Affinage

SLC39A8

Metal cation symporter ZIP8 · UniProt Q9C0K1

Length
460 aa
Mass
49.6 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC39A8 encodes ZIP8, a glycosylated, bicarbonate-coupled divalent metal transporter that imports Mn2+, Zn2+, Fe2+, Cd2+, Co2+ and selenite across cell membranes by an electroneutral symport mechanism in which two HCO3- anions accompany each transported cation (PMID:16638970, PMID:18037372, PMID:22898811, PMID:27166256). The transporter was first identified as the gene underlying cadmium-induced toxicity, with heterologous expression conferring strong Cd2+ influx and Mn2+ acting as the best competing cation, defining ZIP8 as primarily a Mn2+/Cd2+ carrier with kinetics in the sub- to low-micromolar range (PMID:15722412, PMID:16638970). Metal specificity is dictated by an EEXXH motif in transmembrane domain 5 — distinct from the HEXXH motif of most ZIP transporters — and by a conditional outward-facing selectivity filter, such that defined TMD5 and selectivity-filter mutations abolish Mn2+/Cd2+ transport or shift selectivity toward Zn2+ (PMID:35636252, PMID:37495662). ZIP8 localizes predominantly to the apical/canalicular plasma membrane of polarized epithelia, with trafficking to the surface controlled by zinc and iron availability and by cytoplasmic calcium acting through SPCA1-dependent Golgi calcium homeostasis (PMID:18037372, PMID:22898811, PMID:28481222, PMID:35787370). Through tissue-specific transport, ZIP8 is the central regulator of systemic manganese homeostasis: hepatic ZIP8 reclaims Mn from bile at the hepatocyte canalicular membrane, and intestinal epithelial ZIP8 mediates dietary Mn absorption, with loss of either causing organism-wide Mn depletion (PMID:28481222, PMID:38839750). The Mn it supplies is required for the activity of Mn-dependent enzymes including Golgi β-1,4-galactosyltransferase, arginase, and mitochondrial MnSOD/SOD2, linking ZIP8 to protein N-glycosylation and redox balance (PMID:28481222, PMID:29453449, PMID:31086870). Loss-of-function SLC39A8 mutations in humans cause a type II congenital disorder of glycosylation driven by severe manganese deficiency and impaired galactosyltransferase activity, correctable by Mn or galactose supplementation (PMID:26637979, PMID:26637978, PMID:32753748). By controlling intracellular zinc, ZIP8 acts as an NF-κB-induced negative-feedback regulator of NF-κB signaling via zinc-mediated IKK inhibition, and drives a zinc-ZIP8-MTF1 transcriptional axis that controls matrix-degrading enzyme and ADAMTS expression in cartilage catabolism and cardiac extracellular-matrix remodeling (PMID:23403290, PMID:24529376, PMID:29337306). ZIP8 is further required for cardiac ventricular compaction, alveolar progenitor self-renewal (via SIRT1), cerebellar development and hematopoiesis (PMID:22563477, PMID:29337306, PMID:35389887, PMID:39435657).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2005 High

    Established the identity and basic function of the gene by linking it to cadmium toxicity, answering what protein controls cellular cadmium entry.

    Evidence Positional cloning of the mouse Cdm locus with retroviral overexpression in fibroblasts showing >10-fold Cd influx

    PMID:15722412

    Open questions at the time
    • Did not define the physiological substrate or transport mechanism
    • Cadmium is a toxic xenobiotic, not the endogenous cargo
  2. 2006 High

    Defined the transport mechanism and physiological substrate, showing ZIP8 is a bicarbonate-dependent Mn2+/Cd2+ symporter rather than a generic metal channel.

    Evidence Radioisotope uptake kinetics and inhibition profiles in fibroblasts plus confocal localization in polarized MDCK cells

    PMID:16638970

    Open questions at the time
    • Stoichiometry of co-transported ions not yet quantified
    • Endogenous tissue role unaddressed
  3. 2007 High

    Resolved the transport stoichiometry and substrate-regulated trafficking, establishing an electroneutral 2 HCO3-:1 cation mechanism and zinc-dependent surface targeting.

