{"gene":"SLC40A1","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2000,"finding":"IREG1 (SLC40A1) is localized to the basolateral membrane of polarized intestinal epithelial cells and stimulates iron efflux when expressed in Xenopus oocytes, establishing it as the duodenal basolateral iron export protein. Its mRNA contains a functional iron-responsive element (IRE) in the 5' UTR, and expression is increased under conditions of elevated iron absorption.","method":"Xenopus oocyte iron efflux assay, cDNA isolation, immunolocalization, IRE functional analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct iron efflux reconstitution in Xenopus oocytes, replicated by subsequent studies; IRE function confirmed, basolateral localization established","pmids":["10882071"],"is_preprint":false},{"year":2005,"finding":"Embryonic and conditional knockout of murine ferroportin (Fpn/SLC40A1) demonstrates that ferroportin is essential for iron export from enterocytes, macrophages, and hepatocytes. Embryonic lethality of global knockouts is rescued by selective inactivation in the embryo proper, indicating a critical role in extraembryonic visceral endoderm. Intestine-specific inactivation confirms ferroportin is critical for intestinal iron absorption.","method":"Conditional and global gene knockout (Cre-lox), tissue-selective inactivation, histological iron quantification","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional knockout models with defined phenotypic readouts, replicated across cell types in the same study","pmids":["16054062"],"is_preprint":false},{"year":2005,"finding":"Human FPN (SLC40A1) expressed in a human cell line causes iron deficiency via a ~3-fold increase in iron export. Loss-of-function mutations A77D, V162del, and G490D abolish iron export without physically impeding wild-type FPN, indicating haploinsufficiency as the disease mechanism. Variants Y64N, N144D, N144H, Q248H, and C326Y retain iron export function in vitro, suggesting resistance to hepcidin-mediated inhibition rather than loss of export activity.","method":"In vitro iron export assay in human cell lines, site-directed mutagenesis, cellular iron quantification","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro iron export assay with multiple disease-associated mutants tested, orthogonal cellular iron measurement","pmids":["15692071"],"is_preprint":false},{"year":2002,"finding":"MTP1 (SLC40A1) expression in reticuloendothelial system (RES) cells of spleen, liver, and bone marrow is down-regulated by lipopolysaccharide-induced acute inflammation. This down-regulation requires signaling through TLR4, as mice lacking TLR4 do not show altered MTP1 expression after LPS treatment. TNF-receptor 1a is not required for this LPS effect.","method":"LPS mouse model, Northern blotting, TLR4 and TNF-R1a knockout mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using TLR4 and TNF-R1a knockout mice, replicated across multiple tissue types","pmids":["12161425"],"is_preprint":false},{"year":2003,"finding":"FPN1 (SLC40A1) mRNA and protein levels in J774 macrophages increase with iron loading and after erythrophagocytosis (up to 8-fold at 4 hours). Induction after erythrophagocytosis results from erythrocyte-derived iron (blocked by iron chelation) and involves transcriptional control (blocked by actinomycin D). This establishes FPN1's role in macrophage iron recycling.","method":"Northern blotting, Western blotting, actinomycin D transcription block, iron chelation, erythrophagocytosis assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal mRNA and protein analysis, multiple mechanistic interventions (chelation, transcription inhibition) in same study","pmids":["12907459"],"is_preprint":false},{"year":2010,"finding":"FPN1 transcription is inhibited by Bach1 and activated by Nrf2 (Nuclear Factor Erythroid 2-like) via a MARE/ARE element at position -7007 of the FPN1 promoter in macrophages. The protoporphyrin ring of heme is sufficient to increase FPN1 transcriptional activity, while iron released from heme controls FPN1 translation through the IRE in the 5' UTR.","method":"siRNA knockdown, overexpression, reporter construct with truncations and MARE/ARE mutations, luciferase assay","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis combined with siRNA knockdown and overexpression, multiple orthogonal methods in one study","pmids":["20179090"],"is_preprint":false},{"year":2010,"finding":"FPN1 transcription is induced by zinc and cadmium through Metal Transcription Factor-1 (MTF-1), which translocates to the nucleus and binds to two MTF-1 binding sites in the mouse FPN1 promoter. MTF-1 silencing reduces FPN1 transcription in response to zinc but not iron. Fpn can transport zinc and protect zinc-sensitive cells from zinc toxicity.","method":"MTF-1 siRNA knockdown, promoter reporter assay with MTF-1 site mutations, nuclear translocation assay, zinc export functional assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis, siRNA knockdown, functional transport assay, multiple orthogonal methods in one study","pmids":["20688958"],"is_preprint":false},{"year":2003,"finding":"Hephaestin and Ireg1 (SLC40A1) expression respond to systemic rather than local signals of iron status in intestinal enterocytes, in contrast to DMT1 which is regulated by local enterocyte iron levels. This was demonstrated by comparing sla mice (with mutant hephaestin) to iron-deficient wild-type mice.","method":"Genetic comparison (sla mouse model vs. iron-deficient diet), mRNA and protein expression analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model comparison with mRNA and protein analysis, single lab but two genetic/dietary models","pmids":["12730111"],"is_preprint":false},{"year":2004,"finding":"Ferroportin (SLC40A1) is present at the apical membrane (brush border) of enterocytes in addition to the basolateral membrane. A blocking antibody to ferroportin applied to the apical membrane significantly reduced Fe(II) uptake by 40-50% but had no effect on iron release, suggesting ferroportin modulates apical iron uptake possibly through interaction with DMT1.","method":"Blocking antibody assay, iron uptake/efflux assays in IEC-6 and Caco-2 cells, microvillus membrane fractionation, immunofluorescence","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blocking antibody with functional iron transport assay, fractionation showing apical localization, single lab","pmids":["14684575"],"is_preprint":false},{"year":2009,"finding":"The SLC40A1 p.Y501C variant reaches the plasma membrane normally and retains full iron export ability, but is resistant to hepcidin-mediated inhibition in cultured cells, confirming that certain ferroportin mutations confer hepcidin resistance (gain-of-function) leading to iron overload resembling HFE hemochromatosis.","method":"In vitro functional assay in cultured cells, hepcidin inhibition assay, plasma membrane localization by immunofluorescence","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional iron export and hepcidin resistance assay, membrane localization confirmed, single lab","pmids":["19709084"],"is_preprint":false},{"year":2011,"finding":"SLC40A1 p.W158C impairs intracellular trafficking of ferroportin to the plasma membrane, resulting in reduced iron export (loss-of-function). SLC40A1 p.H507R localizes normally to the plasma membrane but does not bind hepcidin in vitro and is resistant to hepcidin-mediated inactivation. A synthetic peptide from amino acids 500-518 of wild-type ferroportin decreased hepcidin inhibitory activity in cells, while the H507R peptide had no effect.","method":"In vitro iron export assay in 293T cells, immunofluorescence for membrane localization, synthetic peptide hepcidin inhibition assay","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro iron export reconstitution, membrane trafficking assay, peptide binding assay, multiple orthogonal methods in one study","pmids":["21396368"],"is_preprint":false},{"year":2018,"finding":"SLC40A1 p.R178Q reduces FPN1 iron export ability without causing protein mislocalization, representing a new category of loss-of-function mutation affecting gating residues required for conformational changes during iron transport. Structural modeling of human FPN1 indicates R178 is part of an interaction network modulating the outward-facing conformation.","method":"In vitro iron export assay, protein localization by immunofluorescence, 3D structural comparative