion kinase (FAK) and inhibits the tyrosine phosphorylation cascade of the FAK-Src-p130Cas signaling pathway. Silencing SCARA5 increased phosphorylation of FAK, Src, and p130Cas, and activated MMP9, promoting HCC cell invasion and metastasis.","method":"Co-immunoprecipitation (physical association with FAK), RNAi knockdown, overexpression, in vitro invasion/colony formation assays, in vivo tumorigenicity and lung metastasis assays, phosphorylation analysis by western blot","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for physical association, combined with loss- and gain-of-function experiments, both in vitro and in vivo","pmids":["20038795"],"is_preprint":false},{"year":2013,"finding":"Snail1 directly represses SCARA5 transcription by binding to E-box elements in the SCARA5 promoter, and this repression is required for TGF-β1-induced EMT-associated cell migration in A549 lung carcinoma cells. DNA methyltransferase 1 (DNMT1) was found to be physically associated with Snail1 to silence SCARA5 expression via a DNA methylation-independent mechanism.","method":"Chromatin immunoprecipitation (ChIP) assay for Snail1 binding to SCARA5 promoter E-boxes, gain- and loss-of-function experiments for Snail1, Co-IP for Snail1-DNMT1 association, TGF-β1-induced EMT model, cell migration assay","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding combined with Co-IP for protein association and functional rescue experiments; single lab but multiple orthogonal methods","pmids":["24061576"],"is_preprint":false},{"year":2014,"finding":"SCARA5 (Scara5) expressed on retinal endothelial cells acts as a receptor for L-ferritin, mediating ferritin transcytosis across the blood-retinal barrier. Intravenously injected ferritin crossed the blood-retinal barrier by binding to Scara5 on endothelial cells.","method":"In vivo intravenous ferritin injection, immunohistochemistry for Scara5/ferritin colocalization in mouse and human retina, murine photoreceptor degeneration model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ferritin injection with colocalization in retinal endothelial cells; single lab, colocalization-based inference for transcytosis mechanism","pmids":["25259650"],"is_preprint":false},{"year":2016,"finding":"SCARA5 acts as an endocytic receptor for HMGB1 in fish (pufferfish/zebrafish) models. SCARA5 associates with HMGB1 through the A and B boxes of HMGB1, depending on the redox state of cysteine residues (T box inhibits the association). SCARA5 mediates endocytosis of HMGB1 into lysosomes and negatively regulates HMGB1-mediated inflammatory signaling by clearing the HMGB1 mediator.","method":"Co-immunoprecipitation for SCARA5-HMGB1 interaction, domain mapping (A/B/T box), redox-state dependency assay, endocytosis/lysosome trafficking assay, overexpression/knockdown in fish cell models, cytokine expression assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping; fish model (ortholog) with multiple functional readouts; single lab","pmids":["27647835"],"is_preprint":false},{"year":2019,"finding":"Human SCARA5 is an adhesive and endocytic receptor for von Willebrand factor (VWF) and the VWF-FVIII complex, binding in a dose- and calcium-dependent manner. SCARA5-expressing HEK293T cells internalized VWF and VWF-FVIII into early endosomes. In human tissues, SCARA5 is expressed by kidney podocytes and splenic littoral endothelial cells lining the red pulp, where it colocalizes with VWF. SCARA5 deficiency had a modest influence on VWF half-life in vivo.","method":"Solid-phase binding assay (recombinant SCARA5 protein), HEK293T cell-based endocytosis assay, immunohistochemistry for tissue localization and VWF colocalization, SCARA5-deficient murine model for VWF half-life","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 / Strong — solid-phase binding assay with recombinant protein, cell-based endocytosis, in vivo murine model, and tissue colocalization; multiple orthogonal methods","pmids":["31126000"],"is_preprint":false},{"year":2017,"finding":"SCARA5 plays a role in adipocyte lineage commitment and differentiation of mesenchymal stem cells. RNAi-mediated knockdown of SCARA5 inhibited adipogenic potential of preadipocyte A33 cells, while overexpression enhanced adipocyte differentiation in C3H10T1/2 pluripotent stem cells. The FAK and ERK signaling pathways were found to be associated with SCARA5-mediated adipocyte commitment. Glucocorticoids induced SCARA5 expression through glucocorticoid response elements (GRE) in the SCARA5 promoter.","method":"Gain- and loss-of-function (RNAi, overexpression) in A33 and C3H10T1/2 cells, adipogenesis assays, western blot for FAK/ERK phosphorylation, promoter-GRE reporter assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function with defined cellular phenotype (adipogenesis), promoter analysis; single lab with multiple functional readouts","pmids":["29093466"],"is_preprint":false},{"year":2016,"finding":"SCARA5 knockdown in vascular smooth muscle cells (HASMCs) inhibited PDGF-BB-induced proliferation and migration by suppressing phosphorylation of PDGFRβ, AKT, and ERK1/2, placing SCARA5 as a positive regulator within the PDGF signaling pathway in VSMCs.","method":"siRNA knockdown of SCARA5 in HASMCs, MTT proliferation assay, migration assay, western blot for PDGFR-β/AKT/ERK1/2 phosphorylation","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, siRNA knockdown with phosphorylation readout; mechanism is loss-of-function with downstream signaling, no direct binding demonstrated","pmids":["27035566"],"is_preprint":false},{"year":2022,"finding":"SCARA5 binds directly to ferritin light chain (FTL) and promotes intracellular Fe2+ accumulation, leading to ferroptosis in esophageal squamous cell carcinoma (ESCC) cells. Co-immunoprecipitation confirmed the SCARA5-FTL interaction; overexpression of SCARA5 induced mitochondrial morphology changes, ROS accumulation, and increased Fe2+ consistent with ferroptosis.","method":"Co-immunoprecipitation (SCARA5-FTL interaction), flow cytometry (ROS, Fe2+), transmission electron microscopy (mitochondrial morphology), western blot (ferroptosis markers), xenograft model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct protein interaction, multiple orthogonal ferroptosis readouts, in vivo validation; single lab","pmids":["36513999"],"is_preprint":false},{"year":2018,"finding":"SPAG5 promotes HCC progression by downregulating SCARA5 expression through the β-catenin/TCF4 signaling pathway, specifically by modulating β-catenin degradation (reduced ubiquitination of β-catenin), which in turn suppresses SCARA5 