{"gene":"SLC22A17","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2015,"finding":"The N-terminal domain of SLC22A17 (LCN2-R-NTD) is an intrinsically disordered, soluble extracellular domain that interacts preferentially with apo-NGAL/LCN2 to form a fuzzy complex, with a relatively weak affinity (~10 µM), suggesting the N-terminus alone cannot fully account for NGAL internalization but may fine-tune receptor–ligand discrimination between apo- and holo-NGAL.","method":"Solution-state biomolecular NMR, biophysical binding assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization plus multiple biophysical methods in a single rigorous study","pmids":["26635366"],"is_preprint":false},{"year":2011,"finding":"Rat SLC22A17 (BOCT1) localizes to the cell surface when expressed in HEK-293 cells but does not transport canonical SLC22 substrates (MPP+ or carnitine), nor a panel of other SLC22 substrates, suggesting its non-conserved N-terminal domain precludes typical organic cation/anion transport activity.","method":"Transfection of HEK-293 cells, Western blot, fluorescence microscopy, radioisotope uptake assays","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional transport assay with cell surface verification, single lab, two orthogonal readouts (microscopy + uptake assay)","pmids":["21359964"],"is_preprint":false},{"year":2015,"finding":"SLC22A17 (BOCT) is expressed in hippocampal neurons, and a direct protein–protein interaction between LCN2 and BOCT was detected in cultured hippocampal neurons; holo-LCN2 (LCN2:iron:enterochelin complex) increases Bim mRNA expression and decreases neuronal survival, while apo-LCN2 without iron does not affect Bim expression or cell survival.","method":"DuoLink proximity ligation assay in cultured hippocampal neurons, immunofluorescence, qPCR, cell survival assays","journal":"Neurochemistry international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity ligation assay for interaction plus functional readouts, single lab","pmids":["26004810"],"is_preprint":false},{"year":2018,"finding":"Hyperosmolarity/hypertonicity upregulates SLC22A17 (~4-fold) and decreases LCN2 expression/secretion in rat primary inner medullary collecting duct (IMCD) cells via activation of Wnt/β-catenin signaling; β-catenin silencing by RNAi reverses these effects. Exposure to apo-LCN2 or LPS decreases cell viability in cells with endogenous or stably overexpressing SLC22A17.","method":"qPCR, immunoblotting, flow cytometry, immunofluorescence microscopy, RNAi silencing of β-catenin, MTT and LDH assays","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi epistasis plus multiple expression readouts, single lab","pmids":["30404645"],"is_preprint":false},{"year":2019,"finding":"In mouse cortical collecting duct cells (mCCD(cl.1)), hyperosmolarity/hypertonicity and arginine vasopressin (AVP) upregulate SLC22A17 via the transcription factors NFAT5 and CREB, respectively, while TLR4 activation by LPS downregulates SLC22A17; these regulatory mechanisms parallel those of Aqp2, placing SLC22A17 in an osmotolerance adaptation pathway.","method":"RT-PCR, qPCR, immunoblotting, immunofluorescence microscopy, RNAi silencing of Nfat5, pharmacological CREB inhibition (666-15), TLR4 activation with LPS","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological epistasis with multiple molecular readouts, single lab","pmids":["31671521"],"is_preprint":false},{"year":2019,"finding":"SLC22A17 serves as the cell-surface receptor mediating interaction of the fungal allergen Alt a 1 (holo-form) with airway epithelial cells; this interaction was identified by pull-down assay and immunofluorescence in Calu-3 cells and mouse tissues, and structural modeling explained the receptor-allergen-ligand interaction.","method":"Pull-down assay, immunofluorescence, computational structural modeling","journal":"Allergy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pull-down and immunofluorescence, single lab, no reciprocal validation","pmids":["31095759"],"is_preprint":false},{"year":2023,"finding":"SLC22A17 mediates receptor-mediated endocytosis (RME) of LCN2 and other filtered proteins (including iron- and cadmium-binding proteins) in the renal distal tubule and collecting duct; it is apically localized and functions as an atypical SLC22 member that does not transport canonical organic cation/anion substrates.","method":"Review of experimental literature (fractionation/localization, functional endocytosis studies cited therein)","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — synthesis of multiple experimental studies from multiple labs establishing RME function and apical localization","pmids":["37589051"],"is_preprint":false},{"year":2023,"finding":"In Alzheimer's disease models, Slc22a17 mediates the anti-neurogenic effects of LCN2 on astroglia; functional knockdown of Slc22a17 recapitulates the pro-neurogenic outcome induced by Ngfr, placing Slc22a17 downstream of Lcn2 in the Ngfr→Lcn2→Slc22a17 signaling axis that suppresses astroglial neurogenesis.","method":"Functional knockdown (siRNA/AAV), single-cell transcriptomics, histological proliferation/neurogenesis analyses in APP/PS1dE9 mouse model and zebrafish","journal":"NPJ Regenerative medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function epistasis with neurogenesis phenotype, multiple model systems, single lab","pmids":["37429840"],"is_preprint":false},{"year":2024,"finding":"SLC22A17 expression increases in brain endothelial cells after cerebral ischemia (in both human stroke tissue and mouse models); siRNA knockdown of SLC22A17 in human brain endothelial cells prevents TNF-α-induced ferroptosis and downregulation of tight junction proteins, and ameliorates blood-brain barrier leakage in vivo. SLC22A17 was also found to repress transcription of tight junctional genes.","method":"siRNA knockdown, lentiviral overexpression, immunostaining, Western blot, water content assay, dextran permeability assay, electrical resistance assay, mouse transient focal ischemia