{"gene":"SLC22A17","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2015,"finding":"The N-terminal domain of SLC22A17 (LCN2-R) is an intrinsically disordered extracellular domain that forms a fuzzy complex with NGAL/LCN2, preferentially binding the apo (iron-free) form with ~10 μM affinity, suggesting it fine-tunes receptor discrimination between apo- and holo-NGAL rather than solely mediating internalization.","method":"Solution-state biomolecular NMR, biophysical methods (binding affinity measurements)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structural characterization combined with biophysical affinity measurements in a single rigorous study","pmids":["26635366"],"is_preprint":false},{"year":2011,"finding":"Rat SLC22A17 (BOCT1) is expressed at the cell surface in brain-enriched tissues (especially choroid plexus, brain endothelial cells, neurons) but does not transport canonical SLC22 substrates such as MPP+ or carnitine in HEK-293 cells, indicating atypical transport function linked to its non-conserved N-terminal domain.","method":"Heterologous expression in HEK-293 cells, radioisotope uptake assay, western blot, fluorescence microscopy","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional transport assay with cell surface verification, single lab","pmids":["21359964"],"is_preprint":false},{"year":2015,"finding":"SLC22A17 (BOCT) is expressed in hippocampal neurons and interacts with LCN2 in cultured hippocampal neurons as shown by DuoLink proximity ligation assay; holo-LCN2 (iron-loaded form) binding to BOCT increases Bim expression and decreases neuronal survival, whereas apo-LCN2 does not.","method":"DuoLink proximity ligation assay, Bim mRNA/protein measurement, cell survival assay in cultured hippocampal neurons","journal":"Neurochemistry international","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct protein interaction shown in neurons with functional outcome, single lab","pmids":["26004810"],"is_preprint":false},{"year":2018,"finding":"Hyperosmolarity/hypertonicity upregulates SLC22A17 expression (~4-fold) while decreasing LCN2 expression/secretion in renal inner medullary collecting duct (IMCD) cells via Wnt/β-catenin signaling; β-catenin silencing by RNAi reverses these effects. Exposure of SLC22A17-expressing cells to apo-LCN2 decreases cell viability, implicating SLC22A17 in osmotolerance and cell survival regulation.","method":"qPCR, immunoblotting, flow cytometry, immunofluorescence microscopy, RNAi (β-catenin silencing), MTT and LDH assays in primary rat IMCD and mIMCD3 cells","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, RNAi epistasis, single lab","pmids":["30404645"],"is_preprint":false},{"year":2019,"finding":"In mouse cortical collecting duct cells, hyperosmolarity and arginine vasopressin (AVP) upregulate SLC22A17 expression via NFAT5 and CREB transcription factors, respectively, while TLR4/LPS signaling downregulates SLC22A17; AVP suppresses LCN2 secretion by a CREB-independent posttranslational mechanism.","method":"RT-PCR, qPCR, immunoblotting, immunofluorescence microscopy, RNAi (Nfat5 silencing), pharmacological CREB inhibition (666-15), LPS treatment in mCCD(cl.1) cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods and genetic/pharmacological pathway dissection, single lab","pmids":["31671521"],"is_preprint":false},{"year":2019,"finding":"SLC22A17 acts as the receptor for the fungal allergen Alt a 1 in human airway epithelial cells; pull-down and immunofluorescence assays demonstrated that holo-Alt a 1 (ligand-bound form) interacts with SLC22A17 on Calu-3 cells, and computational modeling explained the structural basis of this recognition.","method":"Pull-down assay, immunofluorescence, computational modeling, cytokine measurement in Calu-3 epithelial cells","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 3 — pull-down and immunofluorescence with structural modeling, single lab","pmids":["31095759"],"is_preprint":false},{"year":2023,"finding":"SLC22A17 mediates receptor-mediated endocytosis (RME) of LCN2 and other filtered proteins (including metalloproteins such as transferrin and metallothionein) in the renal distal tubule and collecting duct, providing a pathway for reabsorption of proteins and transition metals (iron, cadmium) that escape the proximal tubule.","method":"Literature synthesis with supporting experimental evidence from multiple studies on RME, protein localization, and nephrotoxicity models","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2/3 — mechanistic synthesis supported by multiple independent experimental studies","pmids":["37589051"],"is_preprint":false},{"year":2023,"finding":"In the Alzheimer's disease context, LCN2 exerts anti-neurogenic effects in astroglia that are mediated by SLC22A17; blockade of SLC22A17 recapitulates the pro-neurogenic effects of NGFR, placing SLC22A17 downstream of LCN2 in a pathway