modeling, clinical and histological data from 22 patients across 6 families","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iron export assay and structural modeling, large multi-family clinical correlation, single lab","pmids":["30002125"],"is_preprint":false},{"year":2018,"finding":"SLC40A1 p.Y333H mutant ferroportin is resistant to hepcidin-mediated internalization and degradation in 293T cells, and is associated with gain-of-function iron export activity (hepcidin resistance phenotype), establishing this mutation as a cause of haemochromatosis in China.","method":"Transfection in 293T cells, hepcidin treatment assay, immunofluorescence for cellular localization, Western blotting for FPN1 and ferritin","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with hepcidin treatment and membrane localization, multiple methods in one study","pmids":["30500107"],"is_preprint":false},{"year":2017,"finding":"Nrf2 transcriptionally suppresses SLC40A1 expression in ovarian cancer cells. ChIP and dual-luciferase reporter assay confirmed Nrf2 binds SLC40A1 promoter to inhibit its transcription. Knockdown of Nrf2 increases SLC40A1 expression; overexpression of Nrf2 decreases it. SLC40A1 overexpression reverses Nrf2-induced cisplatin resistance.","method":"ChIP assay, dual-luciferase reporter assay, Nrf2 knockdown and overexpression, SLC40A1 overexpression rescue experiment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assay for direct transcriptional repression, functional rescue, single lab","pmids":["29212168"],"is_preprint":false},{"year":2022,"finding":"miR-147a directly binds the 3'-UTR of SLC40A1 and inhibits SLC40A1-mediated iron export, thereby facilitating iron overload, lipid peroxidation, and ferroptosis in glioblastoma cells.","method":"3'-UTR luciferase reporter assay, miR-147a mimic/inhibitor transfection, SLC40A1 siRNA knockdown, iron and lipid peroxidation measurement","journal":"Analytical cellular pathology (Amsterdam)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR binding validated by luciferase assay, functional rescue with siRNA, single lab","pmids":["35942174"],"is_preprint":false},{"year":2022,"finding":"miR-4735-3p directly targets SLC40A1; its overexpression suppresses SLC40A1-mediated iron export, leading to iron overload and ferroptosis in clear cell renal cell carcinoma cells. SLC40A1 overexpression rescued iron overload and ferroptosis in miR-4735-3p mimic-treated cells.","method":"Mechanistic study identifying SLC40A1 as direct miR-4735-3p target, adenoviral SLC40A1 overexpression rescue, lipid peroxidation and iron assays","journal":"Analytical cellular pathology (Amsterdam)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by rescue experiment, functional iron and oxidative stress assays, single lab","pmids":["35646516"],"is_preprint":false},{"year":2024,"finding":"STING inhibition stabilizes FPN1 protein by decreasing ubiquitin-mediated proteasomal degradation of FPN1 in renal tubular epithelial cells, thereby alleviating ferroptosis. Disruption of FPN1 on the basis of STING inhibition abolished the ferroptosis improvements, confirming FPN1 stabilization as the mechanism.","method":"STING inhibition/deficiency model, ubiquitination assay, proteasomal degradation assay, FPN1 disruption rescue experiment","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with rescue experiment, single lab","pmids":["38428828"],"is_preprint":false},{"year":2024,"finding":"LRSAM1 ubiquitinates and degrades SLC40A1, reducing iron export and inducing ferroptosis in TMZ-resistant glioma stem cells. Erianin suppresses REST transcriptional repression to upregulate LRSAM1, which then ubiquitinates SLC40A1. Co-IP assays confirmed the LRSAM1–SLC40A1 interaction.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assessment, ChIP assay, luciferase reporter assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay confirming the interaction, multiple orthogonal methods, single lab","pmids":["39039049"],"is_preprint":false},{"year":2023,"finding":"Cathepsin B (CTSB) binds FPN and negatively regulates FPN protein levels by promoting its degradation, causing iron accumulation and ferroptosis in macrophages during atherosclerosis. This was confirmed by co-immunoprecipitation and knockdown/inhibition of CTSB.","method":"Co-immunoprecipitation, CTSB knockdown and pharmacological inhibition, iron and ferroptosis assays, single-cell transcriptomics","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirming FPN as CTSB binding target, functional knockdown assay, single lab","pmids":["39960586"],"is_preprint":false},{"year":2023,"finding":"UBA52 ubiquitinates and promotes degradation of ferroportin (FPN/SLC40A1) in neurons following peripheral nerve injury, causing iron accumulation and ferroptosis. Hydralazine binds to UBA52 and competitively inhibits FPN ubiquitination, thereby restoring FPN levels and suppressing neuronal ferroptosis.","method":"In vitro and in vivo ubiquitination assay, Co-IP, competitive binding assay with hydralazine and UBA52, neuronal ferroptosis quantification","journal":"Journal of pharmaceutical analysis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination and Co-IP assays, competitive binding experiment, in vitro and in vivo models, single lab","pmids":["38352945"],"is_preprint":false},{"year":2025,"finding":"H3K14 lactylation (H3K14la) is enriched at the SLC40A1 promoter in pulmonary endothelial cells during sepsis, and this epigenetic mark drives transcriptional regulation of SLC40A1, contributing to EC ferroptosis and lung injury. Suppressing glycolysis reduced H3K14la and EC activation.","method":"Cut&Tag analysis of H3K14la at SLC40A1 promoter, lactylome and proteome integration, glycolysis inhibition","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Cut&Tag ChIP identifying H3K14la enrichment at SLC40A1 promoter, functional link via glycolysis inhibition, single study","pmids":["39822760"],"is_preprint":false},{"year":2025,"finding":"HDAC2 transcriptionally inhibits FPN expression by reducing histone H3K27 acetylation at the FPN promoter region during hypoxia/reoxygenation injury. Dexmedetomidine inhibits HDAC2, restoring H3K27Ac at the FPN promoter, upregulating FPN, and inhibiting cardiomyocyte ferroptosis.","method":"DNA pulldown assay, ChIP assay for HDAC2 binding at FPN promoter and H3K27Ac levels, HDAC2 overexpression/knockdown, FPN knockdown rescue","journal":"Cardiovascular drugs and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and DNA pulldown assay directly linking HDAC2 to FPN promoter H3K27Ac, functional rescue, single lab","pmids":["39747742"],"is_preprint":false},{"year":2024,"finding":"SLC40A1 p.Arg40Gln and p.Ser47Phe substitutions partially reduce FPN1 iron export and partially reduce hepcidin sensitivity. p.Ala350Val more profoundly reduces iron egress and weakens FPN1/hepcidin interaction. Structural analysis indicates the latter prevents rigid-body movements essential to the iron transport cycle, while the first two cause local instabilities.","method":"In vitro iron export assay in cultured cells, hepcidin sensitivity assay, structural modeling, clinical phenotype correlation in 12 affected individuals","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with structural analysis and clinical correlation, single lab","pmids":["39039793"],"is_preprint":false},{"year":2005,"finding":"IREG1 (SLC40A1) expression in neuroblastoma (SH-SY5Y) and hippocampal neurons increases in response to progressive iron accumulation, correlates directly with cellular iron content, and its increased expression correlates with increased iron efflux from cells, establishing its role in neuronal iron homeostasis.","method":"Western blotting, immunocytochemistry, iron efflux assay, correlation analysis","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct iron efflux measurement correlated with IREG1 protein expression, multiple cell types, single lab","pmids":["15667655"],"is_preprint":false},{"year":2019,"finding":"Iron dyshomeostasis induces binding of APP to BACE1, promoting amyloid formation, and decreases the functional APP/Fpn1 complex in microglia, impairing iron export in an iron-overload model.","method":"FeCl3 treatment of microglia, protein expression analysis, co-localization and interaction analysis of APP and Fpn1","journal":"Cell transplantation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization and expression analysis without direct Co-IP or