    Evidence Xenopus oocyte electrogenicity measurements and confocal trafficking in MDCK cells

    PMID:18037372

    Open questions at the time
    • Molecular machinery of internalization not identified
  4. 2008 Medium

    Connected ZIP8 to inflammation and transcriptional control, showing it is inducible and that its promoter is regulated by Sp1 and glutathione.

    Evidence Quantitative RT-PCR of zinc transporters, siRNA, and Sp1 promoter mutagenesis with cadmium uptake readouts in lung epithelial cells

    PMID:18390834 PMID:18556457

    Open questions at the time
    • TNF-α induction pathway upstream of transcription not fully mapped
    • Mitochondrial localization mechanism unclear
  5. 2009 Medium

    Extended ZIP8's regulatory layers to epigenetic silencing and immune cell function, showing CpG methylation controls expression and lysosomal ZIP8 modulates T cell activation via zinc-calcineurin signaling.

    Evidence Bisulfite sequencing with DNMT inhibitor reversal in MT-null cells; confocal, calcineurin activity assays and siRNA in T cells

    PMID:19401385 PMID:19699220

    Open questions at the time
    • Lysosomal versus plasma-membrane functional partitioning not reconciled
    • Direct calcineurin-zinc interaction not biochemically resolved
  6. 2012 High

    Broadened the substrate range to iron and demonstrated organismal essentiality, answering whether ZIP8 is physiologically required.

    Evidence Reconstituted Fe/Zn/Cd/Co/Mn uptake in HEK cells and oocytes, glycosylation-site mutagenesis, plus BAC-rescued hypomorphic mouse with lethal anemia and impaired hematopoiesis

    PMID:22534978 PMID:22563477 PMID:22898811

    Open questions at the time
    • Which substrate(s) drive each developmental phenotype not dissected
    • Tissue-specific contributions not separated
  7. 2013 High

    Defined a signaling role, establishing ZIP8 as an NF-κB target that feeds back to inhibit IKK via zinc, answering how it tempers innate inflammation.

    Evidence In vitro IKK activity assays, NF-κB reporters, and hypomorphic mouse fibroblasts

    PMID:23403290

    Open questions at the time
    • Direct molecular target of zinc within the IKK complex not identified
  8. 2014 High

    Identified the zinc-ZIP8-MTF1 catabolic axis as a driver of osteoarthritis, answering how metal flux translates to tissue destruction.

    Evidence Cartilage-specific knockout, adenoviral ectopic expression, and MTF1 epistasis in mice with surgical OA induction

    PMID:24529376

    Open questions at the time
    • Trigger for ZIP8 upregulation in OA not fully defined at this stage
  9. 2015 High

    Established the human disease mechanism, linking SLC39A8 loss-of-function to Mn deficiency, defective galactosyltransferase, and a type II CDG, while defining renal Mn/Zn wasting.

    Evidence Whole-exome sequencing of multiple pedigrees, transferrin glycosylation analysis, blood/urine Mn and Zn quantification; HIF-2α feedback loop defined in chondrocytes

    PMID:26241779 PMID:26637978 PMID:26637979

    Open questions at the time
    • Tissue-specific basis of variable Mn versus Zn phenotypes not resolved
    • Why galactose supplementation partially corrects glycosylation unclear
  10. 2016 High

    Added selenite to the substrate repertoire and dissected the common A391T variant, defining a zinc/bicarbonate-coupled selenite transport and a transport-reducing risk allele with NF-κB consequences.

    Evidence Oocyte reconstitution and transgenic mouse Se measurements; HEK expression comparing A391 versus T391 with cadmium and signaling readouts

    PMID:27166256 PMID:27466201

    Open questions at the time
    • Physiological importance of selenite transport in vivo not established
    • Mechanistic basis of A391T transport reduction left to later structural work
  11. 2017 High

    Localized organismal Mn homeostasis to hepatic biliary reclamation, answering where ZIP8 acts to set systemic manganese.

