{"gene":"SLC39A1","run_date":"2026-06-10T07:46:33","timeline":{"discoveries":[{"year":2001,"finding":"Human ZIP1 (SLC39A1) is a plasma membrane zinc uptake transporter. Overexpression in K562 erythroleukemia cells increased zinc influx (65Zn uptake), and antisense oligonucleotide knockdown of hZIP1 markedly decreased endogenous zinc uptake activity, establishing ZIP1 as the major zinc transporter in these cells.","method":"65Zn uptake assay in cells overexpressing hZIP1; antisense oligonucleotide knockdown; plasma membrane localization confirmed by subcellular fractionation/immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain-of-function (OE) and loss-of-function (antisense) with direct transport assay, replicated concept across multiple papers","pmids":["11301334"],"is_preprint":false},{"year":2003,"finding":"In prostate PC-3 cells, ZIP1 overexpression increased zinc uptake Vmax without changing Km, and antisense-mediated knockdown decreased zinc uptake, confirming ZIP1 as a major zinc uptake transporter for zinc accumulation in prostate cells. Zinc uptake from citrate-chelated zinc was as rapid as from free Zn2+, but EDTA-chelated zinc was not transported.","method":"65Zn uptake assay; ZIP1 overexpression and antisense knockdown in PC-3 cells; kinetic analysis (Vmax, Km)","journal":"Journal of inorganic biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct transport assay with gain- and loss-of-function, kinetic characterization, independent replication of plasma membrane zinc transporter function","pmids":["12888280"],"is_preprint":false},{"year":2007,"finding":"A di-leucine sorting signal (ETRALL144-149) in the variable loop region of ZIP1 mediates its endocytosis and lysosomal degradation. Alanine substitution of LL148,149 blocked internalization and led to accumulation of ZIP1 on the cell surface; this signal was necessary and sufficient for endocytosis when transferred to a chimeric IL-2 receptor construct.","method":"Site-directed mutagenesis; immunofluorescence microscopy; chimeric protein assay (IL-2 receptor alpha-chain fused to ZIP1 loop peptides)","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of defined residues with direct localization readout plus chimeric protein sufficiency experiment in single study","pmids":["17635580"],"is_preprint":false},{"year":2006,"finding":"Mouse ZIP1 and ZIP3 together are required for adaptation to dietary zinc deficiency during pregnancy. Double knockout of ZIP1 and ZIP3 caused 91% of embryos to develop abnormally under zinc-deficient diet, with no overt phenotype under zinc-replete conditions, indicating these transporters function in redistribution/retention of zinc rather than primary dietary acquisition.","method":"Targeted gene knockout (ZIP1 KO, ZIP1/ZIP3 double KO mice); embryonic morphology assessment under zinc-deficient diet; 67Zn accumulation measurement in liver and pancreas","journal":"Genesis (New York, N.Y. : 2000)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined phenotypic readout, replicated in triple-knockout study","pmids":["16652366"],"is_preprint":false},{"year":2008,"finding":"Mouse ZIP1, ZIP2, and ZIP3 (Slc39a1-3) play important, non-compensatory roles in zinc homeostasis specifically during zinc deficiency; triple knockout mice showed no phenotype under zinc-replete conditions but had severely impaired 67Zn accumulation in liver and pancreas and increased embryonic abnormalities under zinc-deficient diet.","method":"Triple-knockout mouse generation by targeted mutagenesis; 67Zn isotope accumulation assay; embryonic alkaline phosphatase activity; morphological assessment","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — triple-knockout mouse model with isotope transport assay; corroborates and extends double-KO study","pmids":["18353881"],"is_preprint":false},{"year":2005,"finding":"ZIP1 overexpression in human mesenchymal stem cells (MSCs) induced osteogenic differentiation (Alizarin red-positive mineralization, increased alkaline phosphatase, osteopontin, Cbfa1/Runx2 expression); siRNA-mediated ZIP1 knockdown decreased zinc uptake and inhibited osteoblastic differentiation. ZIP1 localized to plasma membrane and cytoplasm of osteoblastic cells.","method":"Adenoviral overexpression of ZIP1; siRNA knockdown; osteogenic differentiation assays (Alizarin red, ALP, gene expression); zinc uptake measurement; immunofluorescence localization","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with functional differentiation readout in single lab study","pmids":["16203195"],"is_preprint":false},{"year":2005,"finding":"ZIP1 is expressed in osteoclasts at the plasma membrane and diffusely in the cytoplasm. Adenoviral overexpression of ZIP1 caused its redistribution to colocalize with actin at the sealing zone, significantly inhibited osteoclast resorptive activity, and decreased NF-κB binding activity.","method":"Adenoviral overexpression; immunofluorescence localization with actin costaining; resorption assay; EMSA for NF-κB activity","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional localization experiment with gain-of-function phenotype and NF-κB readout, single lab","pmids":["16005272"],"is_preprint":false},{"year":2011,"finding":"ZIP1 (Slc39a1) and ZIP3 mediate passive zinc uptake into CA1 hippocampal neurons. In ZIP1/ZIP3 double-knockout mice, passive Zn2+ uptake (measured by intracellular fluorescent Zn dye, with NMDA receptors and voltage-gated Ca2+ channels blocked) was slowed, and kainic acid-induced CA1 neurodegeneration was greatly attenuated in vivo.","method":"Zip1/3 double-knockout mice; intracellular fluorescent Zn dye measurement; kainic acid seizure model; pharmacological channel blockade","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with direct Zn uptake measurement and in vivo neurodegeneration readout, single study","pmids":["21209194"],"is_preprint":false},{"year":2014,"finding":"Mouse ZIP1 (mZIP1) mediates saturable zinc uptake with a Michaelis constant of 5.88 μM. Fe2+ and Ni2+ competitively inhibit mZIP1-mediated zinc uptake (Ki 0.92 and 28.6 μM), Co2+ and Cd2+ show non-competitive inhibition, while Mn2+ and Mg2+ have no effect.","method":"65Zn uptake assay