model","journal":"Stroke","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple functional readouts, validated in vivo and in vitro, single lab","pmids":["38738428"],"is_preprint":false},{"year":2025,"finding":"Conditional knockout of Slc22a17 in the murine brain causes early postnatal mortality, excessive neural stem cell apoptosis, cognitive impairment, and iron overload-driven oxidative stress. Mechanistically, TurboID-based proximity labeling and immunoprecipitation identified an interaction between Slc22a17 and p62, which modulates Nrf2 activity; loss of Slc22a17 activates the Nrf2/HO-1 pathway, paradoxically enhancing iron release while impairing iron efflux, triggering ROS production.","method":"Conditional knockout mouse, TurboID proximity labeling, immunoprecipitation, ROS/iron assays, behavioral testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO with defined phenotype, proximity labeling + IP for interaction, mechanistic pathway dissection with multiple orthogonal methods","pmids":["41397957"],"is_preprint":false},{"year":2025,"finding":"SLC22A17 knockdown in urethral fibroblasts inhibits ferroptosis (reduced MDA, lipid ROS, ACSL4; increased GPX4) and promotes fibroblast activation (increased collagen I and α-SMA); SLC22A17 overexpression has the opposite effects, and deferoxamine (iron chelator) suppresses SLC22A17-overexpression-mediated ferroptosis, indicating SLC22A17 promotes ferroptosis by facilitating iron availability in urethral fibroblasts.","method":"siRNA knockdown, overexpression, ferroptosis markers (MDA, lipid ROS, ACSL4, GPX4), fibroblast activation markers (collagen I, α-SMA), pharmacological iron chelation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with multiple biochemical readouts, single lab","pmids":["41386104"],"is_preprint":false},{"year":2025,"finding":"NGALR (SLC22A17) knockdown in TNBC cells reduces proliferation, induces S-phase arrest, enhances autophagy, decreases expression of Bcl-2/Cox-2/Cyclin A2/survivin/N-cadherin/Vimentin/VEGF-A, increases E-cadherin and p21 levels, and inhibits Akt/mTOR and JAK/STAT3 signaling, demonstrating a role for SLC22A17 in TNBC cell survival and invasion via these oncogenic pathways.","method":"siRNA-mediated silencing, flow cytometry, immunoblotting, migration/invasion assays","journal":"Clinical & translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple functional and biochemical readouts, single lab","pmids":["41212350"],"is_preprint":false},{"year":2026,"finding":"Holo-LCN2 (iron-loaded) secreted by apoptotic BMSCs binds to Slc22a17 on the cell membrane to facilitate Fe3+ transport into β cells, exerting anti-apoptotic effects on grafted islets; inhibition of Fe3+ transport suppressed the anti-apoptotic effect, establishing holo-Lcn2/Slc22a17/Fe3+ as a functional axis.","method":"Conditioned medium experiments, co-transplantation in vivo, proteomic analysis, inhibition of Fe3+ transport","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro and in vivo validation with proteomic identification of Lcn2, single lab","pmids":["41964097"],"is_preprint":false},{"year":2026,"finding":"In a bone cancer pain mouse model, LCN2 and SLC22A17 are upregulated in the anterior cingulate cortex; targeted inhibition of SLC22A17 by siRNA or AAV induces cytoskeletal remodeling in oligodendrocyte progenitor cells (OPCs) and decreases their phagocytic capacity for GABAergic synapses, alleviating pain and anxiety-like behaviors.","method":"AAV-mediated intervention, siRNA knockdown, immunofluorescence 3D reconstruction, immunoelectron microscopy, fiber photometry, chemogenetics","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple loss-of-function approaches with functional and morphological readouts, single lab","pmids":["41964063"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of mouse BOCT1/SLC22A17 reveals a distinctive N-terminal domain with a unique folding pattern dominated by a transmembrane loop atop TM6 (TML6), diverging from known SLC22 transporter structures and AlphaFold predictions. Functional assays demonstrate that BOCT1/SLC22A17 functions as a high-capacity, low-affinity iron transporter independent of LCN2 binding, with iron transport facilitated by a substrate gating mechanism involving TML6.","method":"Cryo-electron microscopy, functional transport assays, biochemical experiments, molecular dynamics simulations","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure combined with functional assays and MD simulations in a single rigorous study","pmids":["bio_10.1101_2025.06.28.662014"],"is_preprint":true}],"current_model":"SLC22A17 (BOCT1/NGALR/LCN2R) is an atypical SLC22 family transmembrane protein whose cryo-EM structure reveals a unique N-terminal transmembrane loop (TML6) that gates iron transport; it functions as a high-capacity, low-affinity iron transporter independent of LCN2 binding, and also mediates receptor-mediated endocytosis of LCN2 and other filtered proteins in the renal distal nephron; its intrinsically disordered N-terminal extracellular domain forms a weak fuzzy complex preferentially with apo-LCN2; in the brain it maintains iron homeostasis via an interaction with p62/Nrf2/HO-1 pathway to regulate neural stem cell survival; and in endothelial cells it promotes ferroptosis and represses tight junction gene transcription after ischemic stress, while its expression in collecting duct cells is regulated by NFAT5 and CREB downstream of tonicity and vasopressin signaling."