transcription.","method":"SPAG5 overexpression and shRNA knockdown in HCC cells, western blot and RT-PCR for β-catenin and SCARA5, rescue experiments with SCARA5, in vivo xenograft model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis by rescue experiment and β-catenin degradation assay; single lab, pathway placement by inhibitor/knockdown studies","pmids":["30249289"],"is_preprint":false},{"year":2016,"finding":"Rock2 (ROCK2 kinase) decreases SCARA5 expression in renal cell carcinoma via the β-catenin/TCF4 pathway. Rock2 knockdown increased SCARA5 expression and suppressed RCC cell proliferation, establishing a Rock2-β-catenin/TCF4-SCARA5 regulatory axis.","method":"Rock2 knockdown by siRNA/shRNA, western blot and RT-PCR for SCARA5 and β-catenin pathway components, in vitro proliferation assay, in vivo xenograft","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach without direct binding or promoter binding evidence for SCARA5","pmids":["27793664"],"is_preprint":false},{"year":2017,"finding":"CSN5 (COP9 signalosome subunit 5 / E3 ubiquitin ligase) decreases β-catenin ubiquitination, leading to elevated β-catenin protein levels that suppress SCARA5 expression in HCC. CSN5 knockdown increased SCARA5 expression and inhibited HCC proliferation and metastasis in vitro and in vivo.","method":"CSN5 overexpression and lentiviral knockdown in HCC cells, western blot for β-catenin ubiquitination and SCARA5, RT-PCR, immunohistochemistry, in vivo xenograft","journal":"Digestive diseases and sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect pathway evidence through β-catenin ubiquitination assay without direct SCARA5 promoter analysis","pmids":["29189991"],"is_preprint":false},{"year":2025,"finding":"SCARA5 enhances intracellular availability of bioactive ferrous iron (Fe2+) by promoting autophagic degradation of ferritin (the major iron storage protein), thereby sensitizing HCC cells to ferroptosis induced by erastin and RSL3. SCARA5-deficient cells showed reduced ferroptosis sensitivity and contributed to sorafenib resistance.","method":"Cell viability assay (erastin/RSL3 treatment), ROS/lipid ROS/MDA/Fe2+ measurement, autophagy flux assay for ferritin degradation, SCARA5-knockout MEFs and HCC cells, sorafenib resistance assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal ferroptosis readouts plus autophagic ferritin degradation measurement in knockout cells; single lab","pmids":["39954713"],"is_preprint":false},{"year":2025,"finding":"SCARA5 physically interacts with GPX4 (glutathione peroxidase 4), negatively regulating its expression. Baicalein promotes SCARA5 expression (via inhibiting DNMT1-mediated methylation of the SCARA5 promoter), which through its negative effect on GPX4 promotes ferroptosis in hepatic stellate cells. HSC-specific knock-in of SCARA5 alleviated liver fibrosis in mice.","method":"Co-immunoprecipitation (SCARA5-GPX4 interaction), molecular docking, western blot for GPX4/SCARA5/DNMT1, Fe2+/MDA/ROS/GSH measurement, SCARA5 knock-in mouse model, Masson staining for fibrosis","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and molecular docking for SCARA5-GPX4 interaction, in vivo knock-in mouse model; single lab, multiple orthogonal methods","pmids":["41270385"],"is_preprint":false},{"year":2021,"finding":"SCARA5 overexpression in NSCLC upregulates HSPA5, which inhibits FOXM1 expression, leading to G2/M cell cycle arrest. This pathway was identified by RNA sequencing and validated with luciferase-based gene reporter assay and western blot.","method":"RNA sequencing transcriptome profiling, luciferase reporter assay, western blot (HSPA5, FOXM1 expression), flow cytometry (G2/M cell cycle arrest), in vivo xenograft","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay and transcriptomic pathway analysis with functional cell cycle readout; single lab","pmids":["34150631"],"is_preprint":false},{"year":2025,"finding":"SCARA5 physically interacts with FTL (ferritin light chain) protein, and SCARA5 upregulation reduces FTL protein ubiquitination, thereby stabilizing FTL and promoting ferroptosis by inhibiting mitochondrial damage in colon cancer cells.","method":"Co-immunoprecipitation (SCARA5-FTL interaction), ubiquitination assay for FTL, si-FTL rescue experiment, cell viability assay, ferroptosis markers","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP for interaction and ubiquitination assay reported; limited methodological detail in abstract","pmids":["40084377"],"is_preprint":false},{"year":2024,"finding":"SCARA5 was identified as an autoantigen target of a CSF-derived IgM antibody in multiple sclerosis patients. The IgM antibody bound SCARA5 on the cell surface and mediated antigen-dependent complement activation. Intrathecal injection of a SCARA5 antibody increased T cell infiltration in an EAE model.","method":"Immunoprecipitation and mass spectrometry for antigen identification, recombinant monoclonal IgM antibody production, complement activation assay, intrathecal antibody injection in EAE mouse model","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry-based antigen identification combined with functional complement assay and in vivo EAE model; single study with multiple orthogonal methods","pmids":["38123517"],"is_preprint":false},{"year":2025,"finding":"FOXO1 transcription factor positively regulates SCARA5 expression in human endometrial stromal cells. Knockdown of FOXO1 decreased SCARA5 expression, and FOXO1 protein was identified as a direct target of miR-424 (via its 3'-UTR by luciferase assay). miR-424/miR-503 overexpression suppressed SCARA5 expression during decidualization.","method":"FOXO1 knockdown (RT-PCR for SCARA5 expression), luciferase reporter assay (miR-424 targeting FOXO1 3'-UTR), miRNA overexpression in HESCs, immunofluorescence","journal":"Medical molecular morphology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown epistasis for FOXO1-SCARA5 relationship and luciferase assay for miR-424/FOXO1; indirect pathway placement for SCARA5","pmids":["40085209"],"is_preprint":false}],"current_model":"SCARA5 is a type II transmembrane homotrimeric class A scavenger receptor that functions as a ferritin (L-ferritin) endocytic receptor mediating non-transferrin iron delivery, binds and internalizes von Willebrand factor and the VWF-FVIII complex, and physically associates with FAK to suppress the FAK-Src-p130Cas signaling cascade; it also promotes ferroptosis by enhancing autophagic ferritin degradation and increasing intracellular Fe2+, interacts with GPX4 to reduce its expression, and its transcription is directly repressed by Snail1 (via E-box binding) and regulated upstream through β-catenin/TCF4, DNMT1-mediated promoter methylation, and FOXO1, collectively supporting roles in iron homeostasis, innate immunity, tumor suppression, and ferroptosis regulation."