in HEK293T cells overexpressing mZIP1 cDNA; kinetic analysis; inhibition studies with divalent cations","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinetic transport assay with substrate competition analysis, single lab","pmids":["25089007"],"is_preprint":false},{"year":2018,"finding":"SLC39A1 (ZIP1) interacts with Drp1 and the mitochondrial calcium uniporter (MCU) to form a Zip1-MCU complex. Upon Drp1 recruitment to mitochondria, Zip1 mediates Zn2+ entry that focally reduces mitochondrial membrane potential (MMP) at fission sites. Interfering with the Drp1-Zip1 interaction blocked MMP reduction and subsequent mitophagic selection of damaged mitochondria.","method":"Co-immunoprecipitation; live imaging of mitochondrial membrane potential; Drp1-Zip1 interaction disruption experiments; mitophagy assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying complex, live functional imaging of MMP, genetic/pharmacological disruption of interaction with defined phenotype","pmids":["30581142"],"is_preprint":false},{"year":2016,"finding":"Oxidative stress (H2O2 treatment) increases ZIP1 protein expression in plasma membrane and cellular fractions of cultured mouse astrocytes, leading to increased maximal velocity of 65Zn uptake (increased Vmax with unchanged Km), indicating ZIP1-mediated upregulation of zinc clearance under oxidative stress.","method":"65Zn uptake assay; Western blotting; immunocytochemistry; plasma membrane fractionation in H2O2-treated astrocytes","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional transport assay with subcellular fractionation and protein quantification, single lab","pmids":["26979775"],"is_preprint":false},{"year":2022,"finding":"ZIP1-positive tumour-associated fibroblasts transfer Zn2+ to lung cancer cells via connexin-43-mediated gap junctions. ZIP1 expression on fibroblasts upregulates connexin-43, and ZIP1+ fibroblasts acting as Zn2+ reservoirs transfer zinc to cancer cells, leading to ABCB1-mediated chemoresistance.","method":"Single-cell RNA sequencing; gap junction assay; Zn2+ transfer measurement; connexin-43 regulation assay; ABCB1 drug efflux assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional mechanistic experiments in cancer-fibroblast co-culture model, single lab with multiple orthogonal approaches","pmids":["36207295"],"is_preprint":false},{"year":2025,"finding":"SLC39A1 interacts with DRP1 (dynamin-related protein 1) to facilitate mitochondrial fission and MMP depolarization in HCC cells. DRP1 inhibition abolished SLC39A1-induced mitochondrial division and MMP depolarization; DRP1 overexpression rescued mitochondrial fusion and cell proliferation in SLC39A1-silenced cells. A peptide disrupting the SLC39A1-DRP1 interaction suppressed HCC progression.","method":"Co-immunoprecipitation; molecular docking; DRP1 inhibition/overexpression rescue experiments; mitochondrial morphology and MMP assays; liver-specific SLC39A1 knockout mouse model","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic rescue experiments and mouse KO model, single lab study","pmids":["40462487"],"is_preprint":false},{"year":2023,"finding":"Loss of ZIP1 and ZIP3 in platelets increases free intracellular Zn2+ content and enhances GPCR-coupled (but not ITAM-coupled) platelet activation responses, resulting in enhanced thrombin-induced aggregation, larger thrombus volume ex vivo, and faster in vivo thrombus formation. This was accompanied by enhanced Ca2+, PKC, CamKII, and ERK1/2 signaling.","method":"ZIP1/ZIP3 double-knockout mice; ICP-MS Zn2+ measurement; FluoZin3 free Zn2+ staining; platelet aggregation assay; ex vivo flow chamber thrombosis; intravital microscopy in vivo thrombus assay; signaling pathway analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with direct transport measurement and multiple functional readouts, single lab","pmids":["37359521"],"is_preprint":false},{"year":1999,"finding":"Human/mammalian ZIP1 (ZIRTL/SLC39A1) gene was mapped to chromosome 1q21 within the epidermal differentiation complex. mRNA was detected in most adult and fetal tissues. Mouse gene maps to chromosome 3 between S100A9 and S100A13, and is developmentally regulated in suprabasal epidermis, osteoblasts, small intestine, and salivary gland.","method":"Genomic mapping; Northern blot/in situ hybridization for tissue expression; cDNA cloning","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — chromosomal mapping and expression profiling, no functional mechanistic experiment on the protein","pmids":["10610721"],"is_preprint":false},{"year":2026,"finding":"In alveolar type II (AT2) cells, SLC39A1 governs zinc uptake required for protection against acute lung injury. Zinc directly binds to and activates TFEB, TFE3, and MITF, inducing transcriptional activation of autophagy to eliminate damaged mitochondria and suppress apoptosis/pyroptosis. Epistasis experiments placing SLC39A1 upstream of autophagy (Lc3b) showed that AAV-shLc3b in AT2 Slc39a1-deficient mice did not further aggravate lung injury, positioning SLC39A1 in a linear pathway upstream of LC3B-dependent autophagy.","method":"AT2-specific Slc39a1 conditional knockout mice; SLC39A1 overexpression; zinc chelation/supplementation; TFEB/TFE3/MITF binding assay; autophagy measurement; epistasis by combined Slc39a1 KO and shLc3b AAV","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with rescue, direct zinc-TFEB/TFE3/MITF interaction, genetic epistasis placing SLC39A1 upstream of autophagy, multiple orthogonal methods","pmids":["42045244"],"is_preprint":false},{"year":2026,"finding":"SLC39A1 overexpression in pancreatic cancer cells elevates intracellular zinc levels and activates the Src/FAK signaling pathway, promoting cancer cell migration and invasion. Zinc chelation or Src/FAK inhibitors suppressed SLC39A1-induced migration/invasion, and SLC39A1 knockdown inhibited liver metastasis in a mouse model.","method":"SLC39A1 KD/OE in PC cells; Transwell invasion and scratch assays; 3D spheroid assay; Western blot for Src/FAK phosphorylation; zinc chelation; in vivo mouse liver metastasis model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal KD/OE with functional invasion readout and pathway analysis, single lab","pmids":["42208832"],"is_preprint":false}],"current_model":"SLC39A1 (ZIP1) is a plasma membrane zinc uptake transporter that mediates saturable, inhibitable Zn2+ influx in diverse cell types; its endocytosis is regulated by a di-leucine motif (LL148-149); it interacts with DRP1 and the MCU complex at mitochondria to mediate focal Zn2+ entry that reduces mitochondrial membrane potential and initiates mitophagy of damaged mitochondria; it is required for adaptation to zinc deficiency in vivo and regulates platelet GPCR signaling, osteogenic and osteoclast activity, and in AT2 epithelial cells governs a protective zinc-autophagy axis (via TFEB/TFE3/MITF activation) against acute lung injury."