    Evidence Liver-specific knockout and AAV overexpression mice with bile Mn measurement and arginase/glycosylation readouts

    PMID:28481222

    Open questions at the time
    • Relative contribution of liver versus intestine to whole-body Mn not yet weighed
  12. 2018 High

    Mechanistically connected disease mutants to mitochondrial dysfunction and extended ZIP8's developmental roles to cardiac ECM remodeling and broader signaling/proliferation phenotypes.

    Evidence Disease-mutant transport and ER-retention assays with MnSOD activity; Slc39a8-null mouse hearts with Zn/MTF1/ADAMTS epistasis in HUVECs; selenium/redox and cisplatin/Bcl-2 cell studies

    PMID:29337306 PMID:29453449 PMID:29927321 PMID:29927450 PMID:30342059

    Open questions at the time
    • How a single transporter coordinates such diverse downstream programs not unified
    • Direct mechanism of Bcl-2/Snail2 modulation unresolved
  13. 2019 Medium

    Mapped tissue-specific Mn/Fe uptake roles across renal, blood-brain-barrier, and muscle compartments, often in partnership with ZIP14.

    Evidence siRNA knockdown with 55Fe/54Mn isotopic uptake and surface biotinylation in ciPTEC, brain microvascular endothelial cells, and primary myoblasts with Mn-rescue

    PMID:30806852 PMID:31086870 PMID:31699897

    Open questions at the time
    • Functional redundancy between ZIP8 and ZIP14 not quantitatively partitioned
    • In vivo relevance of BBB bidirectional flux not tested genetically
  14. 2020 High

    Linked the A391T variant to intestinal disease via impaired colonic Mn absorption and barrier dysfunction, and corroborated Mn-dependent glycome defects in human carriers.

    Evidence CRISPR A391T knock-in mouse with colitis model and glycocalyx analysis; human carrier trace-element and N-glycome profiling with CDG patient Mn supplementation; synoviocyte HIF-1α/TRPA1 studies

    PMID:32753748 PMID:33139556 PMID:34198528

    Open questions at the time
    • Mechanism linking glycocalyx defect to barrier failure incompletely defined
    • Causal chain from variant to Crohn's risk in humans correlative
  15. 2021 Medium

    Defined ZIP8's roles in neuronal zinc signaling and adaptive/innate immune disease, and dissected inflammatory signaling cascades inducing ZIP8 in endothelium.

    Evidence A391T neuron electrophysiology with zinc-chelator rescue; CD4+ and myeloid conditional knockouts in arthritis and pneumonia models; TGF-β1/ALK5-Smad and NF-κB/JNK induction studies in endothelial cells

    PMID:33608496 PMID:33795795 PMID:34380651 PMID:34822840 PMID:35008873

    Open questions at the time
    • Whether neuronal phenotypes reflect zinc versus Mn transport not separated
    • Direct transcription-factor binding to the SLC39A8 promoter not all shown biochemically
  16. 2022 High

    Resolved the structural determinants of metal specificity and added alveolar progenitor and brain-glycosylation functions, defining the EEXXH/TMD5 motif and SPCA1-calcium control of surface abundance.

    Evidence Systematic TMD5 and selectivity-filter mutagenesis with isotopic uptake; AEC2-specific knockout with SIRT1 epistasis; A391T brain N-glycome profiling; SPCA1 RNAi/overexpression with biotinylation

    PMID:35260802 PMID:35389887 PMID:35636252 PMID:35787370

    Open questions at the time
    • No experimental atomic structure of ZIP8 reported
    • How calcium-regulated trafficking integrates with zinc/iron-regulated trafficking unknown
  17. 2023 High

    Refined the selectivity filter mechanism and clarified ZIP8's systemic iron-recycling and lung iron roles, defining a conditional outward-facing filter and a splenic/serum iron phenotype.

    Evidence Rational mutagenesis with molecular modeling and transport assays; global inducible KO mouse with tissue iron quantification and lung injury/infection models

    PMID:36260707 PMID:37495662

    Open questions at the time
    • Filter model not validated against an experimental structure
    • ZIP8 deletion did not worsen acute lung injury, leaving its lung iron role functionally ambiguous
  18. 2024 High

    Defined intestinal Mn absorption and cerebellar developmental roles with downstream effector pathways, answering how ZIP8 connects Mn transport to tissue outcomes via ACER1 and cAMP signaling.