},"narrative":{"mechanistic_narrative":"SCARA5 is a type II transmembrane homotrimeric class A scavenger receptor that functions principally as an endocytic receptor mediating iron homeostasis, innate immunity, and tumor suppression [PMID:16407294]. Its founding role is as a ferritin (L-ferritin) receptor that binds serum ferritin at the cell surface and internalizes it to deliver iron independently of the transferrin/TfR1 pathway [PMID:19154717], an activity later shown to support ferritin transcytosis across the blood-retinal barrier on endothelial cells [PMID:25259650]. Beyond ferritin, SCARA5 acts as an adhesive and endocytic receptor for von Willebrand factor and the VWF-FVIII complex, internalizing them into early endosomes in podocytes and splenic littoral endothelium [PMID:31126000], and it clears the inflammatory mediator HMGB1 into lysosomes to dampen inflammatory signaling [PMID:27647835]. As a tumor suppressor, SCARA5 physically associates with FAK and restrains the FAK-Src-p130Cas cascade, limiting MMP9 activation, invasion, and metastasis [PMID:20038795]. SCARA5 also drives ferroptosis: it binds ferritin light chain (FTL) and promotes autophagic ferritin degradation to raise intracellular Fe2+ and lipid ROS [PMID:36513999, PMID:39954713], and it interacts with GPX4 to reduce its expression, sensitizing cells to ferroptosis [PMID:41270385]. SCARA5 transcription is directly repressed by Snail1 binding to promoter E-boxes during TGF-β1-induced EMT, in concert with DNMT1 [PMID:24061576], and is suppressed downstream of β-catenin/TCF4 signaling [PMID:30249289].","teleology":[{"year":2006,"claim":"Established SCARA5 as a structurally distinct class A scavenger receptor, defining its membrane topology, oligomeric state, and ligand selectivity to separate it from SR-A/MARCO.","evidence":"cDNA cloning and CHO cell transfection with plasma membrane localization, bacterial binding, and modified-LDL uptake assays","pmids":["16407294"],"confidence":"High","gaps":["Does not identify physiological endogenous ligands beyond bacteria","SRCR-domain ligand-binding determinants not mapped at residue level"]},{"year":2009,"claim":"Resolved how cells acquire iron independently of transferrin by identifying SCARA5 as a cell-surface ferritin receptor mediating ferritin endocytosis and iron delivery.","evidence":"TfR1-/- chimeric embryo model with fluorescence-tagged kidney capsule cells plus cell-based ferritin binding/endocytosis and in vivo iron delivery assays","pmids":["19154717"],"confidence":"High","gaps":["Endocytic adaptor and trafficking machinery not defined","Quantitative contribution to systemic iron balance not established"]},{"year":2009,"claim":"Defined a tumor-suppressive mechanism by showing SCARA5 physically binds FAK and suppresses the FAK-Src-p130Cas invasion-promoting cascade.","evidence":"Reciprocal Co-IP for FAK association, RNAi/overexpression with in vitro invasion and in vivo metastasis assays, phosphorylation western blots in HCC","pmids":["20038795"],"confidence":"High","gaps":["How an endocytic surface receptor engages cytoplasmic FAK is structurally unclear","Cytoplasmic-tail residues mediating FAK binding not mapped"]},{"year":2013,"claim":"Identified upstream transcriptional silencing of SCARA5, showing Snail1 directly represses its promoter during EMT in cooperation with DNMT1.","evidence":"ChIP for Snail1 binding to promoter E-boxes, Snail1 gain/loss-of-function, Snail1-DNMT1 Co-IP in a TGF-β1-induced EMT A549 model","pmids":["24061576"],"confidence":"High","gaps":["DNA methylation-independent mechanism of DNMT1 action not fully defined","Generality across non-lung tumor types not tested"]},{"year":2014,"claim":"Extended ferritin-receptor function to a barrier-transport context by showing endothelial SCARA5 mediates L-ferritin transcytosis across the blood-retinal barrier.","evidence":"In vivo intravenous ferritin injection with Scara5/ferritin colocalization immunohistochemistry and photoreceptor degeneration model","pmids":["25259650"],"confidence":"Medium","gaps":["Transcytosis inferred from colocalization rather than directional flux measurement","Single lab, no genetic loss-of-function for barrier transport"]},{"year":2016,"claim":"Broadened the receptor repertoire to innate immune mediator clearance, showing the SCARA5 ortholog endocytoses HMGB1 in a redox-dependent manner to lysosomes and dampens inflammation.","evidence":"Reciprocal Co-IP with A/B/T box domain mapping, redox-dependency and lysosomal trafficking assays in fish cell models with cytokine readouts","pmids":["27647835"],"confidence":"Medium","gaps":["Demonstrated in fish ortholog, not human SCARA5","Single lab"]},{"year":2016,"claim":"Suggested context-dependent pro-proliferative signaling by placing SCARA5 as a positive regulator of PDGF-driven proliferation and migration in vascular smooth muscle.","evidence":"siRNA knockdown in HASMCs with proliferation/migration assays and PDGFRβ/AKT/ERK1/2 phosphorylation western blots","pmids":["27035566"],"confidence":"Medium","gaps":["No direct binding to PDGF pathway components shown","Apparent positive signaling role conflicts with tumor-suppressive FAK data; reconciliation unaddressed"]},{"year":2017,"claim":"Implicated SCARA5 in mesenchymal cell fate by showing it promotes adipocyte lineage commitment via FAK/ERK signaling under glucocorticoid control.","evidence":"RNAi/overexpression in A33 and C3H10T1/2 cells with adipogenesis assays, FAK/ERK western blots, and a promoter-GRE reporter","pmids":["29093466"],"confidence":"Medium","gaps":["Direct receptor ligand driving differentiation not identified","Single lab"]},{"year":2018,"claim":"Connected SCARA5 transcriptional suppression to canonical β-catenin signaling via the SPAG5-β-catenin/TCF4 axis in HCC.","evidence":"SPAG5 overexpression/knockdown with β-catenin ubiquitination assays, SCARA5 rescue, and xenografts","pmids":["30249289"],"confidence":"Medium","gaps":["No direct TCF4 binding to SCARA5 promoter demonstrated","Single lab"]},{"year":2019,"claim":"Established SCARA5 as a receptor for von Willebrand factor and the VWF-FVIII complex, defining a hemostatic clearance/adhesion function in podocytes and splenic littoral endothelium.","evidence":"Solid-phase binding with recombinant SCARA5, HEK293T endocytosis into early endosomes, tissue colocalization, and SCARA5-deficient