},"narrative":{"mechanistic_narrative":"SLC22A17 (BOCT1/NGALR/LCN2R) is an atypical SLC22-family transmembrane protein that functions as a high-capacity, low-affinity iron transporter and as a cell-surface receptor for the iron-carrier lipocalin LCN2, coupling extracellular iron sensing to intracellular iron homeostasis and ferroptotic cell fate [PMID:41397957, PMID:bio_10.1101_2025.06.28.662014]. Unlike canonical SLC22 transporters, it does not transport organic cations or anions such as MPP+ or carnitine; its non-conserved N-terminal domain precludes these activities and instead is organized around a distinctive transmembrane loop atop TM6 (TML6) that gates iron transport independently of LCN2 binding [PMID:21359964, PMID:bio_10.1101_2025.06.28.662014]. Its intrinsically disordered, soluble N-terminal extracellular domain forms a weak fuzzy complex that discriminates apo- from holo-LCN2 [PMID:26635366]. At the apical surface of the renal distal nephron it mediates receptor-mediated endocytosis of LCN2 and other filtered metal-binding proteins, and its expression in collecting-duct cells is induced by hypertonicity and vasopressin through NFAT5 and CREB (with Wnt/β-catenin involvement) and repressed by TLR4/LPS, embedding it in an osmotolerance adaptation program [PMID:30404645, PMID:31671521, PMID:37589051]. In the brain, SLC22A17 maintains neural stem cell survival and iron balance through an interaction with p62 that restrains the Nrf2/HO-1 pathway; its loss causes neural stem cell apoptosis, iron overload, and oxidative stress [PMID:41397957]. Across endothelial, fibroblast, and tumor contexts it promotes iron availability and ferroptosis and modulates barrier integrity and survival signaling: in brain endothelium it drives TNF-α-induced ferroptosis, represses tight-junction gene transcription, and exacerbates blood-brain barrier leakage after ischemia [PMID:38738428, PMID:41386104].","teleology":[{"year":2011,"claim":"Established that SLC22A17, despite belonging to the SLC22 transporter family, does not perform canonical organic cation/anion transport, redefining it as an atypical family member.","evidence":"Heterologous expression in HEK-293 cells with cell-surface verification and radioisotope uptake assays for MPP+, carnitine and other SLC22 substrates","pmids":["21359964"],"confidence":"Medium","gaps":["Did not identify the true transported substrate","Tested only a defined panel of canonical substrates"]},{"year":2015,"claim":"Resolved how the receptor discriminates LCN2 loading states by showing its disordered N-terminal domain binds apo-LCN2 preferentially in a weak fuzzy complex.","evidence":"Solution-state NMR and biophysical binding assays on the isolated N-terminal domain","pmids":["26635366"],"confidence":"High","gaps":["Weak affinity (~10 µM) indicates the N-terminus alone cannot account for full LCN2 internalization","Did not address contribution of the transmembrane region to binding"]},{"year":2015,"claim":"Connected SLC22A17 to neuronal iron-dependent cell death by demonstrating a direct LCN2-BOCT interaction in hippocampal neurons where iron-loaded LCN2 induces Bim and reduces survival.","evidence":"Proximity ligation assay, immunofluorescence, qPCR and survival assays in cultured hippocampal neurons with apo- versus holo-LCN2","pmids":["26004810"],"confidence":"Medium","gaps":["Did not establish whether iron transport rather than binding drives the death phenotype","Single neuronal culture system"]},{"year":2019,"claim":"Defined the transcriptional control of SLC22A17 in collecting-duct cells, placing it within tonicity- and vasopressin-driven osmotolerance signaling.","evidence":"RNAi of Nfat5, pharmacological CREB inhibition, Wnt/β-catenin manipulation and LPS treatment in IMCD and mCCD cells with expression readouts","pmids":["30404645","31671521"],"confidence":"Medium","gaps":["Regulatory mechanisms shown in rodent collecting-duct cells only","Downstream physiological consequence of induction not directly tested"]},{"year":2023,"claim":"Consolidated SLC22A17 as an apically localized receptor mediating endocytosis of LCN2 and other filtered metal-binding proteins in the distal nephron.","evidence":"Synthesis of fractionation/localization and functional endocytosis studies across multiple labs","pmids":["37589051"],"confidence":"Medium","gaps":["Review-level synthesis rather than a single primary dataset","Molecular determinants of cargo selectivity not defined"]},{"year":2023,"claim":"Positioned Slc22a17 as the effector downstream of LCN2 in suppressing astroglial neurogenesis in disease models.","evidence":"siRNA/AAV knockdown with single-cell transcriptomics and neurogenesis histology in APP/PS1dE9 mice and zebrafish","pmids":["37429840"],"confidence":"Medium","gaps":["Molecular mechanism linking receptor to neurogenesis suppression not resolved","Did not test iron-transport dependence of the phenotype"]},{"year":2024,"claim":"Revealed a pathogenic endothelial role in which SLC22A17 drives ferroptosis and represses tight-junction genes after ischemic stress, compromising the blood-brain barrier.","evidence":"siRNA knockdown and lentiviral overexpression in human brain endothelial cells plus a mouse transient focal ischemia model with permeability and barrier readouts","pmids":["38738428"],"confidence":"Medium","gaps":["Mechanism of transcriptional repression of tight-junction genes not defined","Direct DNA/chromatin interaction not demonstrated"]},{"year":2025,"claim":"Identified the brain iron-homeostatic mechanism by showing Slc22a17 interacts with p62 to restrain Nrf2/HO-1 activity, with loss causing iron overload, ROS, neural stem cell apoptosis and lethality.","evidence":"Conditional knockout mouse with TurboID proximity labeling, immunoprecipitation, ROS/iron assays and behavioral testing","pmids":["41397957"],"confidence":"High","gaps":["Direct biochemical mechanism by which p62 binding regulates iron efflux not fully resolved","Whether transporter activity and p62 interaction are functionally separable untested"]},{"year":2025,"claim":"Provided the structural and functional basis for iron transport, showing a unique TML6 gating element and demonstrating LCN2-independent high-capacity, low-affinity iron transport.","evidence":"Cryo-EM structure of mouse BOCT1/SLC22A17 with functional transport assays and molecular dynamics (preprint)","pmids":["bio_10.1101_2025.06.28.662014"],"confidence":"High","gaps":["Preprint, not yet peer-reviewed","Direction and energetics of transport in physiological membranes not fully defined"]},{"year":2025,"claim":"Generalized the pro-ferroptotic, iron-availability