    Evidence Intestinal- and neuron-specific knockout mice with 54Mn radiotracer studies, organoid uptake, RNA-seq identifying ACER1 and cAMP pathways, plus therapeutic ACER1 inhibition; aortic valve ferroptosis/SOD2 study

    PMID:38839750 PMID:38851518 PMID:39435657

    Open questions at the time
    • Whether ACER1 and cAMP effects are direct Mn-enzyme consequences not fully traced
    • Cerebellar cAMP-response dependence on Mn not mechanistically closed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single bicarbonate-coupled transporter is differentially deployed across tissues to control distinct metals (Mn, Zn, Fe, Se) and distinct downstream programs remains unresolved, as does the experimental atomic structure underlying its conformational selectivity filter.
  • No experimental high-resolution structure of ZIP8
  • Quantitative rules governing which metal ZIP8 prefers in each tissue context unknown
  • Functional division of labor between ZIP8 and ZIP14 not resolved in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 9 GO:0140104 molecular carrier activity 4
Localization
GO:0005886 plasma membrane 7 GO:0005739 mitochondrion 2 GO:0005764 lysosome 1 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-382551 Transport of small molecules 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 3
Partners
MTF1SLC39A14

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Mouse SLC39A8 (ZIP8) was identified as the gene responsible for cadmium-induced testicular necrosis (Cdm locus); expression of ZIP8 in cultured mouse fetal fibroblasts caused >10-fold increase in intracellular Cd influx and accumulation and 30-fold increase in sensitivity to Cd-induced cell death. ZIP8 mRNA was localized to vascular endothelial cells of the testis in sensitive strains. Positional cloning, SNP haplotype analysis, retroviral overexpression in fibroblasts, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America High 15722412
2006 ZIP8 functions as a Mn2+/HCO3- symporter; cadmium uptake operated maximally at pH 7.5, was bicarbonate-dependent, inhibited by cyanide, and Mn2+ was the best competitive cation for Cd2+ uptake (Km for Cd2+ ~0.62 µM; Km for Mn2+ ~2.2 µM). ZIP8 was glycosylated and localized to the apical surface of polarized MDCK cells. Stable retroviral infection of mouse fetal fibroblasts, radioisotope uptake assays, Western blot, Z-stack confocal microscopy in polarized MDCK cells Molecular pharmacology High 16638970
2007 ZIP8-mediated Cd2+ and Zn2+ transport in Xenopus oocytes is electroneutral, with two HCO3- anions transported per one Cd2+ or Zn2+ cation. Under Zn2+ depletion, ZIP8 traffics to the cell surface membrane; under Zn2+ homeostasis, ZIP8 is largely internalized. Xenopus oocyte cRNA injection with radioisotope uptake, electrogenicity studies, retroviral infection of MDCK cells with HA-tagged ZIP8, confocal microscopy Biochemical and biophysical research communications High 18037372
2008 In human lung epithelial cells, ZIP8 (SLC39A8) mRNA is strongly induced by TNF-α (unlike other zinc transporters), and the resulting glycosylated ZIP8 protein translocates to the plasma membrane and mitochondria, increasing intracellular zinc content and protecting cells from TNF-α-induced cytotoxicity. siRNA knockdown of ZIP8 reduced cellular zinc content and impaired mitochondrial function, resulting in loss of cell viability. Quantitative RT-PCR of all human zinc transporters, siRNA knockdown, immunofluorescence/translocation assays, mitochondrial function assays, cell viability assays American journal of physiology. Lung cellular and molecular physiology High 18390834
2008 Sp1 binding at the proximal promoter of ZIP8/SLC39A8 drives its transcription; elevated GSH levels suppress Sp1 expression, thereby down-regulating ZIP8 and reducing cadmium uptake, conferring cadmium resistance. Promoter analysis, Sp1 binding site mutagenesis, GSH manipulation via stable GCLC transfection, cadmium uptake assays, Western blot Molecular pharmacology Medium 18556457