mechanistic validation of the APP/Fpn1 complex, single lab","pmids":["30776900"],"is_preprint":false},{"year":2023,"finding":"Conditional deletion of Fpn1 in mouse brain microvascular endothelial cells (Cdh5-Cre) decreased brain iron levels, attenuated oxidative stress, inflammation, ferroptosis, and apoptosis in the acute phase of ischemic stroke, alleviating neurological impairment. However, Fpn1 knockout in ECs delayed neurological recovery in the later stages, associated with iron deficiency-induced inhibition of neuronal development and enhanced glial proliferation.","method":"VE-cadherin-Cre conditional Fpn1 knockout mice, MCAO stroke model, behavioral testing, cerebral infarct measurement, ferroptosis/apoptosis markers","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type specific conditional knockout with defined phenotypic readouts at multiple timepoints, dual consequence established, single lab","pmids":["36841833"],"is_preprint":false},{"year":2025,"finding":"Conditional knockout of Fpn1 in oligodendrocytes (Fpn1Olig2-cKO) caused iron accumulation, elevated ROS, activation of MAPK/ERK, AKT/JNK, and NF-κB pathways, and upregulation of hepcidin in the prefrontal cortex and hippocampus, leading to myelin defects, disrupted synaptic formation, and depression-like behaviors in mice.","method":"Oligodendrocyte-specific Fpn1 conditional knockout (Cre-lox), behavioral testing, Western blotting for signaling pathways, FPN1 silencing in human MO3.13 cells, ICG-001 pharmacological pathway dissection","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type specific conditional knockout with defined cellular and behavioral phenotypes, in vitro mechanistic follow-up, single lab","pmids":["40609802"],"is_preprint":false}],"current_model":"SLC40A1 (ferroportin/IREG1/MTP1/FPN1) is the sole known mammalian non-heme iron export protein, localized predominantly to the basolateral membrane of duodenal enterocytes, macrophages, and other iron-exporting cells, where it mediates cellular iron efflux; its expression is transcriptionally regulated by heme (via Bach1/Nrf2 at a MARE/ARE element), by transition metals (via MTF-1), and by Nrf2 binding at its promoter, while post-translationally it is internalized and degraded in response to hepcidin binding (with disease mutations either causing loss-of-function iron export or gain-of-function hepcidin resistance), and its protein stability is additionally controlled by ubiquitin-mediated proteasomal degradation via E3 ligases including LRSAM1 and UBA52, with its 5' IRE mediating translational regulation by cellular iron status."},"narrative":{"mechanistic_narrative":"SLC40A1 (ferroportin/IREG1/MTP1/FPN1) is the mammalian basolateral iron export protein that mediates cellular iron efflux from enterocytes, macrophages, and other iron-handling cells, placing it at the central control point of systemic iron homeostasis [PMID:10882071, PMID:16054062]. Direct reconstitution in Xenopus oocytes and human cell lines established it as a non-heme iron exporter localized to the basolateral membrane of polarized intestinal epithelium, with conditional knockout confirming its essential role in intestinal iron absorption and macrophage and hepatocyte iron release [PMID:10882071, PMID:16054062, PMID:15692071]. In macrophages it drives iron recycling, with both transcript and protein induced by iron loading and erythrophagocytosis [PMID:12907459]. SLC40A1 expression is controlled at multiple levels: transcriptionally by the heme-responsive Bach1/Nrf2 axis acting at a MARE/ARE promoter element, by zinc and cadmium through MTF-1 (consistent with ferroportin also exporting zinc), and by chromatin-modifying inputs including HDAC2-dependent H3K27 acetylation and H3K14 lactylation at its promoter; translationally through a 5' UTR IRE responsive to cellular iron; and post-transcriptionally via 3' UTR-targeting microRNAs [PMID:20179090, PMID:20688958, PMID:35942174, PMID:39822760, PMID:39747742]. Inflammatory down-regulation in reticuloendothelial cells proceeds through TLR4 signaling [PMID:12161425]. Protein stability is set by ubiquitin-mediated proteasomal degradation through E3 ligases LRSAM1 and UBA52 and by interaction with cathepsin B, loss of which causes iron accumulation, lipid peroxidation, and ferroptosis across glioma, neuronal, atherosclerotic, and renal contexts [PMID:38428828, PMID:39039049, PMID:39960586, PMID:38352945]. Disease mutations partition into loss-of-function alleles that abolish iron export through impaired trafficking or transport-cycle gating (causing iron overload by haploinsufficiency) and gain-of-function alleles that retain export but resist hepcidin-mediated internalization and degradation, defining the SLC40A1-related hemochromatosis spectrum [PMID:15692071, PMID:19709084, PMID:21396368, PMID:30002125, PMID:30500107, PMID:39039793].","teleology":[{"year":2000,"claim":"Established the molecular identity of the long-sought duodenal basolateral iron exporter, defining where dietary iron leaves the enterocyte and how its message is iron-regulated.","evidence":"Xenopus oocyte iron efflux reconstitution, immunolocalization, and 5' UTR IRE functional analysis","pmids":["10882071"],"confidence":"High","gaps":["Transport mechanism and stoichiometry not resolved","No structural model of the transporter"]},{"year":2002,"claim":"Linked ferroportin regulation to innate immune signaling, explaining how inflammation restricts iron availability in reticuloendothelial cells.","evidence":"LPS mouse model with TLR4 and TNF-R1a knockouts, Northern blotting","pmids":["12161425"],"confidence":"High","gaps":["Downstream transcriptional effectors of TLR4 acting on the promoter not defined","Relationship to hepcidin-mediated control not addressed in this study"]},{"year":2003,"claim":"Distinguished systemic from local control, showing ferroportin responds to whole-body iron status rather than enterocyte iron content, unlike DMT1.","evidence":"Comparison of sla (mutant hephaestin) mice with iron-deficient wild-type mice, mRNA/protein analysis","pmids":["12730111"],"confidence":"Medium","gaps":["The systemic signal itself not molecularly identified here","Single-lab genetic/dietary comparison"]},{"year":2003,"claim":"Defined ferroportin's role in macrophage iron recycling and showed erythrophagocytosis-driven induction is transcriptional and iron-dependent.","evidence":"Erythrophagocytosis assay in J774 macrophages with actinomycin D and iron chelation, reciprocal mRNA/protein analysis","pmids":["12907459"],"confidence":"High","gaps":["Specific transcription factors not identified in this study"]},{"year":2004,"claim":"Probed an additional apical localization in enterocytes, raising the possibility ferroportin modulates apical iron uptake beyond basolateral export.","evidence":"Apical blocking-antibody iron uptake/efflux assays and membrane fractionation in IEC-6 and Caco-2 cells","pmids":["14684575"],"confidence":"Medium","gaps":["Proposed DMT1 interaction not directly demonstrated","Apical role not confirmed in vivo or by other labs"]},{"year":2005,"claim":"Demonstrated genetic necessity in vivo across enterocytes, macrophages, and hepatocytes, and revealed a critical extraembryonic role from the embryonic lethality of global knockouts.","evidence":"Conditional and global Cre-lox knockout mice with tissue-selective inactivation and histological iron quantification","pmids":["16054062"],"confidence":"High","gaps":["Does not resolve transport mechanism","Cell-autonomous versus systemic contributions to each phenotype not fully separated"]},{"year":2005,"claim":"Separated the two molecular categories of disease alleles, showing some mutants abolish export (haploinsufficiency) while others retain export but are hepcidin-resistant.","evidence":"In vitro iron export assay in human cells with site-directed mutagenesis of multiple disease variants","pmids":["15692071"],"confidence":"High","gaps":["Hepcidin-resistance mechanism for specific variants not directly assayed here","Structural basis of loss-of-function not defined"]},{"year":2005,"claim":"Extended ferroportin function to neuronal iron homeostasis, correlating its expression with cellular iron content and efflux.","evidence":"Western blot, immunocytochemistry, and iron efflux assays in SH-SY5Y and hippocampal neurons","pmids":["15667655"],"confidence":"Medium","gaps":["Correlative rather than causal in neurons","Regulatory pathway in neurons not