},"narrative":{"mechanistic_narrative":"SLC39A1 (ZIP1) is a plasma membrane zinc uptake transporter that mediates saturable, inhibitable Zn2+ influx and serves as a major route for cellular zinc accumulation across diverse cell types [PMID:11301334, PMID:12888280, PMID:25089007]. Its transport is competitively inhibited by Fe2+ and Ni2+ and exhibits micromolar affinity for Zn2+ [PMID:25089007], and its surface abundance is controlled by a di-leucine sorting signal (LL148-149) that drives endocytosis and lysosomal degradation [PMID:17635580]. At the organismal level, ZIP1 acts redundantly with ZIP2/ZIP3 in zinc redistribution and retention rather than primary dietary acquisition, becoming essential only under dietary zinc deficiency [PMID:16652366, PMID:18353881]. Beyond bulk transport, ZIP1 has a dedicated mitochondrial function: it interacts with DRP1 and the mitochondrial calcium uniporter (MCU) to deliver focal Zn2+ entry at fission sites, locally collapsing mitochondrial membrane potential and licensing mitophagic selection of damaged mitochondria [PMID:30581142, PMID:40462487]. In alveolar type II cells, ZIP1-imported zinc directly binds and activates the TFEB/TFE3/MITF transcription factors to drive a protective autophagy program that clears damaged mitochondria, placing SLC39A1 upstream of LC3B-dependent autophagy [PMID:42045244]. Through these activities ZIP1 modulates cell-type-specific programs including osteogenic differentiation and osteoclast resorption [PMID:16203195, PMID:16005272], GPCR-coupled platelet activation and thrombosis [PMID:37359521], and zinc-dependent oncogenic signaling such as Src/FAK-driven invasion [PMID:42208832].","teleology":[{"year":2001,"claim":"Established that ZIP1 is a functional plasma membrane zinc uptake transporter rather than an inferred family member, defining its core molecular activity.","evidence":"65Zn uptake with reciprocal overexpression and antisense knockdown in K562 cells plus membrane localization","pmids":["11301334"],"confidence":"High","gaps":["No structural basis for transport","Substrate selectivity not yet kinetically characterized","Transport stoichiometry/energetics undefined"]},{"year":2003,"claim":"Showed ZIP1 sets zinc accumulation capacity in prostate cells via Vmax modulation and that citrate-chelated, but not EDTA-chelated, zinc is accessible to the transporter.","evidence":"65Zn uptake kinetics with overexpression/antisense knockdown in PC-3 cells","pmids":["12888280"],"confidence":"High","gaps":["Mechanism of zinc delivery from citrate complexes unresolved","No identification of regulatory inputs controlling Vmax"]},{"year":2006,"claim":"Defined the in vivo physiological role of ZIP1 as conditional, required for adaptation to zinc deficiency together with ZIP3 rather than for baseline zinc acquisition.","evidence":"ZIP1 and ZIP1/ZIP3 double-knockout mice with embryonic phenotype and 67Zn accumulation under zinc-deficient diet","pmids":["16652366"],"confidence":"High","gaps":["Tissue-specific contributions not dissected","Redundancy mechanism with other ZIPs unexplained"]},{"year":2007,"claim":"Identified how ZIP1 surface levels are post-translationally regulated, mapping a di-leucine motif sufficient and necessary for endocytic internalization.","evidence":"Site-directed mutagenesis, immunofluorescence, and IL-2 receptor chimera sufficiency assay","pmids":["17635580"],"confidence":"High","gaps":["Adaptor proteins recognizing the motif not identified","Signals triggering regulated endocytosis unknown"]},{"year":2008,"claim":"Extended the genetic model to show ZIP1-3 act non-compensatorily in zinc homeostasis under deficiency, refining the conditional-essentiality concept.","evidence":"Triple-knockout mice with 67Zn accumulation and embryonic readouts","pmids":["18353881"],"confidence":"High","gaps":["Individual transporter contributions still confounded","Molecular basis of non-compensation unresolved"]},{"year":2014,"claim":"Provided quantitative transport parameters and ion selectivity, distinguishing competitive from non-competitive inhibitors of ZIP1.","evidence":"65Zn kinetic and cation-competition assays in HEK293T cells expressing mZIP1","pmids":["25089007"],"confidence":"Medium","gaps":["Whether Fe2+/Ni2+ are themselves transported is untested","No structural explanation for selectivity"]},{"year":2011,"claim":"Demonstrated a pathophysiological consequence of ZIP1-mediated zinc entry, linking it to neuronal Zn2+ accumulation and excitotoxic neurodegeneration.","evidence":"ZIP1/ZIP3 double-knockout mice with intracellular Zn imaging and kainic acid seizure model","pmids":["21209194"],"confidence":"Medium","gaps":["Relative ZIP1 vs ZIP3 contribution not separated","Downstream zinc toxicity mechanism not defined"]},{"year":2016,"claim":"Showed ZIP1 expression and zinc-clearance activity are inducible by oxidative stress, indicating a stress-responsive regulatory dimension.","evidence":"65Zn uptake, Western blot, and membrane fractionation in H2O2-treated astrocytes","pmids":["26979775"],"confidence":"Medium","gaps":["Transcriptional/post-translational mechanism of upregulation unknown","Single cell type"]},{"year":2018,"claim":"Uncovered a mitochondrial role beyond bulk import: ZIP1 partners with DRP1 and MCU to deliver focal Zn2+ that depolarizes mitochondria at fission sites and triggers mitophagy.","evidence":"Co-IP, live MMP imaging, interaction-disruption experiments, and mitophagy