2009 ZIP8 localizes to the lysosome in T cells, and its abundance increases upon T cell activation. Loss of lysosomal labile zinc following activation (measured by flow cytometry) and ZIP8-mediated zinc transport from lysosomes inhibits calcineurin (CN) phosphatase activity, sustaining CREB phosphorylation and enhancing IFN-γ expression. ZIP8 siRNA knockdown reduced IFN-γ and perforin secretion; ZIP8 overexpression enhanced T cell activation. Confocal microscopy, siRNA knockdown, transient transfection overexpression, flow cytometry with zinc fluorophore, calcineurin phosphatase activity assay Journal of leukocyte biology Medium 19401385
2009 Down-regulation of ZIP8 expression via DNA hypermethylation of the SLC39A8 CpG island is a mechanism of cadmium resistance in metallothionein-null cells. Treatment with the DNMT inhibitor 5-aza-deoxycytidine reversed methylation, restored ZIP8 expression, and re-sensitized cells to cadmium. DNA microarray, real-time PCR, Western blot, bisulfite sequencing/methylation analysis, DNMT inhibitor treatment, cadmium uptake and toxicity assays Toxicology and applied pharmacology Medium 19699220
2012 ZIP8 transports Fe2+ and Zn2+ in HEK 293T cells and Xenopus oocytes (K0.5 ~0.7 µM for Fe2+); Fe2+ and Zn2+ mutually inhibit each other's uptake. ZIP8 also transports Cd2+, Co2+, Zn2+, and Mn2+ but not Cu. ZIP8 localizes to the plasma membrane and partially to early endosomes; iron loading increases total and cell-surface ZIP8 levels. Asparagine residues 40, 88, and 96 are glycosylated (site-directed mutagenesis), but N-glycosylation is not required for transport activity. ZIP8 knockdown in BeWo placental cells reduced iron uptake by ~40%. HEK 293T transfection with radioisotope uptake (59Fe, 65Zn, 109Cd, 57Co, 54Mn), Xenopus oocyte RNA injection, immunofluorescence, site-directed mutagenesis, siRNA knockdown in BeWo cells The Journal of biological chemistry High 22898811
2012 ZIP8 is expressed on the apical membrane of renal proximal tubule cells (S3 segment) and mediates uptake of Cd2+ and Mn2+ from the apical side. siRNA knockdown of ZIP8 in proximal tubule cells significantly reduced apical uptake of both Cd2+ and Mn2+. siRNA knockdown, apical/basolateral compartment transport assays, in situ hybridization Metallomics : integrated biometal science Medium 22534978
2012 ZIP8 hypomorphic (Slc39a8neo/neo) mice exhibit severely decreased ZIP8 expression and develop lethal anemia, hypoplastic spleen, dysorganogenesis, and impaired hematopoiesis. Diminished zinc and iron uptake was confirmed in fetal fibroblast and liver-derived cultures. The phenotype was rescued by introduction of BAC-transgenic extra copies of Slc39a8, proving the phenotype is due to ZIP8 deficiency. Mouse genetics (hypomorphic allele generation, BAC transgenic rescue), flow cytometry of fetal liver erythroid cells, hematological parameters, tissue zinc/iron measurement, cell culture uptake assays PloS one High 22563477
2013 ZIP8 (SLC39A8) is a transcriptional target of NF-κB and functions as a negative feedback regulator of NF-κB signaling: ZIP8-mediated zinc influx inhibits IκB kinase (IKK) activity in vitro. Slc39a8 hypomorphic mouse fibroblasts showed dysregulated zinc uptake and increased NF-κB activation. NF-κB transcriptional target identification, IKK activity assay in vitro, Slc39a8 hypomorphic mouse fibroblasts, zinc uptake assays, NF-κB reporter assays Cell reports High 23403290
2014 ZIP8 is specifically upregulated in osteoarthritis (OA) cartilage, mediating increased intracellular Zn2+ influx in chondrocytes, which activates the transcription factor MTF1 to drive expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, ADAMTS5). Ectopic ZIP8 expression in mouse cartilage caused OA-like destruction; Zip8 knockout suppressed surgically induced OA. The zinc-ZIP8-MTF1 axis was identified as a catabolic regulator of OA. Adenoviral ectopic expression in mouse cartilage, cartilage-specific Zip8 knockout, surgical OA induction, chondrocyte culture zinc measurements, MTF1 genetic manipulation in mice Cell High 24529376