that suppresses astroglial neurogenesis.","method":"Functional knockdown studies, single-cell transcriptomics, histological analyses, spatial proteomics in APP/PS1dE9 mouse model and human AD samples","journal":"NPJ Regenerative medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (knockdown) with multiple orthogonal readouts in vivo, single lab","pmids":["37429840"],"is_preprint":false},{"year":2024,"finding":"SLC22A17 regulates endothelial tight junction integrity after cerebral ischemia; siRNA knockdown of SLC22A17 in human brain endothelial cells prevents TNF-α-induced ferroptosis and prevents downregulation of tight junction proteins and transcellular permeability disruption. SLC22A17 can repress transcription of tight junctional genes, and its knockdown ameliorates BBB leakage in a mouse focal ischemia model.","method":"siRNA knockdown, lentiviral overexpression, Western blot, immunostaining, water content assay, dextran permeability assay, electrical resistance assay in human brain endothelial cultures and mouse MCAO model","journal":"Stroke","confidence":"High","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function with multiple orthogonal functional readouts in vitro and in vivo, validated in human stroke samples","pmids":["38738428"],"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); deferoxamine (iron chelator) suppresses SLC22A17 overexpression-mediated ferroptosis, indicating SLC22A17 promotes ferroptosis via iron-dependent mechanisms in fibroblasts.","method":"siRNA knockdown, overexpression, ferroptosis markers (MDA, lipid ROS, ACSL4, GPX4), fibroblast activation markers in primary human urethral scar fibroblasts","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2/3 — gain and loss-of-function with multiple biochemical readouts, single lab","pmids":["41386104"],"is_preprint":false},{"year":2025,"finding":"Conditional knockout of Slc22a17 in mouse brain causes early postnatal mortality, neural stem cell apoptosis, and cognitive impairment due to iron overload-induced oxidative stress. Using TurboID-based proximity labeling and immunoprecipitation, Slc22a17 was found to interact with p62, modulating Nrf2 activity; loss of Slc22a17 activates the Nrf2/HO-1 pathway, paradoxically enhancing iron release while impairing iron efflux, leading to ROS accumulation.","method":"Conditional knockout mouse, TurboID proximity labeling, immunoprecipitation, Nrf2/HO-1 pathway analysis, oxidative stress assays, cognitive behavioral tests","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1/2 — conditional KO in vivo with proximity labeling and IP to identify p62 interaction, multiple orthogonal mechanistic readouts","pmids":["41397957"],"is_preprint":false},{"year":2025,"finding":"NGALR (SLC22A17) knockdown in TNBC cells inhibits proliferation, induces S-phase arrest, enhances autophagy, reduces migration and invasion, and downregulates Akt/mTOR and JAK/STAT3 signaling pathways, placing SLC22A17 upstream of these oncogenic cascades in TNBC.","method":"siRNA-mediated silencing, flow cytometry (cell cycle), immunoblotting, migration/invasion assays in TNBC cell lines","journal":"Clinical & translational oncology","confidence":"Medium","confidence_rationale":"Tier 2/3 — loss-of-function with multiple functional assays and pathway analysis, single lab","pmids":["41212350"],"is_preprint":false},{"year":2026,"finding":"Holo-LCN2 (iron-loaded) secreted by apoptotic BMSCs binds to SLC22A17 on β-cell membranes and facilitates Fe3+ transport into cells, exerting anti-apoptotic effects on grafted islets; inhibition of Fe3+ transport abolished the anti-apoptotic effect, establishing the holo-Lcn2/Slc22a17/Fe3+ axis.","method":"Proteomic analysis of conditioned medium, cell culture pretreatment, co-transplantation in diabetic rats (in vivo), Fe3+ transport inhibition experiments","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2/3 — functional inhibition of transport with in vivo corroboration, single lab","pmids":["41964097"],"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 structures and AlphaFold predictions. BOCT1 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 — high-resolution cryo-EM structure combined with functional assays, mutagenesis-level mechanistic insight via MD simulations","pmids":["bio_10.1101_2025.06.28.662014"],"is_preprint":true}],"current_model":"SLC22A17 is an atypical SLC22 family transmembrane protein that functions as a high-capacity, low-affinity iron transporter (independent of LCN2 binding) with a unique cryo-EM structure featuring a transmembrane loop (TML6) gating mechanism; it also mediates receptor-mediated endocytosis of LCN2/NGAL and other metalloproteins in the renal distal tubule and collecting duct, interacts with p62 to modulate Nrf2/HO-1-dependent iron homeostasis and oxidative stress in neural stem cells, regulates endothelial tight junction integrity and ferroptosis after cerebral ischemia, and its expression is transcriptionally controlled by NFAT5, CREB, Wnt/β-catenin, and TLR4 signaling in response to osmotic and inflammatory stimuli."