assays","pmids":["30581142"],"confidence":"High","gaps":["Structural basis of the ZIP1-MCU-DRP1 complex unknown","How ZIP1 is recruited to mitochondria unresolved"]},{"year":2005,"claim":"Connected ZIP1 zinc transport to skeletal cell fate, promoting osteogenic differentiation and, when overexpressed, suppressing osteoclast resorption and NF-kB activity.","evidence":"Adenoviral overexpression/siRNA with differentiation, resorption, and EMSA readouts in MSCs and osteoclasts","pmids":["16203195","16005272"],"confidence":"Medium","gaps":["Endogenous requirement not tested by knockout in bone","Link between zinc flux and Runx2/NF-kB indirect"]},{"year":2022,"claim":"Implicated ZIP1 in the tumor microenvironment, showing ZIP1+ fibroblasts serve as zinc reservoirs that transfer Zn2+ to cancer cells via connexin-43 to confer chemoresistance.","evidence":"scRNA-seq, gap junction and Zn2+ transfer assays, connexin-43 regulation, ABCB1 efflux in co-culture","pmids":["36207295"],"confidence":"Medium","gaps":["Direct ZIP1 transport contribution to transferred zinc not isolated","Mechanism linking ZIP1 to connexin-43 unknown"]},{"year":2023,"claim":"Defined a platelet-specific role, showing ZIP1/ZIP3 loss raises free Zn2+ and selectively amplifies GPCR-coupled activation and thrombus formation.","evidence":"ZIP1/ZIP3 knockout mice with ICP-MS/FluoZin3, aggregation, flow-chamber and intravital thrombosis, signaling analysis","pmids":["37359521"],"confidence":"Medium","gaps":["ZIP1-specific contribution vs ZIP3 not separated","Why ITAM signaling is spared unexplained"]},{"year":2025,"claim":"Confirmed and extended the ZIP1-DRP1 axis in cancer, showing the interaction drives mitochondrial fission and depolarization and that disrupting it suppresses tumor progression.","evidence":"Co-IP, docking, DRP1 inhibition/overexpression rescue, MMP/morphology assays, liver-specific knockout mice in HCC","pmids":["40462487"],"confidence":"Medium","gaps":["Whether zinc flux per se mediates fission not fully isolated","Therapeutic peptide specificity not validated broadly"]},{"year":2026,"claim":"Placed ZIP1 atop a protective zinc-autophagy pathway, showing imported zinc directly activates TFEB/TFE3/MITF to drive autophagy and that SLC39A1 acts upstream of LC3B in vivo.","evidence":"AT2-specific conditional knockout/overexpression, zinc chelation/supplementation, TFEB/TFE3/MITF binding assays, and Slc39a1/shLc3b epistasis in lung injury","pmids":["42045244"],"confidence":"High","gaps":["Stoichiometry/mechanism of direct zinc binding to TF not structurally defined","Generality beyond AT2 cells untested"]},{"year":2026,"claim":"Linked ZIP1 zinc import to oncogenic signaling, showing it activates Src/FAK to promote pancreatic cancer migration, invasion, and metastasis.","evidence":"Reciprocal KD/OE with invasion/scratch/spheroid assays, Src/FAK phospho-blots, zinc chelation, and in vivo liver metastasis model","pmids":["42208832"],"confidence":"Medium","gaps":["How zinc activates Src/FAK mechanistically unknown","Single cancer context"]},{"year":null,"claim":"How ZIP1 toggles between plasma-membrane bulk zinc import and targeted mitochondrial zinc delivery, and the structural basis of its transport selectivity and complex assembly, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of ZIP1 or its mitochondrial complex","Trafficking signals routing ZIP1 to mitochondria vs plasma membrane unknown","Regulatory logic selecting between physiological roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,5,6,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[9,12]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4]}],"complexes":["ZIP1-MCU-DRP1 mitochondrial complex"],"partners":["DRP1","MCU"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NY26","full_name":"Zinc transporter ZIP1","aliases":["Solute carrier family 39 member 1","Zinc-iron-regulated transporter-like","Zrt- and Irt-like protein 1","ZIP-1","hZIP1"],"length_aa":324,"mass_kda":34.2,"function":"Transporter for the divalent cation Zn(2+). Mediates the influx of Zn(2+) into cells from extracellular space (PubMed:11301334, PubMed:12888280, PubMed:16844077). Functions as the major importer of zinc from circulating blood plasma into prostate cells (PubMed:12888280)","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9NY26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC39A1","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC39A1","total_profiled":1310},"omim":[{"mim_id":"612168","title":"SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 3; SLC39A3","url":"https://www.omim.org/entry/612168"},{"mim_id":"612166","title":"SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 2; SLC39A2","url":"https://www.omim.org/entry/612166"},{"mim_id":"608736","title":"SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 14; SLC39A14","url":"https://www.omim.org/entry/608736"},{"mim_id":"606464","title":"HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP","url":"https://www.omim.org/entry/606464"},{"mim_id":"604740","title":"SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 1; SLC39A1","url":"https://www.omim.org/entry/604740"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC39A1"},"hgnc":{"alias_symbol":["ZIP1"],"prev_symbol":["ZIRTL"]},"alphafold":{"accession":"Q9NY26","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NY26","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NY26-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NY26-F1-predicted_aligned_error_v6.png","plddt_mean":80.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC39A1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC39A1"},"sequence":{"accession":"Q9NY26","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NY26.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NY26/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NY26"}},"corpus_meta":[{"pmid":"7916652","id":"PMC_7916652","title":"ZIP1 is a synaptonemal complex protein required for meiotic chromosome synapsis.","date":"1993","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7916652","citation_count":541,"is_preprint":false},{"pmid":"11301334","id":"PMC_11301334","title":"The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11301334","citation_count":223,"is_preprint":false},{"pmid":"7860625","id":"PMC_7860625","title":"Zip1-induced changes in synaptonemal complex structure and polycomplex assembly.