defined"]},{"year":2009,"claim":"Confirmed the gain-of-function hepcidin-resistance disease mechanism at the cellular level for a specific variant reaching the membrane normally.","evidence":"In vitro iron export and hepcidin inhibition assays with membrane localization for Y501C","pmids":["19709084"],"confidence":"Medium","gaps":["Structural basis of hepcidin resistance not resolved","Single-lab cellular assay"]},{"year":2010,"claim":"Resolved dual heme-responsive transcriptional control, with Bach1 repressing and Nrf2 activating via a MARE/ARE element, while heme-derived iron acts through the IRE on translation.","evidence":"Promoter reporter mutagenesis, siRNA knockdown, and overexpression in macrophages","pmids":["20179090"],"confidence":"High","gaps":["Quantitative integration of transcriptional and translational control not defined"]},{"year":2010,"claim":"Identified metal-responsive transcriptional control via MTF-1 and showed ferroportin can export zinc to protect against zinc toxicity, broadening its substrate scope.","evidence":"MTF-1 siRNA, promoter reporter with site mutations, nuclear translocation, and zinc export assay","pmids":["20688958"],"confidence":"High","gaps":["Physiological relevance of zinc transport in vivo not established","Selectivity determinants between iron and zinc not defined"]},{"year":2011,"claim":"Mechanistically dissected two mutation classes — trafficking-defective loss-of-function and hepcidin-binding-defective gain-of-function — and mapped a hepcidin-interacting peptide region.","evidence":"In vitro iron export, membrane trafficking imaging, and synthetic peptide hepcidin inhibition assays in 293T cells for W158C and H507R","pmids":["21396368"],"confidence":"High","gaps":["Full hepcidin-binding interface not structurally defined"]},{"year":2017,"claim":"Showed Nrf2 can also act as a transcriptional repressor of SLC40A1 in cancer, linking ferroportin suppression to chemoresistance.","evidence":"ChIP, dual-luciferase reporter, Nrf2 knockdown/overexpression, and SLC40A1 rescue in ovarian cancer cells","pmids":["29212168"],"confidence":"Medium","gaps":["Apparent context-dependent opposite Nrf2 effects versus macrophage data not reconciled","Single-lab study"]},{"year":2018,"claim":"Defined a third mutation category — gating residues that impair the transport conformational cycle without mislocalization — refining the structural basis of loss-of-function.","evidence":"In vitro iron export, localization imaging, and 3D structural modeling for R178Q with multi-family clinical correlation","pmids":["30002125"],"confidence":"Medium","gaps":["Conformational cycle inferred from modeling, not experimental structures","Single-lab functional work"]},{"year":2018,"claim":"Added a hepcidin-resistant gain-of-function allele causing hemochromatosis in an additional population.","evidence":"Transfection, hepcidin treatment, localization imaging, and Western blot for Y333H in 293T cells","pmids":["30500107"],"confidence":"Medium","gaps":["Structural basis of resistance not resolved","Single-lab study"]},{"year":2022,"claim":"Established microRNA control of ferroportin, with miR-147a and miR-4735-3p directly targeting the 3' UTR to suppress iron export and drive ferroptosis in tumor cells.","evidence":"3' UTR luciferase reporters, miRNA mimic/inhibitor, siRNA, and SLC40A1 overexpression rescue with iron and lipid peroxidation assays in glioblastoma and ccRCC","pmids":["35942174","35646516"],"confidence":"Medium","gaps":["Physiological versus tumor-specific relevance not separated","Single-lab per study"]},{"year":2023,"claim":"Identified protein-degradation and binding partners controlling ferroportin stability — UBA52 ubiquitination in injured neurons and cathepsin B binding in atherosclerotic macrophages — linking destabilization to iron accumulation and ferroptosis.","evidence":"Co-IP, ubiquitination assays, knockdown/inhibition, and competitive binding (hydralazine) with ferroptosis readouts","pmids":["38352945","39960586"],"confidence":"Medium","gaps":["Reciprocal validation and direct binding interfaces not fully defined","Single-lab per study"]},{"year":2023,"claim":"Demonstrated cell-type-specific, time-dependent consequences of ferroportin loss in brain endothelium during ischemic stroke, protective acutely but impairing later recovery.","evidence":"VE-cadherin-Cre conditional Fpn1 knockout mice in MCAO model with behavioral, infarct, and ferroptosis/apoptosis readouts","pmids":["36841833"],"confidence":"Medium","gaps":["Molecular trigger of late-phase iron deficiency effects not defined","Single-lab study"]},{"year":2024,"claim":"Connected additional regulators of ferroportin protein stability — STING-dependent ubiquitination and the LRSAM1 E3 ligase under REST/Erianin control — to ferroptosis in renal epithelium and resistant glioma stem cells.","evidence":"Ubiquitination and proteasomal degradation assays, Co-IP, ChIP, and FPN1 disruption rescue","pmids":["38428828","39039049"],"confidence":"Medium","gaps":["Direct versus indirect role of STING in ubiquitination not fully resolved","Single-lab per study"]},{"year":2024,"claim":"Resolved graded biophysical effects of further disease variants, separating local instabilities from impaired rigid-body movements of the transport cycle and partial hepcidin desensitization.","evidence":"In vitro iron export and hepcidin sensitivity assays with structural modeling and clinical correlation for R40Q, S47F, and A350V","pmids":["39039793"],"confidence":"Medium","gaps":["Mechanistic claims rest on modeling rather than experimental structures","Single-lab work"]},{"year":2025,"claim":"Expanded chromatin-level control of SLC40A1 transcription, implicating H3K14 lactylation, HDAC2-dependent H3K27 acetylation, and oligodendrocyte iron homeostasis in tissue injury and behavior.","evidence":"Cut&Tag, ChIP, DNA pulldown, glycolysis/HDAC2 manipulation, and oligodendrocyte-specific conditional knockout with behavioral and signaling readouts","pmids":["39822760","39747742","40609802"],"confidence":"Medium","gaps":["Direct factors writing/reading these marks at the promoter not fully defined","Single-lab per study"]},{"year":null,"claim":"An experimentally determined structure of human ferroportin in distinct transport-cycle conformations and bound to hepcidin would unify the scattered mutation classes into a single mechanistic framework.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental structure in the timeline","Transport stoichiometry and ion coupling unresolved","Hepcidin-binding interface defined only by peptide and modeling"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,6]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,9,10]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,15,16,17,18,19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,6]}],"complexes":[],"partners":["HAMP","LRSAM1","UBA52","CTSB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NP59","full_name":"Ferroportin","aliases":["Ferroportin-1","Iron-regulated transporter 1","Solute carrier family 40 member 1"],"length_aa":571,"mass_kda":62.5,"function":"Transports Fe(2+) from the inside of a cell to the outside of the cell, playing a key role for maintaining systemic iron homeostasis (PubMed:15692071, PubMed:22178646, PubMed:22682227, PubMed:24304836, PubMed:29237594, PubMed:29599243, PubMed:30247984). 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all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC40A1"},"hgnc":{"alias_symbol":["MTP1","IREG1","FPN1","HFE4","FPN"],"prev_symbol":["SLC11A3"]},"alphafold":{"accession":"Q9NP59","domains":[{"cath_id":"1.20.1250","chopping":"22-236","consensus_level":"medium","plddt":91.5719,"start":22,"end":236},{"cath_id":"1.20.1250.20","chopping":"294-411_451-548","consensus_level":"medium","plddt":89.6442,"start":294,"end":548}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP59","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP59-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP59-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC40A1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC40A1"},"sequence":{"accession":"Q9NP59","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NP59.