function to fibroblasts and tumor cells, linking SLC22A17 to fibroblast activation and oncogenic survival pathways.","evidence":"siRNA/overexpression with ferroptosis and activation markers plus iron chelation in urethral fibroblasts, and siRNA silencing with signaling readouts in TNBC cells","pmids":["41386104","41212350"],"confidence":"Medium","gaps":["Whether oncogenic signaling effects are direct or secondary to iron handling unclear","Single cell-type studies without in vivo validation"]},{"year":2026,"claim":"Demonstrated a protective holo-LCN2/SLC22A17/Fe3+ axis in transplanted islets, showing receptor-mediated iron import can be anti-apoptotic.","evidence":"Conditioned-medium and co-transplantation experiments with proteomic identification of LCN2 and Fe3+ transport inhibition","pmids":["41964097"],"confidence":"Medium","gaps":["Context-dependence of pro-survival versus pro-ferroptotic outcomes unresolved","Single transplantation model"]},{"year":null,"claim":"How SLC22A17's two activities — iron transport via TML6 and LCN2 receptor/endocytosis function — are coordinated to produce opposite cell-fate outcomes (ferroptosis versus survival) across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling pro-death and pro-survival iron handling","Determinants of tissue-specific outcome not identified","Human in vivo physiological/disease validation lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[14,9]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,6,2]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6,12]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,10,9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,9]}],"complexes":[],"partners":["LCN2","SQSTM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUG5","full_name":"Solute carrier family 22 member 17","aliases":["24p3 receptor","24p3R","Brain-type organic cation transporter","Lipocalin-2 receptor","Neutrophil gelatinase-associated lipocalin receptor","NgalR"],"length_aa":649,"mass_kda":68.6,"function":"Cell surface receptor for LCN2 (24p3) that plays a key role in iron homeostasis and transport. Able to bind iron-bound LCN2 (holo-24p3), followed by internalization of holo-24p3 and release of iron, thereby increasing intracellular iron concentration and leading to inhibition of apoptosis. Also binds iron-free LCN2 (apo-24p3), followed by internalization of apo-24p3 and its association with an intracellular siderophore, leading to iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration and resulting in apoptosis (By similarity)","subcellular_location":"Cell membrane; Vacuole membrane","url":"https://www.uniprot.org/uniprotkb/Q8WUG5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC22A17","classification":"Not Classified","n_dependent_lines":84,"n_total_lines":1208,"dependency_fraction":0.0695364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC22A17","total_profiled":1310},"omim":[{"mim_id":"611461","title":"SOLUTE CARRIER FAMILY 22 (ORGANIC CATION TRANSPORTER), MEMBER 17; SLC22A17","url":"https://www.omim.org/entry/611461"},{"mim_id":"609965","title":"DEAFNESS, AUTOSOMAL DOMINANT 53; DFNA53","url":"https://www.omim.org/entry/609965"},{"mim_id":"600181","title":"LIPOCALIN 2; LCN2","url":"https://www.omim.org/entry/600181"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":276.8},{"tissue":"choroid plexus","ntpm":234.8},{"tissue":"pituitary gland","ntpm":178.3}],"url":"https://www.proteinatlas.org/search/SLC22A17"},"hgnc":{"alias_symbol":["BOCT","BOIT","NGALR"],"prev_symbol":[]},"alphafold":{"accession":"Q8WUG5","domains":[{"cath_id":"1.20.1250.20","chopping":"2-17_74-237","consensus_level":"medium","plddt":82.6617,"start":2,"end":237},{"cath_id":"1.20.1250.20","chopping":"304-394_405-509","consensus_level":"medium","plddt":81.9352,"start":304,"end":509}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUG5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUG5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUG5-F1-predicted_aligned_error_v6.png","plddt_mean":70.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC22A17","jax_strain_url":"https://www.jax.org/strain/search?query=SLC22A17"},"sequence":{"accession":"Q8WUG5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUG5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUG5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUG5"}},"corpus_meta":[{"pmid":"26635366","id":"PMC_26635366","title":"Biochemical and Structural Characterization of the Interaction between the Siderocalin NGAL/LCN2 (Neutrophil Gelatinase-associated Lipocalin/Lipocalin 2) and the N-terminal Domain of Its Endocytic Receptor SLC22A17.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26635366","citation_count":44,"is_preprint":false},{"pmid":"19047093","id":"PMC_19047093","title":"NGALR is overexpressed and regulated by hypomethylation in esophageal squamous cell carcinoma.","date":"2008","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/19047093","citation_count":36,"is_preprint":false},{"pmid":"21359964","id":"PMC_21359964","title":"Expression and analysis of two novel rat organic cation transporter homologs, SLC22A17 and SLC22A23.","date":"2011","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21359964","citation_count":35,"is_preprint":false},{"pmid":"26004810","id":"PMC_26004810","title":"Expression and localisation of brain-type organic cation transporter (BOCT/24p3R/LCN2R) in the normal rat hippocampus and after kainate-induced excitotoxicity.","date":"2015","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/26004810","citation_count":26,"is_preprint":false},{"pmid":"37429840","id":"PMC_37429840","title":"Nerve growth factor receptor (Ngfr) induces neurogenic plasticity by suppressing reactive astroglial Lcn2/Slc22a17 signaling in Alzheimer's disease.","date":"2023","source":"NPJ Regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37429840","citation_count":22,"is_preprint":false},{"pmid":"30404645","id":"PMC_30404645","title":"Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection.","date":"2018","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/30404645","citation_count":21,"is_preprint":false},{"pmid":"37589051","id":"PMC_37589051","title":"Role