mouse VWF half-life","pmids":["31126000"],"confidence":"High","gaps":["In vivo effect on VWF half-life was modest, leaving physiological significance unclear","Binding domain on SCARA5 not mapped"]},{"year":2021,"claim":"Identified a cell-cycle arrest mechanism downstream of SCARA5 via HSPA5 upregulation and FOXM1 suppression causing G2/M arrest in NSCLC.","evidence":"RNA-seq, luciferase reporter, western blot, flow cytometry, and xenograft","pmids":["34150631"],"confidence":"Medium","gaps":["How a scavenger receptor controls HSPA5 transcription is unresolved","Direct molecular link between SCARA5 and HSPA5 not shown"]},{"year":2022,"claim":"Initiated the ferroptosis model by showing SCARA5 binds FTL and raises intracellular Fe2+ to induce ferroptosis in ESCC.","evidence":"Co-IP for SCARA5-FTL, flow cytometry for ROS/Fe2+, TEM for mitochondrial morphology, ferroptosis markers, and xenograft","pmids":["36513999"],"confidence":"Medium","gaps":["Mechanism linking FTL binding to Fe2+ release not defined here","Single lab"]},{"year":2024,"claim":"Revealed SCARA5 as a cell-surface autoantigen in multiple sclerosis, targeted by a CSF IgM that drives complement activation and T-cell infiltration.","evidence":"IP-mass spectrometry antigen identification, recombinant IgM, complement activation assay, and intrathecal injection in EAE","pmids":["38123517"],"confidence":"Medium","gaps":["Frequency and pathogenic role of anti-SCARA5 IgM across MS patients not established","Mechanism by which the antibody alters SCARA5 receptor function unknown"]},{"year":2025,"claim":"Mechanistically unified SCARA5's pro-ferroptotic activity, showing it promotes autophagic ferritin degradation to elevate Fe2+/lipid ROS and that loss confers sorafenib resistance.","evidence":"Erastin/RSL3 viability, ROS/lipid ROS/MDA/Fe2+ measurements, autophagy flux assays, and SCARA5-knockout MEFs/HCC cells","pmids":["39954713"],"confidence":"Medium","gaps":["How SCARA5 triggers ferritinophagy molecularly not resolved","Single lab"]},{"year":2025,"claim":"Added a GPX4 regulatory arm to the ferroptosis mechanism, showing SCARA5 interacts with and downregulates GPX4 and that its restoration alleviates liver fibrosis.","evidence":"Co-IP and molecular docking for SCARA5-GPX4, redox/iron measurements, DNMT1-methylation analysis, and HSC-specific SCARA5 knock-in mouse","pmids":["41270385"],"confidence":"Medium","gaps":["Mechanism by which SCARA5 lowers GPX4 (transcriptional vs degradation) not defined","Single lab"]},{"year":null,"claim":"How a single surface scavenger receptor reconciles opposing roles—pro-proliferative PDGF signaling versus tumor-suppressive FAK inhibition and ferroptosis induction—and which cytoplasmic-tail determinants route it between endocytosis, signaling, and ferritinophagy remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the SCARA5 cytoplasmic tail engaging FAK, FTL, or GPX4","Context-dependent pro- vs anti-tumor activities not mechanistically reconciled","Direct adaptor machinery for ferritin/VWF/HMGB1 endocytosis undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,4,5,6]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,13,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,17]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[6]}],"complexes":[],"partners":["FAK","FTL","GPX4","VWF","HMGB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZMJ2","full_name":"Scavenger receptor class A member 5","aliases":["Scavenger receptor hlg"],"length_aa":495,"mass_kda":54.0,"function":"Ferritin receptor that mediates non-transferrin-dependent delivery of iron. Mediates cellular uptake of ferritin-bound iron by stimulating ferritin endocytosis from the cell surface with consequent iron delivery within the cell. Delivery of iron to cells by ferritin is required for the development of specific cell types, suggesting the existence of cell type-specific mechanisms of iron traffic in organogenesis, which alternatively utilize transferrin or non-transferrin iron delivery pathways. Ferritin mediates iron uptake in capsule cells of the developing kidney. Preferentially binds ferritin light chain (FTL) compared to heavy chain (FTH1)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q6ZMJ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCARA5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SCARA5","total_profiled":1310},"omim":[{"mim_id":"611306","title":"SCAVENGER RECEPTOR CLASS A, MEMBER 5; SCARA5","url":"https://www.omim.org/entry/611306"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":87.1},{"tissue":"urinary bladder","ntpm":82.3}],"url":"https://www.proteinatlas.org/search/SCARA5"},"hgnc":{"alias_symbol":["FLJ23907","MGC45780","NET33"],"prev_symbol":[]},"alphafold":{"accession":"Q6ZMJ2","domains":[{"cath_id":"-","chopping":"87-244","consensus_level":"high","plddt":80.9556,"start":87,"end":244},{"cath_id":"3.10.250.10","chopping":"392-492","consensus_level":"high","plddt":95.9119,"start":392,"end":492}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZMJ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZMJ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZMJ2-F1-predicted_aligned_error_v6.png","plddt_mean":71.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCARA5","jax_strain_url":"https://www.jax.org/strain/search?query=SCARA5"},"sequence":{"accession":"Q6ZMJ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZMJ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZMJ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZMJ2"}},"corpus_meta":[{"pmid":"19154717","id":"PMC_19154717","title":"Scara5 is a ferritin receptor mediating non-transferrin iron delivery.","date":"2009","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/19154717","citation_count":286,"is_preprint":false},{"pmid":"16407294","id":"PMC_16407294","title":"Identification and characterization of murine SCARA5, a novel class A scavenger receptor that is expressed by populations of epithelial cells.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16407294","citation_count":124,"is_preprint":false},{"pmid":"20038795","id":"PMC_20038795","title":"Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling.","date":"2009","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/20038795","citation_count":121,"is_preprint":false},{"pmid":"24061576","id":"PMC_24061576","title":"Suppression of SCARA5 by Snail1 is essential for EMT-associated cell migration of A549 cells.","date":"2013","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24061576","citation_count":76,"is_preprint":false},{"pmid":"25259650","id":"PMC_25259650","title":"L-ferritin binding to scara5: a new iron traffic pathway potentially implicated in retinopathy.