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NP59/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP59"}},"corpus_meta":[{"pmid":"10882071","id":"PMC_10882071","title":"A 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haematology","url":"https://pubmed.ncbi.nlm.nih.gov/21175851","citation_count":10,"is_preprint":false},{"pmid":"29154924","id":"PMC_29154924","title":"Characterization of three novel pathogenic SLC40A1 mutations and genotype/phenotype correlations in 7 Italian families with type 4 hereditary hemochromatosis.","date":"2017","source":"Biochimica et biophysica acta. 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Its mRNA contains a functional iron-responsive element (IRE) in the 5' UTR, and expression is increased under conditions of elevated iron absorption.\",\n      \"method\": \"Xenopus oocyte iron efflux assay, cDNA isolation, immunolocalization, IRE functional analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct iron efflux reconstitution in Xenopus oocytes, replicated by subsequent studies; IRE function confirmed, basolateral localization established\",\n      \"pmids\": [\"10882071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Embryonic and conditional knockout of murine ferroportin (Fpn/SLC40A1) demonstrates that ferroportin is essential for iron export from enterocytes, macrophages, and hepatocytes. Embryonic lethality of global knockouts is rescued by selective inactivation in the embryo proper, indicating a critical role in extraembryonic visceral endoderm. Intestine-specific inactivation confirms ferroportin is critical for intestinal iron absorption.\",\n      \"method\": \"Conditional and global gene knockout (Cre-lox), tissue-selective inactivation, histological iron quantification\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional knockout models with defined phenotypic readouts, replicated across cell types in the same study\",\n      \"pmids\": [\"16054062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human FPN (SLC40A1) expressed in a human cell line causes iron deficiency via a ~3-fold increase in iron export. Loss-of-function mutations A77D, V162del, and G490D abolish iron export without physically impeding wild-type FPN, indicating haploinsufficiency as the disease mechanism. Variants Y64N, N144D, N144H, Q248H, and C326Y retain iron export function in vitro, suggesting resistance to hepcidin-mediated inhibition rather than loss of export activity.\",\n      \"method\": \"In vitro iron export assay in human cell lines, site-directed mutagenesis, cellular iron quantification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro iron export assay with multiple disease-associated mutants tested, orthogonal cellular iron measurement\",\n      \"pmids\": [\"15692071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MTP1 (SLC40A1) expression in reticuloendothelial system (RES) cells of spleen, liver, and bone marrow is down-regulated by lipopolysaccharide-induced acute inflammation. This down-regulation requires signaling through TLR4, as mice lacking TLR4 do not show altered MTP1 expression after LPS treatment. TNF-receptor 1a is not required for this LPS effect.\",\n      \"method\": \"LPS mouse model, Northern blotting, TLR4 and TNF-R1a knockout mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using TLR4 and TNF-R1a knockout mice, replicated across multiple tissue types\",\n      \"pmids\": [\"12161425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FPN1 (SLC40A1) mRNA and protein levels in J774 macrophages increase with iron loading and after erythrophagocytosis (up to 8-fold at 4 hours). Induction after erythrophagocytosis results from erythrocyte-derived iron (blocked by iron chelation) and involves transcriptional control (blocked by actinomycin D). This establishes FPN1's role in macrophage iron recycling.\",\n      \"method\": \"Northern blotting, Western blotting, actinomycin D transcription block, iron chelation, erythrophagocytosis assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal mRNA and protein analysis, multiple mechanistic interventions (chelation, transcription inhibition) in same study\",\n      \"pmids\": [\"12907459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FPN1 transcription is inhibited by Bach1 and activated by Nrf2 (Nuclear Factor Erythroid 2-like) via a MARE/ARE element at position -7007 of the FPN1 promoter in macrophages. The protoporphyrin ring of heme is sufficient to increase FPN1 transcriptional activity, while iron released from heme controls FPN1 translation through the IRE in the 5' UTR.\",\n      \"method\": \"siRNA knockdown, overexpression, reporter construct with truncations and MARE/ARE mutations, luciferase assay\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis combined with siRNA knockdown and overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20179090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FPN1 transcription is induced by zinc and cadmium through Metal Transcription Factor-1 (MTF-1), which translocates to the nucleus and binds to two MTF-1 binding sites in the mouse FPN1 promoter. MTF-1 silencing reduces FPN1 transcription in response to zinc but not iron. Fpn can transport zinc and protect zinc-sensitive cells from zinc toxicity.\",\n      \"method\": \"MTF-1 siRNA knockdown, promoter reporter assay with MTF-1 site mutations, nuclear translocation assay, zinc export functional assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis, siRNA knockdown, functional transport assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20688958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hephaestin and Ireg1 (SLC40A1) expression respond to systemic rather than local signals of iron status in intestinal enterocytes, in contrast to DMT1 which is regulated by local enterocyte iron levels. This was demonstrated by comparing sla mice (with mutant hephaestin) to iron-deficient wild-type mice.\",\n      \"method\": \"Genetic comparison (sla mouse model vs. iron-deficient diet), mRNA and protein expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model comparison with mRNA and protein analysis, single lab but two genetic/dietary models\",\n      \"pmids\": [\"12730111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ferroportin (SLC40A1) is present at the apical membrane (brush border) of enterocytes in addition to the basolateral membrane. A blocking antibody to ferroportin applied to the apical membrane significantly reduced Fe(II) uptake by 40-50% but had no effect on iron release, suggesting ferroportin modulates apical iron uptake possibly through interaction with DMT1.\",\n      \"method\": \"Blocking antibody assay, iron uptake/efflux assays in IEC-6 and Caco-2 cells, microvillus membrane fractionation, immunofluorescence\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking antibody with functional iron transport assay, fractionation showing apical localization, single lab\",\n      \"pmids\": [\"14684575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The SLC40A1 p.Y501C variant reaches the plasma membrane normally and retains full iron export ability, but is resistant to hepcidin-mediated inhibition in cultured cells, confirming that certain ferroportin mutations confer hepcidin resistance (gain-of-function) leading to iron overload resembling HFE hemochromatosis.\",\n      \"method\": \"In vitro functional assay in cultured cells, hepcidin inhibition assay, plasma membrane localization by immunofluorescence\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional iron export and hepcidin resistance assay, membrane localization confirmed, single lab\",\n      \"pmids\": [\"19709084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SLC40A1 p.W158C impairs intracellular trafficking of ferroportin to the plasma membrane, resulting in reduced iron export (loss-of-function). SLC40A1 p.H507R localizes normally to the plasma membrane but does not bind hepcidin in vitro and is resistant to hepcidin-mediated inactivation. A synthetic peptide from amino acids 500-518 of wild-type ferroportin decreased hepcidin inhibitory activity in cells, while the H507R peptide had no effect.\",\n      \"method\": \"In vitro iron export assay in 293T cells, immunofluorescence for membrane localization, synthetic peptide hepcidin inhibition assay\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro iron export reconstitution, membrane trafficking assay, peptide binding assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21396368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC40A1 p.R178Q reduces FPN1 iron export ability without causing protein mislocalization, representing a new category of loss-of-function mutation affecting gating residues required for conformational changes during iron transport. Structural modeling of human FPN1 indicates R178 is part of an interaction network modulating the outward-facing conformation.