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing SLC22A17 as an atypical SLC22 family member resolved the puzzle of why it does not transport canonical organic cation substrates despite its sequence similarity, redirecting the search toward non-canonical transport or receptor functions.","evidence":"Heterologous expression in HEK-293 cells with radioisotope uptake assays showing absence of MPP+ or carnitine transport","pmids":["21359964"],"confidence":"Medium","gaps":["Actual transported substrate remained unidentified","Only canonical SLC22 substrates tested","Single cell line used"]},{"year":2015,"claim":"Structural characterization of the N-terminal domain as intrinsically disordered and preferentially binding apo-LCN2 established the molecular basis for how SLC22A17 discriminates between iron-loaded and iron-free ligand, reframing it as a receptor that fine-tunes LCN2 signaling rather than simply internalizing cargo.","evidence":"Solution-state NMR and biophysical binding affinity measurements; proximity ligation assay confirming interaction in hippocampal neurons with differential effects of apo- versus holo-LCN2 on cell survival","pmids":["26635366","26004810"],"confidence":"High","gaps":["Full-length receptor structure was unknown","Mechanism of LCN2 internalization not resolved","Whether apo/holo discrimination occurs in vivo not tested"]},{"year":2018,"claim":"Identification of Wnt/β-catenin, NFAT5, and CREB as transcriptional regulators of SLC22A17 in renal collecting duct cells revealed how osmotic and hormonal cues control its expression, connecting SLC22A17 to kidney physiology and osmotolerance.","evidence":"RNAi silencing of β-catenin and Nfat5, pharmacological CREB inhibition, and TLR4/LPS treatment in primary IMCD and mCCD cells with qPCR and immunoblotting readouts","pmids":["30404645","31671521"],"confidence":"Medium","gaps":["Direct promoter binding by these transcription factors not shown (e.g., ChIP)","Physiological consequence of transcriptional regulation in vivo not tested"]},{"year":2019,"claim":"Demonstration that SLC22A17 serves as a receptor for the fungal allergen Alt a 1 broadened its ligand repertoire beyond LCN2, suggesting a general role in recognizing lipocalin-fold proteins.","evidence":"Pull-down assay and immunofluorescence in Calu-3 airway epithelial cells with computational structural modeling","pmids":["31095759"],"confidence":"Medium","gaps":["Functional consequence of Alt a 1 internalization via SLC22A17 on downstream signaling not fully characterized","Specificity versus other airway receptors unclear"]},{"year":2023,"claim":"Consolidation of SLC22A17 as a distal nephron receptor mediating endocytosis of multiple metalloproteins (transferrin, metallothionein, LCN2) provided a unified model for how proteins and transition metals escaping the proximal tubule are recaptured, and linked SLC22A17 to cadmium nephrotoxicity and astroglial neurogenesis regulation in Alzheimer's disease.","evidence":"Mechanistic synthesis of multiple renal RME studies; functional knockdown and single-cell transcriptomics in APP/PS1dE9 mouse model and human AD tissue","pmids":["37589051","37429840"],"confidence":"Medium","gaps":["In vivo renal-specific knockout phenotype not yet reported","Whether SLC22A17-mediated neurogenesis suppression is iron-dependent remains untested"]},{"year":2024,"claim":"Showing that SLC22A17 promotes endothelial ferroptosis and represses tight junction gene transcription after cerebral ischemia established a direct pathological role for the receptor in blood-brain barrier disruption, validated by amelioration of BBB leakage upon knockdown in vivo.","evidence":"Reciprocal siRNA knockdown and lentiviral overexpression in human brain endothelial cells with permeability, electrical resistance, and ferroptosis marker assays; confirmed in mouse MCAO model","pmids":["38738428"],"confidence":"High","gaps":["Mechanism by which SLC22A17 represses tight junction gene transcription not identified","Whether the effect is LCN2-dependent or iron-transport-dependent not dissected"]},{"year":2025,"claim":"Discovery that brain-conditional Slc22a17 knockout causes postnatal lethality, iron overload, and neural stem cell apoptosis via dysregulated p62–Nrf2/HO-1 signaling provided the first genetic loss-of-function evidence that SLC22A17 is essential for brain iron homeostasis and neural development.","evidence":"Conditional knockout mouse with TurboID proximity labeling, immunoprecipitation identifying p62 interaction, and Nrf2/HO-1 pathway analysis with oxidative stress and cognitive behavioral readouts","pmids":["41397957"],"confidence":"High","gaps":["Whether p62 interaction is direct or mediated through