of the SLC22A17/lipocalin-2 receptor in renal endocytosis of proteins/metalloproteins: a focus on iron- and cadmium-binding proteins.","date":"2023","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37589051","citation_count":18,"is_preprint":false},{"pmid":"22797813","id":"PMC_22797813","title":"Expression of NGAL and NGALR in human embryonic, fetal and normal adult tissues.","date":"2012","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/22797813","citation_count":17,"is_preprint":false},{"pmid":"38738428","id":"PMC_38738428","title":"SLC22A17 as a Cell Death-Linked Regulator of Tight Junctions in Cerebral Ischemia.","date":"2024","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/38738428","citation_count":16,"is_preprint":false},{"pmid":"30138675","id":"PMC_30138675","title":"The expression analysis of NGAL and NGALR in clear cell renal cell carcinoma.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30138675","citation_count":14,"is_preprint":false},{"pmid":"31671521","id":"PMC_31671521","title":"Inverse Regulation of Lipocalin-2/24p3 Receptor/SLC22A17 and 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hippocampus.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41397957","citation_count":1,"is_preprint":false},{"pmid":"41212350","id":"PMC_41212350","title":"Suppression of NGALR impedes TNBC cell survival, proliferation, invasion, and migration through Akt/mTOR and JAK/STAT3 pathway inhibition.","date":"2025","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/41212350","citation_count":1,"is_preprint":false},{"pmid":"41386104","id":"PMC_41386104","title":"SLC22A17 affects the development of urethral stricture by promoting ferroptosis and inhibiting the activation of fibroblasts.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41386104","citation_count":1,"is_preprint":false},{"pmid":"41158252","id":"PMC_41158252","title":"The relationship and predictive efficacy of serum lipocalin-2, PDK1, NGALR and lymph node metastasis in postmenopausal endometrial cancer.","date":"2025","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41158252","citation_count":0,"is_preprint":false},{"pmid":"41964063","id":"PMC_41964063","title":"LCN2/SLC22A17 mediates the phagocytosis of GABAergic synapses by oligodendrocyte progenitor cells and contributes to cancer-induced pain and comorbid anxiety-like behaviors in mice.","date":"2026","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/41964063","citation_count":0,"is_preprint":false},{"pmid":"41964097","id":"PMC_41964097","title":"Apoptotic BMSCs reduce grafted islets apoptosis through the holo-Lcn2/Slc22a17/Fe3+ axis.","date":"2026","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41964097","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.28.662014","title":"Structure and iron-transporting mechanism of brain organic cation transporter 1","date":"2025-06-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.28.662014","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.13.628288","title":"Functional fingerprinting for the developing brain using deep metric  learning: an ABCD study","date":"2024-12-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.13.628288","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14455,"output_tokens":4034,"usd":0.051937,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11848,"output_tokens":3740,"usd":0.07637,"stage2_stop_reason":"end_turn"},"total_usd":0.128307,"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\": 2015,\n      \"finding\": \"The N-terminal domain of SLC22A17 (LCN2-R-NTD) is an intrinsically disordered, soluble extracellular domain that interacts preferentially with apo-NGAL/LCN2 to form a fuzzy complex, with a relatively weak affinity (~10 µM), suggesting the N-terminus alone cannot fully account for NGAL internalization but may fine-tune receptor–ligand discrimination between apo- and holo-NGAL.\",\n      \"method\": \"Solution-state biomolecular NMR, biophysical binding assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization plus multiple biophysical methods in a single rigorous study\",\n      \"pmids\": [\"26635366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rat SLC22A17 (BOCT1) localizes to the cell surface when expressed in HEK-293 cells but does not transport canonical SLC22 substrates (MPP+ or carnitine), nor a panel of other SLC22 substrates, suggesting its non-conserved N-terminal domain precludes typical organic cation/anion transport activity.\",\n      \"method\": \"Transfection of HEK-293 cells, Western blot, fluorescence microscopy, radioisotope uptake assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional transport assay with cell surface verification, single lab, two orthogonal readouts (microscopy + uptake assay)\",\n      \"pmids\": [\"21359964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC22A17 (BOCT) is expressed in hippocampal neurons, and a direct protein–protein interaction between LCN2 and BOCT was detected in cultured hippocampal neurons; holo-LCN2 (LCN2:iron:enterochelin complex) increases Bim mRNA expression and decreases neuronal survival, while apo-LCN2 without iron does not affect Bim expression or cell survival.\",\n      \"method\": \"DuoLink proximity ligation assay in cultured hippocampal neurons, immunofluorescence, qPCR, cell survival assays\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation assay for interaction plus functional readouts, single lab\",\n      \"pmids\": [\"26004810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hyperosmolarity/hypertonicity upregulates SLC22A17 (~4-fold) and decreases LCN2 expression/secretion in rat primary inner medullary collecting duct (IMCD) cells via activation of Wnt/β-catenin signaling; β-catenin silencing by RNAi reverses these effects. Exposure to apo-LCN2 or LPS decreases cell viability in cells with endogenous or stably overexpressing SLC22A17.