\",\n      \"method\": \"In vitro iron export assay, protein localization by immunofluorescence, 3D structural comparative modeling, clinical and histological data from 22 patients across 6 families\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iron export assay and structural modeling, large multi-family clinical correlation, single lab\",\n      \"pmids\": [\"30002125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC40A1 p.Y333H mutant ferroportin is resistant to hepcidin-mediated internalization and degradation in 293T cells, and is associated with gain-of-function iron export activity (hepcidin resistance phenotype), establishing this mutation as a cause of haemochromatosis in China.\",\n      \"method\": \"Transfection in 293T cells, hepcidin treatment assay, immunofluorescence for cellular localization, Western blotting for FPN1 and ferritin\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with hepcidin treatment and membrane localization, multiple methods in one study\",\n      \"pmids\": [\"30500107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nrf2 transcriptionally suppresses SLC40A1 expression in ovarian cancer cells. ChIP and dual-luciferase reporter assay confirmed Nrf2 binds SLC40A1 promoter to inhibit its transcription. Knockdown of Nrf2 increases SLC40A1 expression; overexpression of Nrf2 decreases it. SLC40A1 overexpression reverses Nrf2-induced cisplatin resistance.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, Nrf2 knockdown and overexpression, SLC40A1 overexpression rescue experiment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assay for direct transcriptional repression, functional rescue, single lab\",\n      \"pmids\": [\"29212168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-147a directly binds the 3'-UTR of SLC40A1 and inhibits SLC40A1-mediated iron export, thereby facilitating iron overload, lipid peroxidation, and ferroptosis in glioblastoma cells.\",\n      \"method\": \"3'-UTR luciferase reporter assay, miR-147a mimic/inhibitor transfection, SLC40A1 siRNA knockdown, iron and lipid peroxidation measurement\",\n      \"journal\": \"Analytical cellular pathology (Amsterdam)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR binding validated by luciferase assay, functional rescue with siRNA, single lab\",\n      \"pmids\": [\"35942174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-4735-3p directly targets SLC40A1; its overexpression suppresses SLC40A1-mediated iron export, leading to iron overload and ferroptosis in clear cell renal cell carcinoma cells. SLC40A1 overexpression rescued iron overload and ferroptosis in miR-4735-3p mimic-treated cells.\",\n      \"method\": \"Mechanistic study identifying SLC40A1 as direct miR-4735-3p target, adenoviral SLC40A1 overexpression rescue, lipid peroxidation and iron assays\",\n      \"journal\": \"Analytical cellular pathology (Amsterdam)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by rescue experiment, functional iron and oxidative stress assays, single lab\",\n      \"pmids\": [\"35646516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STING inhibition stabilizes FPN1 protein by decreasing ubiquitin-mediated proteasomal degradation of FPN1 in renal tubular epithelial cells, thereby alleviating ferroptosis. Disruption of FPN1 on the basis of STING inhibition abolished the ferroptosis improvements, confirming FPN1 stabilization as the mechanism.\",\n      \"method\": \"STING inhibition/deficiency model, ubiquitination assay, proteasomal degradation assay, FPN1 disruption rescue experiment\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with rescue experiment, single lab\",\n      \"pmids\": [\"38428828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRSAM1 ubiquitinates and degrades SLC40A1, reducing iron export and inducing ferroptosis in TMZ-resistant glioma stem cells. Erianin suppresses REST transcriptional repression to upregulate LRSAM1, which then ubiquitinates SLC40A1. Co-IP assays confirmed the LRSAM1–SLC40A1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assessment, ChIP assay, luciferase reporter assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay confirming the interaction, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39039049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cathepsin B (CTSB) binds FPN and negatively regulates FPN protein levels by promoting its degradation, causing iron accumulation and ferroptosis in macrophages during atherosclerosis. This was confirmed by co-immunoprecipitation and knockdown/inhibition of CTSB.\",\n      \"method\": \"Co-immunoprecipitation, CTSB knockdown and pharmacological inhibition, iron and ferroptosis assays, single-cell transcriptomics\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirming FPN as CTSB binding target, functional knockdown assay, single lab\",\n      \"pmids\": [\"39960586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBA52 ubiquitinates and promotes degradation of ferroportin (FPN/SLC40A1) in neurons following peripheral nerve injury, causing iron accumulation and ferroptosis. Hydralazine binds to UBA52 and competitively inhibits FPN ubiquitination, thereby restoring FPN levels and suppressing neuronal ferroptosis.\",\n      \"method\": \"In vitro and in vivo ubiquitination assay, Co-IP, competitive binding assay with hydralazine and UBA52, neuronal ferroptosis quantification\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination and Co-IP assays, competitive binding experiment, in vitro and in vivo models, single lab\",\n      \"pmids\": [\"38352945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H3K14 lactylation (H3K14la) is enriched at the SLC40A1 promoter in pulmonary endothelial cells during sepsis, and this epigenetic mark drives transcriptional regulation of SLC40A1, contributing to EC ferroptosis and lung injury. Suppressing glycolysis reduced H3K14la and EC activation.\",\n      \"method\": \"Cut&Tag analysis of H3K14la at SLC40A1 promoter, lactylome and proteome integration, glycolysis inhibition\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Cut&Tag ChIP identifying H3K14la enrichment at SLC40A1 promoter, functional link via glycolysis inhibition, single study\",\n      \"pmids\": [\"39822760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC2 transcriptionally inhibits FPN expression by reducing histone H3K27 acetylation at the FPN promoter region during hypoxia/reoxygenation injury. Dexmedetomidine inhibits HDAC2, restoring H3K27Ac at the FPN promoter, upregulating FPN, and inhibiting cardiomyocyte ferroptosis.\",\n      \"method\": \"DNA pulldown assay, ChIP assay for HDAC2 binding at FPN promoter and H3K27Ac levels, HDAC2 overexpression/knockdown, FPN knockdown rescue\",\n      \"journal\": \"Cardiovascular drugs and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and DNA pulldown assay directly linking HDAC2 to FPN promoter H3K27Ac, functional rescue, single lab\",\n      \"pmids\": [\"39747742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC40A1 p.Arg40Gln and p.Ser47Phe substitutions partially reduce FPN1 iron export and partially reduce hepcidin sensitivity. p.Ala350Val more profoundly reduces iron egress and weakens FPN1/hepcidin interaction. Structural analysis indicates the latter prevents rigid-body movements essential to the iron transport cycle, while the first two cause local instabilities.\",\n      \"method\": \"In vitro iron export assay in cultured cells, hepcidin sensitivity assay, structural modeling, clinical phenotype correlation in 12 affected individuals\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with structural analysis and clinical correlation, single lab\",\n      \"pmids\": [\"39039793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IREG1 (SLC40A1) expression in neuroblastoma (SH-SY5Y) and hippocampal neurons increases in response to progressive iron accumulation, correlates directly with cellular iron content, and its increased expression correlates with increased iron efflux from cells, establishing its role in neuronal iron homeostasis.