additional partners not resolved","Mechanism of iron efflux impairment downstream of Nrf2/HO-1 activation unclear","Contribution of LCN2-dependent versus LCN2-independent iron transport not separated"]},{"year":2025,"claim":"Functional and structural studies demonstrated that SLC22A17 operates as a high-capacity, low-affinity iron transporter independent of LCN2, with a cryo-EM structure revealing a unique transmembrane loop (TML6) gating mechanism that diverges from other SLC22 transporters.","evidence":"(preprint) Cryo-EM structure of mouse BOCT1, functional iron transport assays, mutagenesis, and molecular dynamics simulations","pmids":["bio_10.1101_2025.06.28.662014"],"confidence":"High","gaps":["Preprint not yet peer-reviewed","Human SLC22A17 structure not yet determined","Specific iron coordination residues in the transport pathway not fully validated by mutagenesis"]},{"year":2025,"claim":"SLC22A17 was shown to promote ferroptosis in fibroblasts via iron-dependent mechanisms and to support TNBC cell proliferation through Akt/mTOR and JAK/STAT3 signaling, extending its pro-ferroptotic and pro-survival roles to non-neural tissues.","evidence":"siRNA knockdown and overexpression with ferroptosis marker quantification in urethral fibroblasts; siRNA silencing with flow cytometry and pathway immunoblotting in TNBC cell lines","pmids":["41386104","41212350"],"confidence":"Medium","gaps":["Whether SLC22A17's oncogenic role in TNBC is iron-transport-dependent not tested","In vivo tumor models lacking","Mechanism linking SLC22A17 to Akt/mTOR activation unresolved"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution mechanism of iron transport through TML6 gating in human SLC22A17, whether its receptor and transporter functions are separable in vivo, and how the p62 interaction mechanistically couples to Nrf2/HO-1 signaling and iron efflux regulation.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Human structure not determined","No conditional kidney-specific knockout phenotype reported","LCN2-dependent versus LCN2-independent iron transport contributions not separated in any tissue in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[6,12,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,5,12]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[6,12,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,9,10]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,4,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,11]}],"complexes":[],"partners":["LCN2","SQSTM1","NFE2L2","CTNNB1"],"other_free_text":[]},"mechanistic_narrative":"SLC22A17 is an atypical member of the SLC22 solute carrier family that functions as both an iron transporter and a receptor for lipocalin-2 (LCN2/NGAL) and other metalloproteins, linking iron homeostasis to cell survival, ferroptosis, and blood-brain barrier integrity across multiple tissues. Its intrinsically disordered N-terminal extracellular domain forms a fuzzy complex with LCN2, preferentially binding the apo (iron-free) form, and mediates receptor-mediated endocytosis of LCN2, transferrin, and metallothionein in the renal distal tubule and collecting duct [PMID:26635366, PMID:37589051]. In the brain, SLC22A17 interacts with p62 to modulate Nrf2/HO-1 signaling and iron efflux; conditional knockout causes iron overload, oxidative stress, neural stem cell apoptosis, and cognitive impairment, while in brain endothelial cells it promotes ferroptosis and represses tight junction gene transcription after ischemia [PMID:41397957, PMID:38738428]. SLC22A17 expression is transcriptionally regulated by NFAT5, CREB, and Wnt/β-catenin signaling in renal collecting duct cells in response to osmotic and inflammatory stimuli, and it promotes iron-dependent ferroptosis in fibroblasts and endothelial cells [PMID:30404645, PMID:31671521, PMID:41386104]."},"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":42,"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":35,"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":34,"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":25,"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":"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":20,"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":17,"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":16,"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":15,"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 Lipocalin-2 Expression by Tonicity, NFAT5/TonEBP and Arginine Vasopressin in Mouse Cortical Collecting Duct Cells mCCD(cl.1): Implications for Osmotolerance.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31671521","citation_count":12,"is_preprint":false},{"pmid":"31095759","id":"PMC_31095759","title":"Interaction of Alt a 1 with SLC22A17 in the airway mucosa.","date":"2019","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/31095759","citation_count":10,"is_preprint":false},{"pmid":"39358721","id":"PMC_39358721","title":"Identification of SLC22A17 DNA methylation hotspot as a potential biomarker in cutaneous melanoma.