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7860625","citation_count":149,"is_preprint":false},{"pmid":"8799151","id":"PMC_8799151","title":"Synaptonemal complex (SC) component Zip1 plays a role in meiotic recombination independent of SC polymerization along the chromosomes.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of 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transporter induces an osteogenic phenotype in mesenchymal stem cells.","date":"2005","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/16203195","citation_count":68,"is_preprint":false},{"pmid":"21209194","id":"PMC_21209194","title":"Knockout of Zn transporters Zip-1 and Zip-3 attenuates seizure-induced CA1 neurodegeneration.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21209194","citation_count":63,"is_preprint":false},{"pmid":"20080752","id":"PMC_20080752","title":"The synaptonemal complex protein, Zip1, promotes the segregation of nonexchange chromosomes at meiosis I.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20080752","citation_count":61,"is_preprint":false},{"pmid":"20011112","id":"PMC_20011112","title":"The synaptonemal complex protein Zip1 promotes bi-orientation of 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Overexpression in K562 erythroleukemia cells increased zinc influx (65Zn uptake), and antisense oligonucleotide knockdown of hZIP1 markedly decreased endogenous zinc uptake activity, establishing ZIP1 as the major zinc transporter in these cells.\",\n      \"method\": \"65Zn uptake assay in cells overexpressing hZIP1; antisense oligonucleotide knockdown; plasma membrane localization confirmed by subcellular fractionation/immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain-of-function (OE) and loss-of-function (antisense) with direct transport assay, replicated concept across multiple papers\",\n      \"pmids\": [\"11301334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In prostate PC-3 cells, ZIP1 overexpression increased zinc uptake Vmax without changing Km, and antisense-mediated knockdown decreased zinc uptake, confirming ZIP1 as a major zinc uptake transporter for zinc accumulation in prostate cells. Zinc uptake from citrate-chelated zinc was as rapid as from free Zn2+, but EDTA-chelated zinc was not transported.\",\n      \"method\": \"65Zn uptake assay; ZIP1 overexpression and antisense knockdown in PC-3 cells; kinetic analysis (Vmax, Km)\",\n      \"journal\": \"Journal of inorganic biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct transport assay with gain- and loss-of-function, kinetic characterization, independent replication of plasma membrane zinc transporter function\",\n      \"pmids\": [\"12888280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A di-leucine sorting signal (ETRALL144-149) in the variable loop region of ZIP1 mediates its endocytosis and lysosomal degradation. Alanine substitution of LL148,149 blocked internalization and led to accumulation of ZIP1 on the cell surface; this signal was necessary and sufficient for endocytosis when transferred to a chimeric IL-2 receptor construct.\",\n      \"method\": \"Site-directed mutagenesis; immunofluorescence microscopy; chimeric protein assay (IL-2 receptor alpha-chain fused to ZIP1 loop peptides)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of defined residues with direct localization readout plus chimeric protein sufficiency experiment in single study\",\n      \"pmids\": [\"17635580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mouse ZIP1 and ZIP3 together are required for adaptation to dietary zinc deficiency during pregnancy. Double knockout of ZIP1 and ZIP3 caused 91% of embryos to develop abnormally under zinc-deficient diet, with no overt phenotype under zinc-replete conditions, indicating these transporters function in redistribution/retention of zinc rather than primary dietary acquisition.\",\n      \"method\": \"Targeted gene knockout (ZIP1 KO, ZIP1/ZIP3 double KO mice); embryonic morphology assessment under zinc-deficient diet; 67Zn accumulation measurement in liver and pancreas\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined phenotypic readout, replicated in triple-knockout study\",\n      \"pmids\": [\"16652366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mouse ZIP1, ZIP2, and ZIP3 (Slc39a1-3) play important, non-compensatory roles in zinc homeostasis specifically during zinc deficiency; triple knockout mice showed no phenotype under zinc-replete conditions but had severely impaired 67Zn accumulation in liver and pancreas and increased embryonic abnormalities under zinc-deficient diet.\",\n      \"method\": \"Triple-knockout mouse generation by targeted mutagenesis; 67Zn isotope accumulation assay; embryonic alkaline phosphatase activity; morphological assessment\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — triple-knockout mouse model with isotope transport assay; corroborates and extends double-KO study\",\n      \"pmids\": [\"18353881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ZIP1 overexpression in human mesenchymal stem cells (MSCs) induced osteogenic differentiation (Alizarin red-positive mineralization, increased alkaline phosphatase, osteopontin, Cbfa1/Runx2 expression); siRNA-mediated ZIP1 knockdown decreased zinc uptake and inhibited osteoblastic differentiation. ZIP1 localized to plasma membrane and cytoplasm of osteoblastic cells.\",\n      \"method\": \"Adenoviral overexpression of ZIP1; siRNA knockdown; osteogenic differentiation assays (Alizarin red, ALP, gene expression); zinc uptake measurement; immunofluorescence localization\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with functional differentiation readout in single lab study\",\n      \"pmids\": [\"16203195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ZIP1 is expressed in osteoclasts at the plasma membrane and diffusely in the cytoplasm. Adenoviral overexpression of ZIP1 caused its redistribution to colocalize with actin at the sealing zone, significantly inhibited osteoclast resorptive activity, and decreased NF-κB binding activity.