\",\n      \"method\": \"qPCR, immunoblotting, flow cytometry, immunofluorescence microscopy, RNAi silencing of β-catenin, MTT and LDH assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi epistasis plus multiple expression readouts, single lab\",\n      \"pmids\": [\"30404645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In mouse cortical collecting duct cells (mCCD(cl.1)), hyperosmolarity/hypertonicity and arginine vasopressin (AVP) upregulate SLC22A17 via the transcription factors NFAT5 and CREB, respectively, while TLR4 activation by LPS downregulates SLC22A17; these regulatory mechanisms parallel those of Aqp2, placing SLC22A17 in an osmotolerance adaptation pathway.\",\n      \"method\": \"RT-PCR, qPCR, immunoblotting, immunofluorescence microscopy, RNAi silencing of Nfat5, pharmacological CREB inhibition (666-15), TLR4 activation with LPS\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological epistasis with multiple molecular readouts, single lab\",\n      \"pmids\": [\"31671521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLC22A17 serves as the cell-surface receptor mediating interaction of the fungal allergen Alt a 1 (holo-form) with airway epithelial cells; this interaction was identified by pull-down assay and immunofluorescence in Calu-3 cells and mouse tissues, and structural modeling explained the receptor-allergen-ligand interaction.\",\n      \"method\": \"Pull-down assay, immunofluorescence, computational structural modeling\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pull-down and immunofluorescence, single lab, no reciprocal validation\",\n      \"pmids\": [\"31095759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC22A17 mediates receptor-mediated endocytosis (RME) of LCN2 and other filtered proteins (including iron- and cadmium-binding proteins) in the renal distal tubule and collecting duct; it is apically localized and functions as an atypical SLC22 member that does not transport canonical organic cation/anion substrates.\",\n      \"method\": \"Review of experimental literature (fractionation/localization, functional endocytosis studies cited therein)\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — synthesis of multiple experimental studies from multiple labs establishing RME function and apical localization\",\n      \"pmids\": [\"37589051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Alzheimer's disease models, Slc22a17 mediates the anti-neurogenic effects of LCN2 on astroglia; functional knockdown of Slc22a17 recapitulates the pro-neurogenic outcome induced by Ngfr, placing Slc22a17 downstream of Lcn2 in the Ngfr→Lcn2→Slc22a17 signaling axis that suppresses astroglial neurogenesis.\",\n      \"method\": \"Functional knockdown (siRNA/AAV), single-cell transcriptomics, histological proliferation/neurogenesis analyses in APP/PS1dE9 mouse model and zebrafish\",\n      \"journal\": \"NPJ Regenerative medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function epistasis with neurogenesis phenotype, multiple model systems, single lab\",\n      \"pmids\": [\"37429840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC22A17 expression increases in brain endothelial cells after cerebral ischemia (in both human stroke tissue and mouse models); siRNA knockdown of SLC22A17 in human brain endothelial cells prevents TNF-α-induced ferroptosis and downregulation of tight junction proteins, and ameliorates blood-brain barrier leakage in vivo. SLC22A17 was also found to repress transcription of tight junctional genes.\",\n      \"method\": \"siRNA knockdown, lentiviral overexpression, immunostaining, Western blot, water content assay, dextran permeability assay, electrical resistance assay, mouse transient focal ischemia model\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple functional readouts, validated in vivo and in vitro, single lab\",\n      \"pmids\": [\"38738428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of Slc22a17 in the murine brain causes early postnatal mortality, excessive neural stem cell apoptosis, cognitive impairment, and iron overload-driven oxidative stress. Mechanistically, TurboID-based proximity labeling and immunoprecipitation identified an interaction between Slc22a17 and p62, which modulates Nrf2 activity; loss of Slc22a17 activates the Nrf2/HO-1 pathway, paradoxically enhancing iron release while impairing iron efflux, triggering ROS production.\",\n      \"method\": \"Conditional knockout mouse, TurboID proximity labeling, immunoprecipitation, ROS/iron assays, behavioral testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO with defined phenotype, proximity labeling + IP for interaction, mechanistic pathway dissection with multiple orthogonal methods\",\n      \"pmids\": [\"41397957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC22A17 knockdown in urethral fibroblasts inhibits ferroptosis (reduced MDA, lipid ROS, ACSL4; increased GPX4) and promotes fibroblast activation (increased collagen I and α-SMA); SLC22A17 overexpression has the opposite effects, and deferoxamine (iron chelator) suppresses SLC22A17-overexpression-mediated ferroptosis, indicating SLC22A17 promotes ferroptosis by facilitating iron availability in urethral fibroblasts.\",\n      \"method\": \"siRNA knockdown, overexpression, ferroptosis markers (MDA, lipid ROS, ACSL4, GPX4), fibroblast activation markers (collagen I, α-SMA), pharmacological iron chelation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with multiple biochemical readouts, single lab\",\n      \"pmids\": [\"41386104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NGALR (SLC22A17) knockdown in TNBC cells reduces proliferation, induces S-phase arrest, enhances autophagy, decreases expression of Bcl-2/Cox-2/Cyclin A2/survivin/N-cadherin/Vimentin/VEGF-A, increases E-cadherin and p21 levels, and inhibits Akt/mTOR and JAK/STAT3 signaling, demonstrating a role for SLC22A17 in TNBC cell survival and invasion via these oncogenic pathways.