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25259650","citation_count":54,"is_preprint":false},{"pmid":"30249289","id":"PMC_30249289","title":"SPAG5 promotes hepatocellular carcinoma progression by downregulating SCARA5 through modifying β-catenin degradation.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30249289","citation_count":49,"is_preprint":false},{"pmid":"28497372","id":"PMC_28497372","title":"SCARA5 plays a critical role in the progression and metastasis of breast cancer by inactivating the ERK1/2, STAT3, and AKT signaling pathways.","date":"2017","source":"Molecular and cellular 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This was demonstrated in kidney capsule cells during organogenesis.\",\n      \"method\": \"Chimeric embryo model (TfR1-/- fluorescence-tagged cells), cell-based ferritin binding and endocytosis assays, in vivo iron delivery assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-based binding and endocytosis assays combined with in vivo chimeric embryo model; foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"19154717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SCARA5 is a type II transmembrane protein that assembles as a homotrimer at the plasma membrane. It contains C-terminal intracellular, transmembrane, extracellular spacer, collagenous, and N-terminal scavenger receptor cysteine-rich (SRCR) domains. SCARA5-transfected cells bound E. coli and S. aureus in a polyanionic-inhibitable manner but could not endocytose acetylated or oxidized LDL, distinguishing it from SR-A1/II and MARCO.\",\n      \"method\": \"cDNA cloning, CHO cell transfection, plasma membrane localization assay, bacterial binding assay, modified LDL uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct expression in CHO cells with functional assays for ligand binding, oligomerization, and localization; multiple orthogonal readouts in single study\",\n      \"pmids\": [\"16407294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SCARA5 physically associates with focal adhesion kinase (FAK) and inhibits the tyrosine phosphorylation cascade of the FAK-Src-p130Cas signaling pathway. Silencing SCARA5 increased phosphorylation of FAK, Src, and p130Cas, and activated MMP9, promoting HCC cell invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation (physical association with FAK), RNAi knockdown, overexpression, in vitro invasion/colony formation assays, in vivo tumorigenicity and lung metastasis assays, phosphorylation analysis by western blot\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for physical association, combined with loss- and gain-of-function experiments, both in vitro and in vivo\",\n      \"pmids\": [\"20038795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Snail1 directly represses SCARA5 transcription by binding to E-box elements in the SCARA5 promoter, and this repression is required for TGF-β1-induced EMT-associated cell migration in A549 lung carcinoma cells. DNA methyltransferase 1 (DNMT1) was found to be physically associated with Snail1 to silence SCARA5 expression via a DNA methylation-independent mechanism.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay for Snail1 binding to SCARA5 promoter E-boxes, gain- and loss-of-function experiments for Snail1, Co-IP for Snail1-DNMT1 association, TGF-β1-induced EMT model, cell migration assay\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding combined with Co-IP for protein association and functional rescue experiments; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24061576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SCARA5 (Scara5) expressed on retinal endothelial cells acts as a receptor for L-ferritin, mediating ferritin transcytosis across the blood-retinal barrier. Intravenously injected ferritin crossed the blood-retinal barrier by binding to Scara5 on endothelial cells.\",\n      \"method\": \"In vivo intravenous ferritin injection, immunohistochemistry for Scara5/ferritin colocalization in mouse and human retina, murine photoreceptor degeneration model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ferritin injection with colocalization in retinal endothelial cells; single lab, colocalization-based inference for transcytosis mechanism\",\n      \"pmids\": [\"25259650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SCARA5 acts as an endocytic receptor for HMGB1 in fish (pufferfish/zebrafish) models. SCARA5 associates with HMGB1 through the A and B boxes of HMGB1, depending on the redox state of cysteine residues (T box inhibits the association). SCARA5 mediates endocytosis of HMGB1 into lysosomes and negatively regulates HMGB1-mediated inflammatory signaling by clearing the HMGB1 mediator.\",\n      \"method\": \"Co-immunoprecipitation for SCARA5-HMGB1 interaction, domain mapping (A/B/T box), redox-state dependency assay, endocytosis/lysosome trafficking assay, overexpression/knockdown in fish cell models, cytokine expression assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping; fish model (ortholog) with multiple functional readouts; single lab\",\n      \"pmids\": [\"27647835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human SCARA5 is an adhesive and endocytic receptor for von Willebrand factor (VWF) and the VWF-FVIII complex, binding in a dose- and calcium-dependent manner. SCARA5-expressing HEK293T cells internalized VWF and VWF-FVIII into early endosomes. In human tissues, SCARA5 is expressed by kidney podocytes and splenic littoral endothelial cells lining the red pulp, where it colocalizes with VWF. SCARA5 deficiency had a modest influence on VWF half-life in vivo.\",\n      \"method\": \"Solid-phase binding assay (recombinant SCARA5 protein), HEK293T cell-based endocytosis assay, immunohistochemistry for tissue localization and VWF colocalization, SCARA5-deficient murine model for VWF half-life\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — solid-phase binding assay with recombinant protein, cell-based endocytosis, in vivo murine model, and tissue colocalization; multiple orthogonal methods\",\n      \"pmids\": [\"31126000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SCARA5 plays a role in adipocyte lineage commitment and differentiation of mesenchymal stem cells. RNAi-mediated knockdown of SCARA5 inhibited adipogenic potential of preadipocyte A33 cells, while overexpression enhanced adipocyte differentiation in C3H10T1/2 pluripotent stem cells. The FAK and ERK signaling pathways were found to be associated with SCARA5-mediated adipocyte commitment. Glucocorticoids induced SCARA5 expression through glucocorticoid response elements (GRE) in the SCARA5 promoter.