\",\n      \"method\": \"Adenoviral overexpression; immunofluorescence localization with actin costaining; resorption assay; EMSA for NF-κB activity\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional localization experiment with gain-of-function phenotype and NF-κB readout, single lab\",\n      \"pmids\": [\"16005272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZIP1 (Slc39a1) and ZIP3 mediate passive zinc uptake into CA1 hippocampal neurons. In ZIP1/ZIP3 double-knockout mice, passive Zn2+ uptake (measured by intracellular fluorescent Zn dye, with NMDA receptors and voltage-gated Ca2+ channels blocked) was slowed, and kainic acid-induced CA1 neurodegeneration was greatly attenuated in vivo.\",\n      \"method\": \"Zip1/3 double-knockout mice; intracellular fluorescent Zn dye measurement; kainic acid seizure model; pharmacological channel blockade\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with direct Zn uptake measurement and in vivo neurodegeneration readout, single study\",\n      \"pmids\": [\"21209194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mouse ZIP1 (mZIP1) mediates saturable zinc uptake with a Michaelis constant of 5.88 μM. Fe2+ and Ni2+ competitively inhibit mZIP1-mediated zinc uptake (Ki 0.92 and 28.6 μM), Co2+ and Cd2+ show non-competitive inhibition, while Mn2+ and Mg2+ have no effect.\",\n      \"method\": \"65Zn uptake assay in HEK293T cells overexpressing mZIP1 cDNA; kinetic analysis; inhibition studies with divalent cations\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinetic transport assay with substrate competition analysis, single lab\",\n      \"pmids\": [\"25089007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC39A1 (ZIP1) interacts with Drp1 and the mitochondrial calcium uniporter (MCU) to form a Zip1-MCU complex. Upon Drp1 recruitment to mitochondria, Zip1 mediates Zn2+ entry that focally reduces mitochondrial membrane potential (MMP) at fission sites. Interfering with the Drp1-Zip1 interaction blocked MMP reduction and subsequent mitophagic selection of damaged mitochondria.\",\n      \"method\": \"Co-immunoprecipitation; live imaging of mitochondrial membrane potential; Drp1-Zip1 interaction disruption experiments; mitophagy assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying complex, live functional imaging of MMP, genetic/pharmacological disruption of interaction with defined phenotype\",\n      \"pmids\": [\"30581142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Oxidative stress (H2O2 treatment) increases ZIP1 protein expression in plasma membrane and cellular fractions of cultured mouse astrocytes, leading to increased maximal velocity of 65Zn uptake (increased Vmax with unchanged Km), indicating ZIP1-mediated upregulation of zinc clearance under oxidative stress.\",\n      \"method\": \"65Zn uptake assay; Western blotting; immunocytochemistry; plasma membrane fractionation in H2O2-treated astrocytes\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional transport assay with subcellular fractionation and protein quantification, single lab\",\n      \"pmids\": [\"26979775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZIP1-positive tumour-associated fibroblasts transfer Zn2+ to lung cancer cells via connexin-43-mediated gap junctions. ZIP1 expression on fibroblasts upregulates connexin-43, and ZIP1+ fibroblasts acting as Zn2+ reservoirs transfer zinc to cancer cells, leading to ABCB1-mediated chemoresistance.\",\n      \"method\": \"Single-cell RNA sequencing; gap junction assay; Zn2+ transfer measurement; connexin-43 regulation assay; ABCB1 drug efflux assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional mechanistic experiments in cancer-fibroblast co-culture model, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"36207295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC39A1 interacts with DRP1 (dynamin-related protein 1) to facilitate mitochondrial fission and MMP depolarization in HCC cells. DRP1 inhibition abolished SLC39A1-induced mitochondrial division and MMP depolarization; DRP1 overexpression rescued mitochondrial fusion and cell proliferation in SLC39A1-silenced cells. A peptide disrupting the SLC39A1-DRP1 interaction suppressed HCC progression.\",\n      \"method\": \"Co-immunoprecipitation; molecular docking; DRP1 inhibition/overexpression rescue experiments; mitochondrial morphology and MMP assays; liver-specific SLC39A1 knockout mouse model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic rescue experiments and mouse KO model, single lab study\",\n      \"pmids\": [\"40462487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of ZIP1 and ZIP3 in platelets increases free intracellular Zn2+ content and enhances GPCR-coupled (but not ITAM-coupled) platelet activation responses, resulting in enhanced thrombin-induced aggregation, larger thrombus volume ex vivo, and faster in vivo thrombus formation. This was accompanied by enhanced Ca2+, PKC, CamKII, and ERK1/2 signaling.\",\n      \"method\": \"ZIP1/ZIP3 double-knockout mice; ICP-MS Zn2+ measurement; FluoZin3 free Zn2+ staining; platelet aggregation assay; ex vivo flow chamber thrombosis; intravital microscopy in vivo thrombus assay; signaling pathway analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with direct transport measurement and multiple functional readouts, single lab\",\n      \"pmids\": [\"37359521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human/mammalian ZIP1 (ZIRTL/SLC39A1) gene was mapped to chromosome 1q21 within the epidermal differentiation complex. mRNA was detected in most adult and fetal tissues. Mouse gene maps to chromosome 3 between S100A9 and S100A13, and is developmentally regulated in suprabasal epidermis, osteoblasts, small intestine, and salivary gland.