\",\n      \"method\": \"siRNA-mediated silencing, flow cytometry, immunoblotting, migration/invasion assays\",\n      \"journal\": \"Clinical & translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple functional and biochemical readouts, single lab\",\n      \"pmids\": [\"41212350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Holo-LCN2 (iron-loaded) secreted by apoptotic BMSCs binds to Slc22a17 on the cell membrane to facilitate Fe3+ transport into β cells, exerting anti-apoptotic effects on grafted islets; inhibition of Fe3+ transport suppressed the anti-apoptotic effect, establishing holo-Lcn2/Slc22a17/Fe3+ as a functional axis.\",\n      \"method\": \"Conditioned medium experiments, co-transplantation in vivo, proteomic analysis, inhibition of Fe3+ transport\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro and in vivo validation with proteomic identification of Lcn2, single lab\",\n      \"pmids\": [\"41964097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In a bone cancer pain mouse model, LCN2 and SLC22A17 are upregulated in the anterior cingulate cortex; targeted inhibition of SLC22A17 by siRNA or AAV induces cytoskeletal remodeling in oligodendrocyte progenitor cells (OPCs) and decreases their phagocytic capacity for GABAergic synapses, alleviating pain and anxiety-like behaviors.\",\n      \"method\": \"AAV-mediated intervention, siRNA knockdown, immunofluorescence 3D reconstruction, immunoelectron microscopy, fiber photometry, chemogenetics\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple loss-of-function approaches with functional and morphological readouts, single lab\",\n      \"pmids\": [\"41964063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of mouse BOCT1/SLC22A17 reveals a distinctive N-terminal domain with a unique folding pattern dominated by a transmembrane loop atop TM6 (TML6), diverging from known SLC22 transporter structures and AlphaFold predictions. Functional assays demonstrate that BOCT1/SLC22A17 functions as a high-capacity, low-affinity iron transporter independent of LCN2 binding, with iron transport facilitated by a substrate gating mechanism involving TML6.\",\n      \"method\": \"Cryo-electron microscopy, functional transport assays, biochemical experiments, molecular dynamics simulations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure combined with functional assays and MD simulations in a single rigorous study\",\n      \"pmids\": [\"bio_10.1101_2025.06.28.662014\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SLC22A17 (BOCT1/NGALR/LCN2R) is an atypical SLC22 family transmembrane protein whose cryo-EM structure reveals a unique N-terminal transmembrane loop (TML6) that gates iron transport; it functions as a high-capacity, low-affinity iron transporter independent of LCN2 binding, and also mediates receptor-mediated endocytosis of LCN2 and other filtered proteins in the renal distal nephron; its intrinsically disordered N-terminal extracellular domain forms a weak fuzzy complex preferentially with apo-LCN2; in the brain it maintains iron homeostasis via an interaction with p62/Nrf2/HO-1 pathway to regulate neural stem cell survival; and in endothelial cells it promotes ferroptosis and represses tight junction gene transcription after ischemic stress, while its expression in collecting duct cells is regulated by NFAT5 and CREB downstream of tonicity and vasopressin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC22A17 (BOCT1/NGALR/LCN2R) is an atypical SLC22-family transmembrane protein that functions as a high-capacity, low-affinity iron transporter and as a cell-surface receptor for the iron-carrier lipocalin LCN2, coupling extracellular iron sensing to intracellular iron homeostasis and ferroptotic cell fate [#9, #14]. Unlike canonical SLC22 transporters, it does not transport organic cations or anions such as MPP+ or carnitine; its non-conserved N-terminal domain precludes these activities and instead is organized around a distinctive transmembrane loop atop TM6 (TML6) that gates iron transport independently of LCN2 binding [#1, #14]. Its intrinsically disordered, soluble N-terminal extracellular domain forms a weak fuzzy complex that discriminates apo- from holo-LCN2 [#0]. At the apical surface of the renal distal nephron it mediates receptor-mediated endocytosis of LCN2 and other filtered metal-binding proteins, and its expression in collecting-duct cells is induced by hypertonicity and vasopressin through NFAT5 and CREB (with Wnt/\\u03b2-catenin involvement) and repressed by TLR4/LPS, embedding it in an osmotolerance adaptation program [#3, #4, #6]. In the brain, SLC22A17 maintains neural stem cell survival and iron balance through an interaction with p62 that restrains the Nrf2/HO-1 pathway; its loss causes neural stem cell apoptosis, iron overload, and oxidative stress [#9]. Across endothelial, fibroblast, and tumor contexts it promotes iron availability and ferroptosis and modulates barrier integrity and survival signaling: in brain endothelium it drives TNF-\\u03b1-induced ferroptosis, represses tight-junction gene transcription, and exacerbates blood-brain barrier leakage after ischemia [#8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that SLC22A17, despite belonging to the SLC22 transporter family, does not perform canonical organic cation/anion transport, redefining it as an atypical family member.\",\n      \"evidence\": \"Heterologous expression in HEK-293 cells with cell-surface verification and radioisotope uptake assays for MPP+, carnitine and other SLC22 substrates\",\n      \"pmids\": [\"21359964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the true transported substrate\", \"Tested only a defined panel of canonical substrates\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how the receptor discriminates LCN2 loading states by showing its disordered N-terminal domain binds apo-LCN2 preferentially in a weak fuzzy complex.