\",\n      \"method\": \"Western blotting, immunocytochemistry, iron efflux assay, correlation analysis\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct iron efflux measurement correlated with IREG1 protein expression, multiple cell types, single lab\",\n      \"pmids\": [\"15667655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Iron dyshomeostasis induces binding of APP to BACE1, promoting amyloid formation, and decreases the functional APP/Fpn1 complex in microglia, impairing iron export in an iron-overload model.\",\n      \"method\": \"FeCl3 treatment of microglia, protein expression analysis, co-localization and interaction analysis of APP and Fpn1\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization and expression analysis without direct Co-IP or mechanistic validation of the APP/Fpn1 complex, single lab\",\n      \"pmids\": [\"30776900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional deletion of Fpn1 in mouse brain microvascular endothelial cells (Cdh5-Cre) decreased brain iron levels, attenuated oxidative stress, inflammation, ferroptosis, and apoptosis in the acute phase of ischemic stroke, alleviating neurological impairment. However, Fpn1 knockout in ECs delayed neurological recovery in the later stages, associated with iron deficiency-induced inhibition of neuronal development and enhanced glial proliferation.\",\n      \"method\": \"VE-cadherin-Cre conditional Fpn1 knockout mice, MCAO stroke model, behavioral testing, cerebral infarct measurement, ferroptosis/apoptosis markers\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type specific conditional knockout with defined phenotypic readouts at multiple timepoints, dual consequence established, single lab\",\n      \"pmids\": [\"36841833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of Fpn1 in oligodendrocytes (Fpn1Olig2-cKO) caused iron accumulation, elevated ROS, activation of MAPK/ERK, AKT/JNK, and NF-κB pathways, and upregulation of hepcidin in the prefrontal cortex and hippocampus, leading to myelin defects, disrupted synaptic formation, and depression-like behaviors in mice.\",\n      \"method\": \"Oligodendrocyte-specific Fpn1 conditional knockout (Cre-lox), behavioral testing, Western blotting for signaling pathways, FPN1 silencing in human MO3.13 cells, ICG-001 pharmacological pathway dissection\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type specific conditional knockout with defined cellular and behavioral phenotypes, in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"40609802\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC40A1 (ferroportin/IREG1/MTP1/FPN1) is the sole known mammalian non-heme iron export protein, localized predominantly to the basolateral membrane of duodenal enterocytes, macrophages, and other iron-exporting cells, where it mediates cellular iron efflux; its expression is transcriptionally regulated by heme (via Bach1/Nrf2 at a MARE/ARE element), by transition metals (via MTF-1), and by Nrf2 binding at its promoter, while post-translationally it is internalized and degraded in response to hepcidin binding (with disease mutations either causing loss-of-function iron export or gain-of-function hepcidin resistance), and its protein stability is additionally controlled by ubiquitin-mediated proteasomal degradation via E3 ligases including LRSAM1 and UBA52, with its 5' IRE mediating translational regulation by cellular iron status.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC40A1 (ferroportin/IREG1/MTP1/FPN1) is the mammalian basolateral iron export protein that mediates cellular iron efflux from enterocytes, macrophages, and other iron-handling cells, placing it at the central control point of systemic iron homeostasis [#0, #1]. Direct reconstitution in Xenopus oocytes and human cell lines established it as a non-heme iron exporter localized to the basolateral membrane of polarized intestinal epithelium, with conditional knockout confirming its essential role in intestinal iron absorption and macrophage and hepatocyte iron release [#0, #1, #2]. In macrophages it drives iron recycling, with both transcript and protein induced by iron loading and erythrophagocytosis [#4]. SLC40A1 expression is controlled at multiple levels: transcriptionally by the heme-responsive Bach1/Nrf2 axis acting at a MARE/ARE promoter element, by zinc and cadmium through MTF-1 (consistent with ferroportin also exporting zinc), and by chromatin-modifying inputs including HDAC2-dependent H3K27 acetylation and H3K14 lactylation at its promoter; translationally through a 5' UTR IRE responsive to cellular iron; and post-transcriptionally via 3' UTR-targeting microRNAs [#5, #6, #14, #20, #21]. Inflammatory down-regulation in reticuloendothelial cells proceeds through TLR4 signaling [#3]. Protein stability is set by ubiquitin-mediated proteasomal degradation through E3 ligases LRSAM1 and UBA52 and by interaction with cathepsin B, loss of which causes iron accumulation, lipid peroxidation, and ferroptosis across glioma, neuronal, atherosclerotic, and renal contexts [#16, #17, #18, #19]. Disease mutations partition into loss-of-function alleles that abolish iron export through impaired trafficking or transport-cycle gating (causing iron overload by haploinsufficiency) and gain-of-function alleles that retain export but resist hepcidin-mediated internalization and degradation, defining the SLC40A1-related hemochromatosis spectrum [#2, #9, #10, #11, #12, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the molecular identity of the long-sought duodenal basolateral iron exporter, defining where dietary iron leaves the enterocyte and how its message is iron-regulated.\",\n      \"evidence\": \"Xenopus oocyte iron efflux reconstitution, immunolocalization, and 5' UTR IRE functional analysis\",\n      \"pmids\": [\"10882071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transport mechanism and stoichiometry not resolved\", \"No structural model of the transporter\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked ferroportin regulation to innate immune signaling, explaining how inflammation restricts iron availability in reticuloendothelial cells.\",\n      \"evidence\": \"LPS mouse model with TLR4 and TNF-R1a knockouts, Northern blotting\",\n      \"pmids\": [\"12161425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional effectors of TLR4 acting on the promoter not defined\", \"Relationship to hepcidin-mediated control not addressed in this study\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Distinguished systemic from local control, showing ferroportin responds to whole-body iron status rather than enterocyte iron content, unlike DMT1.\",\n      \"evidence\": \"Comparison of sla (mutant hephaestin) mice with iron-deficient wild-type mice, mRNA/protein analysis\",\n      \"pmids\": [\"12730111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The systemic signal itself not molecularly identified here\", \"Single-lab genetic/dietary comparison\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined ferroportin's role in macrophage iron recycling and showed erythrophagocytosis-driven induction is transcriptional and iron-dependent.\",\n      \"evidence\": \"Erythrophagocytosis assay in J774 macrophages with actinomycin D and iron chelation, reciprocal mRNA/protein analysis\",\n      \"pmids\": [\"12907459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific transcription factors not identified in this study\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Probed an additional apical localization in enterocytes, raising the possibility ferroportin modulates apical iron uptake beyond basolateral export.\",\n      \"evidence\": \"Apical blocking-antibody iron uptake/efflux assays and membrane fractionation in IEC-6 and Caco-2 cells\",\n      \"pmids\": [\"14684575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proposed DMT1 interaction not directly demonstrated\", \"Apical role not confirmed in vivo or by other labs\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated genetic necessity in vivo across enterocytes, macrophages, and hepatocytes, and revealed a critical extraembryonic role from the embryonic lethality of global knockouts.\",\n      \"evidence\": \"Conditional and global Cre-lox knockout mice with tissue-selective inactivation and histological iron quantification\",\n      \"pmids\": [\"16054062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve transport mechanism\", \"Cell-autonomous versus systemic contributions to each phenotype not fully separated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Separated the two molecular categories of disease alleles, showing some mutants abolish export (haploinsufficiency) while others retain export but are hepcidin-resistant.