\",\n      \"method\": \"Genomic mapping; Northern blot/in situ hybridization for tissue expression; cDNA cloning\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — chromosomal mapping and expression profiling, no functional mechanistic experiment on the protein\",\n      \"pmids\": [\"10610721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In alveolar type II (AT2) cells, SLC39A1 governs zinc uptake required for protection against acute lung injury. Zinc directly binds to and activates TFEB, TFE3, and MITF, inducing transcriptional activation of autophagy to eliminate damaged mitochondria and suppress apoptosis/pyroptosis. Epistasis experiments placing SLC39A1 upstream of autophagy (Lc3b) showed that AAV-shLc3b in AT2 Slc39a1-deficient mice did not further aggravate lung injury, positioning SLC39A1 in a linear pathway upstream of LC3B-dependent autophagy.\",\n      \"method\": \"AT2-specific Slc39a1 conditional knockout mice; SLC39A1 overexpression; zinc chelation/supplementation; TFEB/TFE3/MITF binding assay; autophagy measurement; epistasis by combined Slc39a1 KO and shLc3b AAV\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with rescue, direct zinc-TFEB/TFE3/MITF interaction, genetic epistasis placing SLC39A1 upstream of autophagy, multiple orthogonal methods\",\n      \"pmids\": [\"42045244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SLC39A1 overexpression in pancreatic cancer cells elevates intracellular zinc levels and activates the Src/FAK signaling pathway, promoting cancer cell migration and invasion. Zinc chelation or Src/FAK inhibitors suppressed SLC39A1-induced migration/invasion, and SLC39A1 knockdown inhibited liver metastasis in a mouse model.\",\n      \"method\": \"SLC39A1 KD/OE in PC cells; Transwell invasion and scratch assays; 3D spheroid assay; Western blot for Src/FAK phosphorylation; zinc chelation; in vivo mouse liver metastasis model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal KD/OE with functional invasion readout and pathway analysis, single lab\",\n      \"pmids\": [\"42208832\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC39A1 (ZIP1) is a plasma membrane zinc uptake transporter that mediates saturable, inhibitable Zn2+ influx in diverse cell types; its endocytosis is regulated by a di-leucine motif (LL148-149); it interacts with DRP1 and the MCU complex at mitochondria to mediate focal Zn2+ entry that reduces mitochondrial membrane potential and initiates mitophagy of damaged mitochondria; it is required for adaptation to zinc deficiency in vivo and regulates platelet GPCR signaling, osteogenic and osteoclast activity, and in AT2 epithelial cells governs a protective zinc-autophagy axis (via TFEB/TFE3/MITF activation) against acute lung injury.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC39A1 (ZIP1) is a plasma membrane zinc uptake transporter that mediates saturable, inhibitable Zn2+ influx and serves as a major route for cellular zinc accumulation across diverse cell types [#0, #1, #8]. Its transport is competitively inhibited by Fe2+ and Ni2+ and exhibits micromolar affinity for Zn2+ [#8], and its surface abundance is controlled by a di-leucine sorting signal (LL148-149) that drives endocytosis and lysosomal degradation [#2]. At the organismal level, ZIP1 acts redundantly with ZIP2/ZIP3 in zinc redistribution and retention rather than primary dietary acquisition, becoming essential only under dietary zinc deficiency [#3, #4]. Beyond bulk transport, ZIP1 has a dedicated mitochondrial function: it interacts with DRP1 and the mitochondrial calcium uniporter (MCU) to deliver focal Zn2+ entry at fission sites, locally collapsing mitochondrial membrane potential and licensing mitophagic selection of damaged mitochondria [#9, #12]. In alveolar type II cells, ZIP1-imported zinc directly binds and activates the TFEB/TFE3/MITF transcription factors to drive a protective autophagy program that clears damaged mitochondria, placing SLC39A1 upstream of LC3B-dependent autophagy [#15]. Through these activities ZIP1 modulates cell-type-specific programs including osteogenic differentiation and osteoclast resorption [#5, #6], GPCR-coupled platelet activation and thrombosis [#13], and zinc-dependent oncogenic signaling such as Src/FAK-driven invasion [#16].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that ZIP1 is a functional plasma membrane zinc uptake transporter rather than an inferred family member, defining its core molecular activity.\",\n      \"evidence\": \"65Zn uptake with reciprocal overexpression and antisense knockdown in K562 cells plus membrane localization\",\n      \"pmids\": [\"11301334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for transport\", \"Substrate selectivity not yet kinetically characterized\", \"Transport stoichiometry/energetics undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed ZIP1 sets zinc accumulation capacity in prostate cells via Vmax modulation and that citrate-chelated, but not EDTA-chelated, zinc is accessible to the transporter.\",\n      \"evidence\": \"65Zn uptake kinetics with overexpression/antisense knockdown in PC-3 cells\",\n      \"pmids\": [\"12888280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of zinc delivery from citrate complexes unresolved\", \"No identification of regulatory inputs controlling Vmax\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the in vivo physiological role of ZIP1 as conditional, required for adaptation to zinc deficiency together with ZIP3 rather than for baseline zinc acquisition.\",\n      \"evidence\": \"ZIP1 and ZIP1/ZIP3 double-knockout mice with embryonic phenotype and 67Zn accumulation under zinc-deficient diet\",\n      \"pmids\": [\"16652366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions not dissected\", \"Redundancy mechanism with other ZIPs unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified how ZIP1 surface levels are post-translationally regulated, mapping a di-leucine motif sufficient and necessary for endocytic internalization.\",\n      \"evidence\": \"Site-directed mutagenesis, immunofluorescence, and IL-2 receptor chimera sufficiency assay\",\n      \"pmids\": [\"17635580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor proteins recognizing the motif not identified\", \"Signals triggering regulated endocytosis unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended the genetic model to show ZIP1-3 act non-compensatorily in zinc homeostasis under deficiency, refining the conditional-essentiality concept.