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39358721","citation_count":6,"is_preprint":false},{"pmid":"41386104","id":"PMC_41386104","title":"SLC22A17 affects the development of urethral stricture by promoting ferroptosis and inhibiting the 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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":13007,"output_tokens":3637,"usd":0.046788},"stage2":{"model":"claude-opus-4-6","input_tokens":7048,"output_tokens":2819,"usd":0.158573},"total_usd":0.205361,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","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) is an intrinsically disordered extracellular domain that forms a fuzzy complex with NGAL/LCN2, preferentially binding the apo (iron-free) form with ~10 μM affinity, suggesting it fine-tunes receptor discrimination between apo- and holo-NGAL rather than solely mediating internalization.\",\n      \"method\": \"Solution-state biomolecular NMR, biophysical methods (binding affinity measurements)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural characterization combined with biophysical affinity measurements in a single rigorous study\",\n      \"pmids\": [\"26635366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rat SLC22A17 (BOCT1) is expressed at the cell surface in brain-enriched tissues (especially choroid plexus, brain endothelial cells, neurons) but does not transport canonical SLC22 substrates such as MPP+ or carnitine in HEK-293 cells, indicating atypical transport function linked to its non-conserved N-terminal domain.\",\n      \"method\": \"Heterologous expression in HEK-293 cells, radioisotope uptake assay, western blot, fluorescence microscopy\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional transport assay with cell surface verification, single lab\",\n      \"pmids\": [\"21359964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC22A17 (BOCT) is expressed in hippocampal neurons and interacts with LCN2 in cultured hippocampal neurons as shown by DuoLink proximity ligation assay; holo-LCN2 (iron-loaded form) binding to BOCT increases Bim expression and decreases neuronal survival, whereas apo-LCN2 does not.\",\n      \"method\": \"DuoLink proximity ligation assay, Bim mRNA/protein measurement, cell survival assay in cultured hippocampal neurons\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct protein interaction shown in neurons with functional outcome, single lab\",\n      \"pmids\": [\"26004810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hyperosmolarity/hypertonicity upregulates SLC22A17 expression (~4-fold) while decreasing LCN2 expression/secretion in renal inner medullary collecting duct (IMCD) cells via Wnt/β-catenin signaling; β-catenin silencing by RNAi reverses these effects. Exposure of SLC22A17-expressing cells to apo-LCN2 decreases cell viability, implicating SLC22A17 in osmotolerance and cell survival regulation.\",\n      \"method\": \"qPCR, immunoblotting, flow cytometry, immunofluorescence microscopy, RNAi (β-catenin silencing), MTT and LDH assays in primary rat IMCD and mIMCD3 cells\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, RNAi epistasis, single lab\",\n      \"pmids\": [\"30404645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In mouse cortical collecting duct cells, hyperosmolarity and arginine vasopressin (AVP) upregulate SLC22A17 expression via NFAT5 and CREB transcription factors, respectively, while TLR4/LPS signaling downregulates SLC22A17; AVP suppresses LCN2 secretion by a CREB-independent posttranslational mechanism.\",\n      \"method\": \"RT-PCR, qPCR, immunoblotting, immunofluorescence microscopy, RNAi (Nfat5 silencing), pharmacological CREB inhibition (666-15), LPS treatment in mCCD(cl.1) cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods and genetic/pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"31671521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLC22A17 acts as the receptor for the fungal allergen Alt a 1 in human airway epithelial cells; pull-down and immunofluorescence assays demonstrated that holo-Alt a 1 (ligand-bound form) interacts with SLC22A17 on Calu-3 cells, and computational modeling explained the structural basis of this recognition.\",\n      \"method\": \"Pull-down assay, immunofluorescence, computational modeling, cytokine measurement in Calu-3 epithelial cells\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pull-down and immunofluorescence with structural modeling, single lab\",\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 metalloproteins such as transferrin and metallothionein) in the renal distal tubule and collecting duct, providing a pathway for reabsorption of proteins and transition metals (iron, cadmium) that escape the proximal tubule.