2015 Loss-of-function mutations in SLC39A8 cause severe manganese deficiency (undetectable blood Mn) leading to impaired activity of the Mn-dependent Golgi enzyme β-1,4-galactosyltransferase, resulting in defective protein glycosylation (type II CDG). Oral galactose supplementation normalized glycosylation. Whole-exome sequencing, transferrin glycosylation analysis (type II CDG diagnosis), blood Mn measurement, identification of two unrelated pedigrees with compound heterozygous SLC39A8 variants American journal of human genetics High 26637979
2015 SLC39A8 deficiency in humans causes variably low blood Mn and Zn levels with elevated urinary excretion (renal wasting), establishing SLC39A8 as a Mn and Zn transporter critical for maintaining systemic homeostasis of both metals. The homozygous Gly38Arg variant arose independently in Hutterite and Egyptian families. Exome sequencing, blood/urine Mn and Zn quantification, haplotype analysis American journal of human genetics High 26637978
2015 HIF-2α activates the zinc-ZIP8-MTF1 catabolic axis in chondrocytes by upregulating ZIP8 expression, increasing Zn2+ influx, and activating MTF1. Reciprocally, the zinc-ZIP8-MTF1 axis transcriptionally upregulates HIF-2α, creating a positive feedback loop that amplifies OA cartilage destruction. Cartilage-specific conditional knockout of ZIP8 abolished HIF-2α-induced enzyme expression. Microarray, adenoviral intra-articular injection, cartilage-specific conditional knockouts (Zip8fl/fl;Col2a1-Cre), chondrocyte primary culture assays Osteoarthritis and cartilage High 26241779
2016 ZIP8-mediated transport of selenite (HSeO3-) requires bicarbonate and zinc; the transported complex is proposed to be Zn2+/(HCO3-)(HSeO3-). ZIP8 knockdown or transgenic overexpression in mice directly altered tissue selenium content, establishing ZIP8 as a selenite uptake transporter. shRNA knockdown in human/mouse cells, Xenopus oocyte cRNA injection, transgenic mouse lines with altered ZIP8 expression, tissue Se quantification Oncotarget High 27166256
2016 The SLC39A8 missense variant A391T (rs13107325) reduces cadmium transport capacity; cells expressing ZIP8-Ala391 accumulated more intracellular cadmium than ZIP8-Thr391 cells, leading to increased ERK2 phosphorylation, NFκB activation, and reduced cell viability. HEK293 heterologous expression of ZIP8-Ala391 vs ZIP8-Thr391, cadmium accumulation measurement, phospho-ERK2 and NFκB assays, vascular endothelial cell genotyping experiments Human molecular genetics Medium 27466201
2017 Hepatic ZIP8 is localized to the hepatocyte canalicular membrane where it reclaims Mn from bile; liver-specific ZIP8 knockout (ZIP8-LSKO) mice had markedly decreased Mn in multiple organs and increased bile Mn, while liver-specific overexpression (AAV-ZIP8) increased tissue Mn and decreased bile Mn. ZIP8-LSKO mice showed decreased activity of the Mn-dependent enzyme arginase and defective protein N-glycosylation. Liver-specific knockout mouse (Slc39a8-LSKO), inducible global knockout, AAV-mediated liver-specific overexpression, tissue Mn quantification, bile Mn measurement, arginase activity assay, N-glycosylation analysis The Journal of clinical investigation High 28481222
2017 ZIP8 is transcriptionally induced in human macrophages by LPS via NF-κB; ZIP8 knockdown inhibited LPS-driven cellular zinc accumulation and prevented zinc-dependent reduction of IL-10 release. Zinc supplementation reduced nuclear localization and activity of C/EBPβ, a transcription factor driving IL-10 expression, in a ZIP8-dependent manner. siRNA knockdown of ZIP8 in human macrophages, zinc accumulation measurement, IL-10/TNFα/IL-6/IL-8 protein and mRNA assays, C/EBPβ nuclear localization assay PloS one Medium 28056086