\",\n      \"method\": \"Gain- and loss-of-function (RNAi, overexpression) in A33 and C3H10T1/2 cells, adipogenesis assays, western blot for FAK/ERK phosphorylation, promoter-GRE reporter assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function with defined cellular phenotype (adipogenesis), promoter analysis; single lab with multiple functional readouts\",\n      \"pmids\": [\"29093466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SCARA5 knockdown in vascular smooth muscle cells (HASMCs) inhibited PDGF-BB-induced proliferation and migration by suppressing phosphorylation of PDGFRβ, AKT, and ERK1/2, placing SCARA5 as a positive regulator within the PDGF signaling pathway in VSMCs.\",\n      \"method\": \"siRNA knockdown of SCARA5 in HASMCs, MTT proliferation assay, migration assay, western blot for PDGFR-β/AKT/ERK1/2 phosphorylation\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, siRNA knockdown with phosphorylation readout; mechanism is loss-of-function with downstream signaling, no direct binding demonstrated\",\n      \"pmids\": [\"27035566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SCARA5 binds directly to ferritin light chain (FTL) and promotes intracellular Fe2+ accumulation, leading to ferroptosis in esophageal squamous cell carcinoma (ESCC) cells. Co-immunoprecipitation confirmed the SCARA5-FTL interaction; overexpression of SCARA5 induced mitochondrial morphology changes, ROS accumulation, and increased Fe2+ consistent with ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation (SCARA5-FTL interaction), flow cytometry (ROS, Fe2+), transmission electron microscopy (mitochondrial morphology), western blot (ferroptosis markers), xenograft model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct protein interaction, multiple orthogonal ferroptosis readouts, in vivo validation; single lab\",\n      \"pmids\": [\"36513999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPAG5 promotes HCC progression by downregulating SCARA5 expression through the β-catenin/TCF4 signaling pathway, specifically by modulating β-catenin degradation (reduced ubiquitination of β-catenin), which in turn suppresses SCARA5 transcription.\",\n      \"method\": \"SPAG5 overexpression and shRNA knockdown in HCC cells, western blot and RT-PCR for β-catenin and SCARA5, rescue experiments with SCARA5, in vivo xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis by rescue experiment and β-catenin degradation assay; single lab, pathway placement by inhibitor/knockdown studies\",\n      \"pmids\": [\"30249289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rock2 (ROCK2 kinase) decreases SCARA5 expression in renal cell carcinoma via the β-catenin/TCF4 pathway. Rock2 knockdown increased SCARA5 expression and suppressed RCC cell proliferation, establishing a Rock2-β-catenin/TCF4-SCARA5 regulatory axis.\",\n      \"method\": \"Rock2 knockdown by siRNA/shRNA, western blot and RT-PCR for SCARA5 and β-catenin pathway components, in vitro proliferation assay, in vivo xenograft\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach without direct binding or promoter binding evidence for SCARA5\",\n      \"pmids\": [\"27793664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CSN5 (COP9 signalosome subunit 5 / E3 ubiquitin ligase) decreases β-catenin ubiquitination, leading to elevated β-catenin protein levels that suppress SCARA5 expression in HCC. CSN5 knockdown increased SCARA5 expression and inhibited HCC proliferation and metastasis in vitro and in vivo.\",\n      \"method\": \"CSN5 overexpression and lentiviral knockdown in HCC cells, western blot for β-catenin ubiquitination and SCARA5, RT-PCR, immunohistochemistry, in vivo xenograft\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect pathway evidence through β-catenin ubiquitination assay without direct SCARA5 promoter analysis\",\n      \"pmids\": [\"29189991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SCARA5 enhances intracellular availability of bioactive ferrous iron (Fe2+) by promoting autophagic degradation of ferritin (the major iron storage protein), thereby sensitizing HCC cells to ferroptosis induced by erastin and RSL3. SCARA5-deficient cells showed reduced ferroptosis sensitivity and contributed to sorafenib resistance.\",\n      \"method\": \"Cell viability assay (erastin/RSL3 treatment), ROS/lipid ROS/MDA/Fe2+ measurement, autophagy flux assay for ferritin degradation, SCARA5-knockout MEFs and HCC cells, sorafenib resistance assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal ferroptosis readouts plus autophagic ferritin degradation measurement in knockout cells; single lab\",\n      \"pmids\": [\"39954713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SCARA5 physically interacts with GPX4 (glutathione peroxidase 4), negatively regulating its expression. Baicalein promotes SCARA5 expression (via inhibiting DNMT1-mediated methylation of the SCARA5 promoter), which through its negative effect on GPX4 promotes ferroptosis in hepatic stellate cells. HSC-specific knock-in of SCARA5 alleviated liver fibrosis in mice.\",\n      \"method\": \"Co-immunoprecipitation (SCARA5-GPX4 interaction), molecular docking, western blot for GPX4/SCARA5/DNMT1, Fe2+/MDA/ROS/GSH measurement, SCARA5 knock-in mouse model, Masson staining for fibrosis\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and molecular docking for SCARA5-GPX4 interaction, in vivo knock-in mouse model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41270385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCARA5 overexpression in NSCLC upregulates HSPA5, which inhibits FOXM1 expression, leading to G2/M cell cycle arrest. This pathway was identified by RNA sequencing and validated with luciferase-based gene reporter assay and western blot.