\",\n      \"method\": \"Literature synthesis with supporting experimental evidence from multiple studies on RME, protein localization, and nephrotoxicity models\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — mechanistic synthesis supported by multiple independent experimental studies\",\n      \"pmids\": [\"37589051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In the Alzheimer's disease context, LCN2 exerts anti-neurogenic effects in astroglia that are mediated by SLC22A17; blockade of SLC22A17 recapitulates the pro-neurogenic effects of NGFR, placing SLC22A17 downstream of LCN2 in a pathway that suppresses astroglial neurogenesis.\",\n      \"method\": \"Functional knockdown studies, single-cell transcriptomics, histological analyses, spatial proteomics in APP/PS1dE9 mouse model and human AD samples\",\n      \"journal\": \"NPJ Regenerative medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (knockdown) with multiple orthogonal readouts in vivo, single lab\",\n      \"pmids\": [\"37429840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC22A17 regulates endothelial tight junction integrity after cerebral ischemia; siRNA knockdown of SLC22A17 in human brain endothelial cells prevents TNF-α-induced ferroptosis and prevents downregulation of tight junction proteins and transcellular permeability disruption. SLC22A17 can repress transcription of tight junctional genes, and its knockdown ameliorates BBB leakage in a mouse focal ischemia model.\",\n      \"method\": \"siRNA knockdown, lentiviral overexpression, Western blot, immunostaining, water content assay, dextran permeability assay, electrical resistance assay in human brain endothelial cultures and mouse MCAO model\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with multiple orthogonal functional readouts in vitro and in vivo, validated in human stroke samples\",\n      \"pmids\": [\"38738428\"],\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); deferoxamine (iron chelator) suppresses SLC22A17 overexpression-mediated ferroptosis, indicating SLC22A17 promotes ferroptosis via iron-dependent mechanisms in fibroblasts.\",\n      \"method\": \"siRNA knockdown, overexpression, ferroptosis markers (MDA, lipid ROS, ACSL4, GPX4), fibroblast activation markers in primary human urethral scar fibroblasts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — gain and loss-of-function with multiple biochemical readouts, single lab\",\n      \"pmids\": [\"41386104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of Slc22a17 in mouse brain causes early postnatal mortality, neural stem cell apoptosis, and cognitive impairment due to iron overload-induced oxidative stress. Using TurboID-based proximity labeling and immunoprecipitation, Slc22a17 was found to interact with p62, modulating Nrf2 activity; loss of Slc22a17 activates the Nrf2/HO-1 pathway, paradoxically enhancing iron release while impairing iron efflux, leading to ROS accumulation.\",\n      \"method\": \"Conditional knockout mouse, TurboID proximity labeling, immunoprecipitation, Nrf2/HO-1 pathway analysis, oxidative stress assays, cognitive behavioral tests\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — conditional KO in vivo with proximity labeling and IP to identify p62 interaction, multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"41397957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NGALR (SLC22A17) knockdown in TNBC cells inhibits proliferation, induces S-phase arrest, enhances autophagy, reduces migration and invasion, and downregulates Akt/mTOR and JAK/STAT3 signaling pathways, placing SLC22A17 upstream of these oncogenic cascades in TNBC.\",\n      \"method\": \"siRNA-mediated silencing, flow cytometry (cell cycle), immunoblotting, migration/invasion assays in TNBC cell lines\",\n      \"journal\": \"Clinical & translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — loss-of-function with multiple functional assays and pathway analysis, 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 β-cell membranes and facilitates Fe3+ transport into cells, exerting anti-apoptotic effects on grafted islets; inhibition of Fe3+ transport abolished the anti-apoptotic effect, establishing the holo-Lcn2/Slc22a17/Fe3+ axis.