\",\n      \"evidence\": \"Solution-state NMR and biophysical binding assays on the isolated N-terminal domain\",\n      \"pmids\": [\"26635366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Weak affinity (~10 \\u00b5M) indicates the N-terminus alone cannot account for full LCN2 internalization\", \"Did not address contribution of the transmembrane region to binding\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected SLC22A17 to neuronal iron-dependent cell death by demonstrating a direct LCN2-BOCT interaction in hippocampal neurons where iron-loaded LCN2 induces Bim and reduces survival.\",\n      \"evidence\": \"Proximity ligation assay, immunofluorescence, qPCR and survival assays in cultured hippocampal neurons with apo- versus holo-LCN2\",\n      \"pmids\": [\"26004810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether iron transport rather than binding drives the death phenotype\", \"Single neuronal culture system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the transcriptional control of SLC22A17 in collecting-duct cells, placing it within tonicity- and vasopressin-driven osmotolerance signaling.\",\n      \"evidence\": \"RNAi of Nfat5, pharmacological CREB inhibition, Wnt/\\u03b2-catenin manipulation and LPS treatment in IMCD and mCCD cells with expression readouts\",\n      \"pmids\": [\"30404645\", \"31671521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulatory mechanisms shown in rodent collecting-duct cells only\", \"Downstream physiological consequence of induction not directly tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Consolidated SLC22A17 as an apically localized receptor mediating endocytosis of LCN2 and other filtered metal-binding proteins in the distal nephron.\",\n      \"evidence\": \"Synthesis of fractionation/localization and functional endocytosis studies across multiple labs\",\n      \"pmids\": [\"37589051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis rather than a single primary dataset\", \"Molecular determinants of cargo selectivity not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned Slc22a17 as the effector downstream of LCN2 in suppressing astroglial neurogenesis in disease models.\",\n      \"evidence\": \"siRNA/AAV knockdown with single-cell transcriptomics and neurogenesis histology in APP/PS1dE9 mice and zebrafish\",\n      \"pmids\": [\"37429840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking receptor to neurogenesis suppression not resolved\", \"Did not test iron-transport dependence of the phenotype\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a pathogenic endothelial role in which SLC22A17 drives ferroptosis and represses tight-junction genes after ischemic stress, compromising the blood-brain barrier.\",\n      \"evidence\": \"siRNA knockdown and lentiviral overexpression in human brain endothelial cells plus a mouse transient focal ischemia model with permeability and barrier readouts\",\n      \"pmids\": [\"38738428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of transcriptional repression of tight-junction genes not defined\", \"Direct DNA/chromatin interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the brain iron-homeostatic mechanism by showing Slc22a17 interacts with p62 to restrain Nrf2/HO-1 activity, with loss causing iron overload, ROS, neural stem cell apoptosis and lethality.\",\n      \"evidence\": \"Conditional knockout mouse with TurboID proximity labeling, immunoprecipitation, ROS/iron assays and behavioral testing\",\n      \"pmids\": [\"41397957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism by which p62 binding regulates iron efflux not fully resolved\", \"Whether transporter activity and p62 interaction are functionally separable untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural and functional basis for iron transport, showing a unique TML6 gating element and demonstrating LCN2-independent high-capacity, low-affinity iron transport.\",\n      \"evidence\": \"Cryo-EM structure of mouse BOCT1/SLC22A17 with functional transport assays and molecular dynamics (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.28.662014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Direction and energetics of transport in physiological membranes not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generalized the pro-ferroptotic, iron-availability function to fibroblasts and tumor cells, linking SLC22A17 to fibroblast activation and oncogenic survival pathways.\",\n      \"evidence\": \"siRNA/overexpression with ferroptosis and activation markers plus iron chelation in urethral fibroblasts, and siRNA silencing with signaling readouts in TNBC cells\",\n      \"pmids\": [\"41386104\", \"41212350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether oncogenic signaling effects are direct or secondary to iron handling unclear\", \"Single cell-type studies without in vivo validation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a protective holo-LCN2/SLC22A17/Fe3+ axis in transplanted islets, showing receptor-mediated iron import can be anti-apoptotic.\",\n      \"evidence\": \"Conditioned-medium and co-transplantation experiments with proteomic identification of LCN2 and Fe3+ transport inhibition\",\n      \"pmids\": [\"41964097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence of pro-survival versus pro-ferroptotic outcomes unresolved\", \"Single transplantation model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLC22A17's two activities — iron transport via TML6 and LCN2 receptor/endocytosis function — are coordinated to produce opposite cell-fate outcomes (ferroptosis versus survival) across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling pro-death and pro-survival iron handling\", \"Determinants of tissue-specific outcome not identified\", \"Human in vivo physiological/disease validation lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [14, 9]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 6, 2]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 10, 9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LCN2\", \"SQSTM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}