\",\n      \"method\": \"RNA sequencing transcriptome profiling, luciferase reporter assay, western blot (HSPA5, FOXM1 expression), flow cytometry (G2/M cell cycle arrest), in vivo xenograft\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay and transcriptomic pathway analysis with functional cell cycle readout; single lab\",\n      \"pmids\": [\"34150631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SCARA5 physically interacts with FTL (ferritin light chain) protein, and SCARA5 upregulation reduces FTL protein ubiquitination, thereby stabilizing FTL and promoting ferroptosis by inhibiting mitochondrial damage in colon cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (SCARA5-FTL interaction), ubiquitination assay for FTL, si-FTL rescue experiment, cell viability assay, ferroptosis markers\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP for interaction and ubiquitination assay reported; limited methodological detail in abstract\",\n      \"pmids\": [\"40084377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SCARA5 was identified as an autoantigen target of a CSF-derived IgM antibody in multiple sclerosis patients. The IgM antibody bound SCARA5 on the cell surface and mediated antigen-dependent complement activation. Intrathecal injection of a SCARA5 antibody increased T cell infiltration in an EAE model.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry for antigen identification, recombinant monoclonal IgM antibody production, complement activation assay, intrathecal antibody injection in EAE mouse model\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry-based antigen identification combined with functional complement assay and in vivo EAE model; single study with multiple orthogonal methods\",\n      \"pmids\": [\"38123517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXO1 transcription factor positively regulates SCARA5 expression in human endometrial stromal cells. Knockdown of FOXO1 decreased SCARA5 expression, and FOXO1 protein was identified as a direct target of miR-424 (via its 3'-UTR by luciferase assay). miR-424/miR-503 overexpression suppressed SCARA5 expression during decidualization.\",\n      \"method\": \"FOXO1 knockdown (RT-PCR for SCARA5 expression), luciferase reporter assay (miR-424 targeting FOXO1 3'-UTR), miRNA overexpression in HESCs, immunofluorescence\",\n      \"journal\": \"Medical molecular morphology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown epistasis for FOXO1-SCARA5 relationship and luciferase assay for miR-424/FOXO1; indirect pathway placement for SCARA5\",\n      \"pmids\": [\"40085209\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCARA5 is a type II transmembrane homotrimeric class A scavenger receptor that functions as a ferritin (L-ferritin) endocytic receptor mediating non-transferrin iron delivery, binds and internalizes von Willebrand factor and the VWF-FVIII complex, and physically associates with FAK to suppress the FAK-Src-p130Cas signaling cascade; it also promotes ferroptosis by enhancing autophagic ferritin degradation and increasing intracellular Fe2+, interacts with GPX4 to reduce its expression, and its transcription is directly repressed by Snail1 (via E-box binding) and regulated upstream through β-catenin/TCF4, DNMT1-mediated promoter methylation, and FOXO1, collectively supporting roles in iron homeostasis, innate immunity, tumor suppression, and ferroptosis regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCARA5 is a type II transmembrane homotrimeric class A scavenger receptor that functions principally as an endocytic receptor mediating iron homeostasis, innate immunity, and tumor suppression [#1]. Its founding role is as a ferritin (L-ferritin) receptor that binds serum ferritin at the cell surface and internalizes it to deliver iron independently of the transferrin/TfR1 pathway [#0], an activity later shown to support ferritin transcytosis across the blood-retinal barrier on endothelial cells [#4]. Beyond ferritin, SCARA5 acts as an adhesive and endocytic receptor for von Willebrand factor and the VWF-FVIII complex, internalizing them into early endosomes in podocytes and splenic littoral endothelium [#6], and it clears the inflammatory mediator HMGB1 into lysosomes to dampen inflammatory signaling [#5]. As a tumor suppressor, SCARA5 physically associates with FAK and restrains the FAK-Src-p130Cas cascade, limiting MMP9 activation, invasion, and metastasis [#2]. SCARA5 also drives ferroptosis: it binds ferritin light chain (FTL) and promotes autophagic ferritin degradation to raise intracellular Fe2+ and lipid ROS [#9, #13], and it interacts with GPX4 to reduce its expression, sensitizing cells to ferroptosis [#14]. SCARA5 transcription is directly repressed by Snail1 binding to promoter E-boxes during TGF-\\u03b21-induced EMT, in concert with DNMT1 [#3], and is suppressed downstream of \\u03b2-catenin/TCF4 signaling [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established SCARA5 as a structurally distinct class A scavenger receptor, defining its membrane topology, oligomeric state, and ligand selectivity to separate it from SR-A/MARCO.\",\n      \"evidence\": \"cDNA cloning and CHO cell transfection with plasma membrane localization, bacterial binding, and modified-LDL uptake assays\",\n      \"pmids\": [\"16407294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify physiological endogenous ligands beyond bacteria\", \"SRCR-domain ligand-binding determinants not mapped at residue level\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how cells acquire iron independently of transferrin by identifying SCARA5 as a cell-surface ferritin receptor mediating ferritin endocytosis and iron delivery.\",\n      \"evidence\": \"TfR1-/- chimeric embryo model with fluorescence-tagged kidney capsule cells plus cell-based ferritin binding/endocytosis and in vivo iron delivery assays\",\n      \"pmids\": [\"19154717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endocytic adaptor and trafficking machinery not defined\", \"Quantitative contribution to systemic iron balance not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a tumor-suppressive mechanism by showing SCARA5 physically binds FAK and suppresses the FAK-Src-p130Cas invasion-promoting cascade.\",\n      \"evidence\": \"Reciprocal Co-IP for FAK association, RNAi/overexpression with in vitro invasion and in vivo metastasis assays, phosphorylation western blots in HCC\",\n      \"pmids\": [\"20038795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an endocytic surface receptor engages cytoplasmic FAK is structurally unclear\", \"Cytoplasmic-tail residues mediating FAK binding not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified upstream transcriptional silencing of SCARA5, showing Snail1 directly represses its promoter during EMT in cooperation with DNMT1.\",\n      \"evidence\": \"ChIP for Snail1 binding to promoter E-boxes, Snail1 gain/loss-of-function, Snail1-DNMT1 Co-IP in a TGF-\\u03b21-induced EMT A549 model\",\n      \"pmids\": [\"24061576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA methylation-independent mechanism of DNMT1 action not fully defined\", \"Generality across non-lung tumor types not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended ferritin-receptor function to a barrier-transport context by showing endothelial SCARA5 mediates L-ferritin transcytosis across the blood-retinal barrier.