\",\n      \"method\": \"Proteomic analysis of conditioned medium, cell culture pretreatment, co-transplantation in diabetic rats (in vivo), Fe3+ transport inhibition experiments\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — functional inhibition of transport with in vivo corroboration, single lab\",\n      \"pmids\": [\"41964097\"],\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 structures and AlphaFold predictions. BOCT1 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 — high-resolution cryo-EM structure combined with functional assays, mutagenesis-level mechanistic insight via MD simulations\",\n      \"pmids\": [\"bio_10.1101_2025.06.28.662014\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SLC22A17 is an atypical SLC22 family transmembrane protein that functions as a high-capacity, low-affinity iron transporter (independent of LCN2 binding) with a unique cryo-EM structure featuring a transmembrane loop (TML6) gating mechanism; it also mediates receptor-mediated endocytosis of LCN2/NGAL and other metalloproteins in the renal distal tubule and collecting duct, interacts with p62 to modulate Nrf2/HO-1-dependent iron homeostasis and oxidative stress in neural stem cells, regulates endothelial tight junction integrity and ferroptosis after cerebral ischemia, and its expression is transcriptionally controlled by NFAT5, CREB, Wnt/β-catenin, and TLR4 signaling in response to osmotic and inflammatory stimuli.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC22A17 is an atypical member of the SLC22 solute carrier family that functions as both an iron transporter and a receptor for lipocalin-2 (LCN2/NGAL) and other metalloproteins, linking iron homeostasis to cell survival, ferroptosis, and blood-brain barrier integrity across multiple tissues. Its intrinsically disordered N-terminal extracellular domain forms a fuzzy complex with LCN2, preferentially binding the apo (iron-free) form, and mediates receptor-mediated endocytosis of LCN2, transferrin, and metallothionein in the renal distal tubule and collecting duct [PMID:26635366, PMID:37589051]. In the brain, SLC22A17 interacts with p62 to modulate Nrf2/HO-1 signaling and iron efflux; conditional knockout causes iron overload, oxidative stress, neural stem cell apoptosis, and cognitive impairment, while in brain endothelial cells it promotes ferroptosis and represses tight junction gene transcription after ischemia [PMID:41397957, PMID:38738428]. SLC22A17 expression is transcriptionally regulated by NFAT5, CREB, and Wnt/β-catenin signaling in renal collecting duct cells in response to osmotic and inflammatory stimuli, and it promotes iron-dependent ferroptosis in fibroblasts and endothelial cells [PMID:30404645, PMID:31671521, PMID:41386104].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing SLC22A17 as an atypical SLC22 family member resolved the puzzle of why it does not transport canonical organic cation substrates despite its sequence similarity, redirecting the search toward non-canonical transport or receptor functions.\",\n      \"evidence\": \"Heterologous expression in HEK-293 cells with radioisotope uptake assays showing absence of MPP+ or carnitine transport\",\n      \"pmids\": [\"21359964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Actual transported substrate remained unidentified\", \"Only canonical SLC22 substrates tested\", \"Single cell line used\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Structural characterization of the N-terminal domain as intrinsically disordered and preferentially binding apo-LCN2 established the molecular basis for how SLC22A17 discriminates between iron-loaded and iron-free ligand, reframing it as a receptor that fine-tunes LCN2 signaling rather than simply internalizing cargo.\",\n      \"evidence\": \"Solution-state NMR and biophysical binding affinity measurements; proximity ligation assay confirming interaction in hippocampal neurons with differential effects of apo- versus holo-LCN2 on cell survival\",\n      \"pmids\": [\"26635366\", \"26004810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor structure was unknown\", \"Mechanism of LCN2 internalization not resolved\", \"Whether apo/holo discrimination occurs in vivo not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of Wnt/β-catenin, NFAT5, and CREB as transcriptional regulators of SLC22A17 in renal collecting duct cells revealed how osmotic and hormonal cues control its expression, connecting SLC22A17 to kidney physiology and osmotolerance.\",\n      \"evidence\": \"RNAi silencing of β-catenin and Nfat5, pharmacological CREB inhibition, and TLR4/LPS treatment in primary IMCD and mCCD cells with qPCR and immunoblotting readouts\",\n      \"pmids\": [\"30404645\", \"31671521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding by these transcription factors not shown (e.g., ChIP)\", \"Physiological consequence of transcriptional regulation in vivo not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that SLC22A17 serves as a receptor for the fungal allergen Alt a 1 broadened its ligand repertoire beyond LCN2, suggesting a general role in recognizing lipocalin-fold proteins.