\",\n      \"evidence\": \"Triple-knockout mice with 67Zn accumulation and embryonic readouts\",\n      \"pmids\": [\"18353881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual transporter contributions still confounded\", \"Molecular basis of non-compensation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided quantitative transport parameters and ion selectivity, distinguishing competitive from non-competitive inhibitors of ZIP1.\",\n      \"evidence\": \"65Zn kinetic and cation-competition assays in HEK293T cells expressing mZIP1\",\n      \"pmids\": [\"25089007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Fe2+/Ni2+ are themselves transported is untested\", \"No structural explanation for selectivity\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated a pathophysiological consequence of ZIP1-mediated zinc entry, linking it to neuronal Zn2+ accumulation and excitotoxic neurodegeneration.\",\n      \"evidence\": \"ZIP1/ZIP3 double-knockout mice with intracellular Zn imaging and kainic acid seizure model\",\n      \"pmids\": [\"21209194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative ZIP1 vs ZIP3 contribution not separated\", \"Downstream zinc toxicity mechanism not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed ZIP1 expression and zinc-clearance activity are inducible by oxidative stress, indicating a stress-responsive regulatory dimension.\",\n      \"evidence\": \"65Zn uptake, Western blot, and membrane fractionation in H2O2-treated astrocytes\",\n      \"pmids\": [\"26979775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional/post-translational mechanism of upregulation unknown\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a mitochondrial role beyond bulk import: ZIP1 partners with DRP1 and MCU to deliver focal Zn2+ that depolarizes mitochondria at fission sites and triggers mitophagy.\",\n      \"evidence\": \"Co-IP, live MMP imaging, interaction-disruption experiments, and mitophagy assays\",\n      \"pmids\": [\"30581142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ZIP1-MCU-DRP1 complex unknown\", \"How ZIP1 is recruited to mitochondria unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected ZIP1 zinc transport to skeletal cell fate, promoting osteogenic differentiation and, when overexpressed, suppressing osteoclast resorption and NF-kB activity.\",\n      \"evidence\": \"Adenoviral overexpression/siRNA with differentiation, resorption, and EMSA readouts in MSCs and osteoclasts\",\n      \"pmids\": [\"16203195\", \"16005272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous requirement not tested by knockout in bone\", \"Link between zinc flux and Runx2/NF-kB indirect\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated ZIP1 in the tumor microenvironment, showing ZIP1+ fibroblasts serve as zinc reservoirs that transfer Zn2+ to cancer cells via connexin-43 to confer chemoresistance.\",\n      \"evidence\": \"scRNA-seq, gap junction and Zn2+ transfer assays, connexin-43 regulation, ABCB1 efflux in co-culture\",\n      \"pmids\": [\"36207295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ZIP1 transport contribution to transferred zinc not isolated\", \"Mechanism linking ZIP1 to connexin-43 unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a platelet-specific role, showing ZIP1/ZIP3 loss raises free Zn2+ and selectively amplifies GPCR-coupled activation and thrombus formation.\",\n      \"evidence\": \"ZIP1/ZIP3 knockout mice with ICP-MS/FluoZin3, aggregation, flow-chamber and intravital thrombosis, signaling analysis\",\n      \"pmids\": [\"37359521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ZIP1-specific contribution vs ZIP3 not separated\", \"Why ITAM signaling is spared unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed and extended the ZIP1-DRP1 axis in cancer, showing the interaction drives mitochondrial fission and depolarization and that disrupting it suppresses tumor progression.\",\n      \"evidence\": \"Co-IP, docking, DRP1 inhibition/overexpression rescue, MMP/morphology assays, liver-specific knockout mice in HCC\",\n      \"pmids\": [\"40462487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether zinc flux per se mediates fission not fully isolated\", \"Therapeutic peptide specificity not validated broadly\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed ZIP1 atop a protective zinc-autophagy pathway, showing imported zinc directly activates TFEB/TFE3/MITF to drive autophagy and that SLC39A1 acts upstream of LC3B in vivo.\",\n      \"evidence\": \"AT2-specific conditional knockout/overexpression, zinc chelation/supplementation, TFEB/TFE3/MITF binding assays, and Slc39a1/shLc3b epistasis in lung injury\",\n      \"pmids\": [\"42045244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/mechanism of direct zinc binding to TF not structurally defined\", \"Generality beyond AT2 cells untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked ZIP1 zinc import to oncogenic signaling, showing it activates Src/FAK to promote pancreatic cancer migration, invasion, and metastasis.\",\n      \"evidence\": \"Reciprocal KD/OE with invasion/scratch/spheroid assays, Src/FAK phospho-blots, zinc chelation, and in vivo liver metastasis model\",\n      \"pmids\": [\"42208832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How zinc activates Src/FAK mechanistically unknown\", \"Single cancer context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZIP1 toggles between plasma-membrane bulk zinc import and targeted mitochondrial zinc delivery, and the structural basis of its transport selectivity and complex assembly, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of ZIP1 or its mitochondrial complex\", \"Trafficking signals routing ZIP1 to mitochondria vs plasma membrane unknown\", \"Regulatory logic selecting between physiological roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005385\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 5, 6, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"ZIP1-MCU-DRP1 mitochondrial complex\"\n    ],\n    \"partners\": [\n      \"DRP1\",\n      \"MCU\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}