2018 Slc39a8 (ZIP8) is expressed by endothelial cells in the developing mouse heart and is required for cardiac ventricular compaction. Slc39a8-null hearts showed marked ECM accumulation and reduction of ADAMTS metalloproteinases. Mechanistically, SLC39A8 knockdown in HUVECs decreased ADAMTS1 transcription by reducing cellular Zn uptake and MTF1 transcriptional activity, placing ZIP8 upstream of the Zn/MTF1/ADAMTS axis in ECM remodeling. Slc39a8-null mouse embryo analysis, HUVEC siRNA knockdown, Zn uptake measurement, MTF1 transcriptional activity assay, ADAMTS1 mRNA quantification, histology/ECM staining The Journal of clinical investigation High 29337306
2018 Disease-associated SLC39A8 mutations (CDG-associated variants) abolish Mn uptake activity and cause retention of ZIP8 protein in the ER rather than localization to the cell surface. These mutants reduce mitochondrial Mn levels and activity of MnSOD, increasing oxidative stress. Wild-type SLC39A8 restored normal mitochondrial function. 54Mn uptake assays in transfected cells, immunofluorescence localization, MnSOD activity assay, oxidative stress measurement, loss-of-function by siRNA Scientific reports High 29453449
2018 ZIP8 deficiency in hepatocytes leads to decreased hepatic selenium content, downregulation of selenoproteins GPX1 and GPX2, decreased antioxidant SOD1/SOD2, and increased oxidative stress, establishing ZIP8 as a hepatic selenium transporter required for redox homeostasis. Slc39a8+/neo hypomorphic mice and Ad-shZip8 acute liver knockdown, ICP-MS for tissue Se and Zn quantification, immunohistochemistry, Western blot for selenoproteins American journal of physiology. Gastrointestinal and liver physiology Medium 29927321
2019 ZIP8 and ZIP14 together mediate NTBI (non-transferrin-bound iron) uptake in human proximal tubular epithelial cells; combined siRNA silencing of both ZIP8 and ZIP14 (but not either alone) significantly reduced 55Fe uptake. ZIP8 did not colocalize with early endosomes or mediate TBI-derived iron uptake (unlike ZIP14). siRNA knockdown of ZIP8 and/or ZIP14 in ciPTEC cells, 55Fe uptake assay, immunofluorescence colocalization with EEA1, fluorescent transferrin uptake Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine Medium 30806852
2019 ZIP8 and ZIP14 support Mn2+ uptake in brain microvascular endothelial cells (BMVECs) at both apical and basal sides, enabling bidirectional Mn2+ flux across the blood-brain barrier. siRNA knockdown of ZIP8/ZIP14 reduced Mn uptake; kinetic analysis confirmed pH and bicarbonate dependence characteristic of ZIP8/ZIP14; LPS upregulated Mn uptake. Cell-surface biotinylation confirmed membrane presentation of both transporters. siRNA knockdown, 54Mn radioisotope uptake assay, kinetic analysis, surface protein biotinylation, LPS stimulation The Journal of biological chemistry Medium 31699897
2019 ZIP8 mediates Mn uptake in primary skeletal myoblasts; ZIP8 knockdown severely impaired myoblast growth and led to cell death under differentiation conditions. ZIP8 knockdown reduced activity of Mn-dependent SOD2. Growth defects were rescued only by Mn supplementation, and reintroduction of wild-type ZIP8 rescued proliferation and differentiation phenotypes. siRNA knockdown in primary myoblasts, SOD2 activity assay, Mn supplementation rescue, ZIP8 re-expression rescue, differentiation assays Metallomics : integrated biometal science Medium 31086870
2020 The Slc39a8 A391T knock-in mouse model exhibits Mn deficiency in the colon, impaired intestinal barrier function, disrupted epithelial glycocalyx, and increased sensitivity to epithelial injury and pathological colitis, mechanistically linking the variant to Crohn's disease risk through impaired intestinal Mn absorption and barrier integrity. CRISPR knock-in mouse (Slc39a8 A391T), colon Mn quantification, intestinal barrier function assays, glycocalyx analysis, dextran sulfate sodium-induced colitis model Proceedings of the National Academy of Sciences of the United States of America High 33139556