\",\n      \"evidence\": \"Pull-down assay and immunofluorescence in Calu-3 airway epithelial cells with computational structural modeling\",\n      \"pmids\": [\"31095759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Alt a 1 internalization via SLC22A17 on downstream signaling not fully characterized\", \"Specificity versus other airway receptors unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Consolidation of SLC22A17 as a distal nephron receptor mediating endocytosis of multiple metalloproteins (transferrin, metallothionein, LCN2) provided a unified model for how proteins and transition metals escaping the proximal tubule are recaptured, and linked SLC22A17 to cadmium nephrotoxicity and astroglial neurogenesis regulation in Alzheimer's disease.\",\n      \"evidence\": \"Mechanistic synthesis of multiple renal RME studies; functional knockdown and single-cell transcriptomics in APP/PS1dE9 mouse model and human AD tissue\",\n      \"pmids\": [\"37589051\", \"37429840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo renal-specific knockout phenotype not yet reported\", \"Whether SLC22A17-mediated neurogenesis suppression is iron-dependent remains untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that SLC22A17 promotes endothelial ferroptosis and represses tight junction gene transcription after cerebral ischemia established a direct pathological role for the receptor in blood-brain barrier disruption, validated by amelioration of BBB leakage upon knockdown in vivo.\",\n      \"evidence\": \"Reciprocal siRNA knockdown and lentiviral overexpression in human brain endothelial cells with permeability, electrical resistance, and ferroptosis marker assays; confirmed in mouse MCAO model\",\n      \"pmids\": [\"38738428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SLC22A17 represses tight junction gene transcription not identified\", \"Whether the effect is LCN2-dependent or iron-transport-dependent not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that brain-conditional Slc22a17 knockout causes postnatal lethality, iron overload, and neural stem cell apoptosis via dysregulated p62–Nrf2/HO-1 signaling provided the first genetic loss-of-function evidence that SLC22A17 is essential for brain iron homeostasis and neural development.\",\n      \"evidence\": \"Conditional knockout mouse with TurboID proximity labeling, immunoprecipitation identifying p62 interaction, and Nrf2/HO-1 pathway analysis with oxidative stress and cognitive behavioral readouts\",\n      \"pmids\": [\"41397957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p62 interaction is direct or mediated through additional partners not resolved\", \"Mechanism of iron efflux impairment downstream of Nrf2/HO-1 activation unclear\", \"Contribution of LCN2-dependent versus LCN2-independent iron transport not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Functional and structural studies demonstrated that SLC22A17 operates as a high-capacity, low-affinity iron transporter independent of LCN2, with a cryo-EM structure revealing a unique transmembrane loop (TML6) gating mechanism that diverges from other SLC22 transporters.\",\n      \"evidence\": \"(preprint) Cryo-EM structure of mouse BOCT1, functional iron transport assays, mutagenesis, and molecular dynamics simulations\",\n      \"pmids\": [\"bio_10.1101_2025.06.28.662014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Human SLC22A17 structure not yet determined\", \"Specific iron coordination residues in the transport pathway not fully validated by mutagenesis\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SLC22A17 was shown to promote ferroptosis in fibroblasts via iron-dependent mechanisms and to support TNBC cell proliferation through Akt/mTOR and JAK/STAT3 signaling, extending its pro-ferroptotic and pro-survival roles to non-neural tissues.\",\n      \"evidence\": \"siRNA knockdown and overexpression with ferroptosis marker quantification in urethral fibroblasts; siRNA silencing with flow cytometry and pathway immunoblotting in TNBC cell lines\",\n      \"pmids\": [\"41386104\", \"41212350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SLC22A17's oncogenic role in TNBC is iron-transport-dependent not tested\", \"In vivo tumor models lacking\", \"Mechanism linking SLC22A17 to Akt/mTOR activation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution mechanism of iron transport through TML6 gating in human SLC22A17, whether its receptor and transporter functions are separable in vivo, and how the p62 interaction mechanistically couples to Nrf2/HO-1 signaling and iron efflux regulation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human structure not determined\", \"No conditional kidney-specific knockout phenotype reported\", \"LCN2-dependent versus LCN2-independent iron transport contributions not separated in any tissue in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [6, 12, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 5, 12]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [6, 12, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 4, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LCN2\",\n      \"SQSTM1\",\n      \"NFE2L2\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}