\",\n      \"evidence\": \"In vivo intravenous ferritin injection with Scara5/ferritin colocalization immunohistochemistry and photoreceptor degeneration model\",\n      \"pmids\": [\"25259650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcytosis inferred from colocalization rather than directional flux measurement\", \"Single lab, no genetic loss-of-function for barrier transport\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened the receptor repertoire to innate immune mediator clearance, showing the SCARA5 ortholog endocytoses HMGB1 in a redox-dependent manner to lysosomes and dampens inflammation.\",\n      \"evidence\": \"Reciprocal Co-IP with A/B/T box domain mapping, redox-dependency and lysosomal trafficking assays in fish cell models with cytokine readouts\",\n      \"pmids\": [\"27647835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in fish ortholog, not human SCARA5\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Suggested context-dependent pro-proliferative signaling by placing SCARA5 as a positive regulator of PDGF-driven proliferation and migration in vascular smooth muscle.\",\n      \"evidence\": \"siRNA knockdown in HASMCs with proliferation/migration assays and PDGFR\\u03b2/AKT/ERK1/2 phosphorylation western blots\",\n      \"pmids\": [\"27035566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding to PDGF pathway components shown\", \"Apparent positive signaling role conflicts with tumor-suppressive FAK data; reconciliation unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated SCARA5 in mesenchymal cell fate by showing it promotes adipocyte lineage commitment via FAK/ERK signaling under glucocorticoid control.\",\n      \"evidence\": \"RNAi/overexpression in A33 and C3H10T1/2 cells with adipogenesis assays, FAK/ERK western blots, and a promoter-GRE reporter\",\n      \"pmids\": [\"29093466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor ligand driving differentiation not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected SCARA5 transcriptional suppression to canonical \\u03b2-catenin signaling via the SPAG5-\\u03b2-catenin/TCF4 axis in HCC.\",\n      \"evidence\": \"SPAG5 overexpression/knockdown with \\u03b2-catenin ubiquitination assays, SCARA5 rescue, and xenografts\",\n      \"pmids\": [\"30249289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct TCF4 binding to SCARA5 promoter demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established SCARA5 as a receptor for von Willebrand factor and the VWF-FVIII complex, defining a hemostatic clearance/adhesion function in podocytes and splenic littoral endothelium.\",\n      \"evidence\": \"Solid-phase binding with recombinant SCARA5, HEK293T endocytosis into early endosomes, tissue colocalization, and SCARA5-deficient mouse VWF half-life\",\n      \"pmids\": [\"31126000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo effect on VWF half-life was modest, leaving physiological significance unclear\", \"Binding domain on SCARA5 not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a cell-cycle arrest mechanism downstream of SCARA5 via HSPA5 upregulation and FOXM1 suppression causing G2/M arrest in NSCLC.\",\n      \"evidence\": \"RNA-seq, luciferase reporter, western blot, flow cytometry, and xenograft\",\n      \"pmids\": [\"34150631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a scavenger receptor controls HSPA5 transcription is unresolved\", \"Direct molecular link between SCARA5 and HSPA5 not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Initiated the ferroptosis model by showing SCARA5 binds FTL and raises intracellular Fe2+ to induce ferroptosis in ESCC.\",\n      \"evidence\": \"Co-IP for SCARA5-FTL, flow cytometry for ROS/Fe2+, TEM for mitochondrial morphology, ferroptosis markers, and xenograft\",\n      \"pmids\": [\"36513999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking FTL binding to Fe2+ release not defined here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed SCARA5 as a cell-surface autoantigen in multiple sclerosis, targeted by a CSF IgM that drives complement activation and T-cell infiltration.\",\n      \"evidence\": \"IP-mass spectrometry antigen identification, recombinant IgM, complement activation assay, and intrathecal injection in EAE\",\n      \"pmids\": [\"38123517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Frequency and pathogenic role of anti-SCARA5 IgM across MS patients not established\", \"Mechanism by which the antibody alters SCARA5 receptor function unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mechanistically unified SCARA5's pro-ferroptotic activity, showing it promotes autophagic ferritin degradation to elevate Fe2+/lipid ROS and that loss confers sorafenib resistance.\",\n      \"evidence\": \"Erastin/RSL3 viability, ROS/lipid ROS/MDA/Fe2+ measurements, autophagy flux assays, and SCARA5-knockout MEFs/HCC cells\",\n      \"pmids\": [\"39954713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SCARA5 triggers ferritinophagy molecularly not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a GPX4 regulatory arm to the ferroptosis mechanism, showing SCARA5 interacts with and downregulates GPX4 and that its restoration alleviates liver fibrosis.\",\n      \"evidence\": \"Co-IP and molecular docking for SCARA5-GPX4, redox/iron measurements, DNMT1-methylation analysis, and HSC-specific SCARA5 knock-in mouse\",\n      \"pmids\": [\"41270385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SCARA5 lowers GPX4 (transcriptional vs degradation) not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single surface scavenger receptor reconciles opposing roles—pro-proliferative PDGF signaling versus tumor-suppressive FAK inhibition and ferroptosis induction—and which cytoplasmic-tail determinants route it between endocytosis, signaling, and ferritinophagy remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the SCARA5 cytoplasmic tail engaging FAK, FTL, or GPX4\", \"Context-dependent pro- vs anti-tumor activities not mechanistically reconciled\", \"Direct adaptor machinery for ferritin/VWF/HMGB1 endocytosis undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 4, 5, 6]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 13, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 17]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FAK\", \"FTL\", \"GPX4\", \"VWF\", \"HMGB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}