\",\n      \"evidence\": \"In vitro iron export assay in human cells with site-directed mutagenesis of multiple disease variants\",\n      \"pmids\": [\"15692071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hepcidin-resistance mechanism for specific variants not directly assayed here\", \"Structural basis of loss-of-function not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended ferroportin function to neuronal iron homeostasis, correlating its expression with cellular iron content and efflux.\",\n      \"evidence\": \"Western blot, immunocytochemistry, and iron efflux assays in SH-SY5Y and hippocampal neurons\",\n      \"pmids\": [\"15667655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative rather than causal in neurons\", \"Regulatory pathway in neurons not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed the gain-of-function hepcidin-resistance disease mechanism at the cellular level for a specific variant reaching the membrane normally.\",\n      \"evidence\": \"In vitro iron export and hepcidin inhibition assays with membrane localization for Y501C\",\n      \"pmids\": [\"19709084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of hepcidin resistance not resolved\", \"Single-lab cellular assay\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved dual heme-responsive transcriptional control, with Bach1 repressing and Nrf2 activating via a MARE/ARE element, while heme-derived iron acts through the IRE on translation.\",\n      \"evidence\": \"Promoter reporter mutagenesis, siRNA knockdown, and overexpression in macrophages\",\n      \"pmids\": [\"20179090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative integration of transcriptional and translational control not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified metal-responsive transcriptional control via MTF-1 and showed ferroportin can export zinc to protect against zinc toxicity, broadening its substrate scope.\",\n      \"evidence\": \"MTF-1 siRNA, promoter reporter with site mutations, nuclear translocation, and zinc export assay\",\n      \"pmids\": [\"20688958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of zinc transport in vivo not established\", \"Selectivity determinants between iron and zinc not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mechanistically dissected two mutation classes — trafficking-defective loss-of-function and hepcidin-binding-defective gain-of-function — and mapped a hepcidin-interacting peptide region.\",\n      \"evidence\": \"In vitro iron export, membrane trafficking imaging, and synthetic peptide hepcidin inhibition assays in 293T cells for W158C and H507R\",\n      \"pmids\": [\"21396368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full hepcidin-binding interface not structurally defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed Nrf2 can also act as a transcriptional repressor of SLC40A1 in cancer, linking ferroportin suppression to chemoresistance.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, Nrf2 knockdown/overexpression, and SLC40A1 rescue in ovarian cancer cells\",\n      \"pmids\": [\"29212168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent context-dependent opposite Nrf2 effects versus macrophage data not reconciled\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a third mutation category — gating residues that impair the transport conformational cycle without mislocalization — refining the structural basis of loss-of-function.\",\n      \"evidence\": \"In vitro iron export, localization imaging, and 3D structural modeling for R178Q with multi-family clinical correlation\",\n      \"pmids\": [\"30002125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conformational cycle inferred from modeling, not experimental structures\", \"Single-lab functional work\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added a hepcidin-resistant gain-of-function allele causing hemochromatosis in an additional population.\",\n      \"evidence\": \"Transfection, hepcidin treatment, localization imaging, and Western blot for Y333H in 293T cells\",\n      \"pmids\": [\"30500107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of resistance not resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established microRNA control of ferroportin, with miR-147a and miR-4735-3p directly targeting the 3' UTR to suppress iron export and drive ferroptosis in tumor cells.\",\n      \"evidence\": \"3' UTR luciferase reporters, miRNA mimic/inhibitor, siRNA, and SLC40A1 overexpression rescue with iron and lipid peroxidation assays in glioblastoma and ccRCC\",\n      \"pmids\": [\"35942174\", \"35646516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological versus tumor-specific relevance not separated\", \"Single-lab per study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified protein-degradation and binding partners controlling ferroportin stability — UBA52 ubiquitination in injured neurons and cathepsin B binding in atherosclerotic macrophages — linking destabilization to iron accumulation and ferroptosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, knockdown/inhibition, and competitive binding (hydralazine) with ferroptosis readouts\",\n      \"pmids\": [\"38352945\", \"39960586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation and direct binding interfaces not fully defined\", \"Single-lab per study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated cell-type-specific, time-dependent consequences of ferroportin loss in brain endothelium during ischemic stroke, protective acutely but impairing later recovery.\",\n      \"evidence\": \"VE-cadherin-Cre conditional Fpn1 knockout mice in MCAO model with behavioral, infarct, and ferroptosis/apoptosis readouts\",\n      \"pmids\": [\"36841833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger of late-phase iron deficiency effects not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected additional regulators of ferroportin protein stability — STING-dependent ubiquitination and the LRSAM1 E3 ligase under REST/Erianin control — to ferroptosis in renal epithelium and resistant glioma stem cells.\",\n      \"evidence\": \"Ubiquitination and proteasomal degradation assays, Co-IP, ChIP, and FPN1 disruption rescue\",\n      \"pmids\": [\"38428828\", \"39039049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect role of STING in ubiquitination not fully resolved\", \"Single-lab per study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved graded biophysical effects of further disease variants, separating local instabilities from impaired rigid-body movements of the transport cycle and partial hepcidin desensitization.\",\n      \"evidence\": \"In vitro iron export and hepcidin sensitivity assays with structural modeling and clinical correlation for R40Q, S47F, and A350V\",\n      \"pmids\": [\"39039793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic claims rest on modeling rather than experimental structures\", \"Single-lab work\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded chromatin-level control of SLC40A1 transcription, implicating H3K14 lactylation, HDAC2-dependent H3K27 acetylation, and oligodendrocyte iron homeostasis in tissue injury and behavior.\",\n      \"evidence\": \"Cut&Tag, ChIP, DNA pulldown, glycolysis/HDAC2 manipulation, and oligodendrocyte-specific conditional knockout with behavioral and signaling readouts\",\n      \"pmids\": [\"39822760\", \"39747742\", \"40609802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct factors writing/reading these marks at the promoter not fully defined\", \"Single-lab per study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"An experimentally determined structure of human ferroportin in distinct transport-cycle conformations and bound to hepcidin would unify the scattered mutation classes into a single mechanistic framework.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure in the timeline\", \"Transport stoichiometry and ion coupling unresolved\", \"Hepcidin-binding interface defined only by peptide and modeling\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 15, 16, 17, 18, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HAMP\", \"LRSAM1\", \"UBA52\", \"CTSB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}