2020 Human carriers of the common SLC39A8 A391T missense variant have reduced serum Mn specifically (among trace elements) and altered plasma protein N-glycome with reduced branching, consistent with reduced β-1,4-galactosyltransferase activity. Brain MRI showed dose-dependent signal changes in multiple regions. Mn supplementation in SLC39A8-CDG patients improved glycosylation branching. Trace element analysis, plasma N-glycome profiling (mass spectrometry), structural brain MRI analysis, Mn supplementation in CDG patients Scientific reports High 32753748
2021 The ZIP8 A391T variant results in reduced zinc transport into cells, decreased NMDA- and AMPA-mediated spontaneous EPSCs, and reduced surface expression of GluN2A and GluA1/2/3 receptors in neurons. These phenotypes were rescued by re-expression of wild-type ZIP8 or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also decreased BBB integrity and increased NF-κB-dependent inflammation. Electrophysiological recordings in neurons, surface receptor expression assays, zinc chelator rescue (ZX1), wild-type ZIP8 re-expression rescue, BBB integrity assay, NF-κB signaling assay Translational psychiatry Medium 33608496
2021 ZIP8 deficiency in CD4+ T cells abrogates collagen-induced arthritis by reducing Zn2+ influx in effector T cells and profoundly impairing TCR-mediated NF-κB and MAPK signaling, reducing Th17 cell differentiation. CD4+ T cell-specific ZIP8 knockout, collagen-induced arthritis model, Zn2+ flux measurement in effector T cells, NF-κB and MAPK signaling assays, Th17 differentiation assay Experimental & molecular medicine Medium 33795795
2021 Myeloid-specific ZIP8 knockout mice showed increased NF-κB signaling, deficits in phagocytosis, increased cytokine production upon bacterial stimulation, and imbalanced Th17/Th2 responses leading to increased morbidity and mortality after S. pneumoniae infection. Myeloid-specific Zip8 conditional knockout mouse, S. pneumoniae lung infection model, phagocytosis assay, cytokine measurement, NF-κB signaling assay, T cell subset analysis Journal of immunology (Baltimore, Md. : 1950) Medium 34380651
2022 ZIP8 deficiency in type 2 alveolar epithelial cells (AEC2s) impairs AEC2 progenitor renewal and promotes lung fibrosis in a SIRT1-dependent manner. Deletion of Zip8 in AEC2s in mice caused impaired self-renewal, increased bleomycin injury susceptibility, and spontaneous lung fibrosis. Replenishment of zinc and SIRT1 activation restored AEC2 renewal. AEC2-specific Zip8 knockout mice, bleomycin injury model, AEC2 self-renewal and differentiation assays, SIRT1 activity assays, zinc replenishment experiments The Journal of clinical investigation High 35389887
2022 The A391T variant of ZIP8 in a knock-in mouse model alters protein N-glycosylation in the brain, particularly in the cortex and cerebellum, affecting glycoproteins including cell adhesion molecules and neurotransmitter receptors relevant to schizophrenia. Changes reflected altered glycosyltransferase activity rather than gene expression changes. A391T knock-in mouse model, brain region-specific N-glycome profiling by mass spectrometry, RNAseq, glycoprotein identification Molecular psychiatry High 35260802
2022 Cytoplasmic calcium regulates ZIP8 (and ZIP14) plasma membrane abundance in brain microvascular endothelial cells through SPCA1-dependent Golgi calcium homeostasis. SPCA1 knockdown increased cytoplasmic Ca2+, which enhanced membrane-localized ZIP8 and increased 54Mn2+ uptake; SPCA1 overexpression decreased cytoplasmic Ca2+ and reduced manganese transport. SPCA1 RNAi knockdown and overexpression, surface protein biotinylation, indirect immunofluorescence, GFP-tagged protein imaging, 54Mn2+ uptake assay, Ca2+ chelation experiments The Journal of biological chemistry Medium 35787370
2022 Individual amino acid mutations in ZIP8 transmembrane domain 5 (TMD5) define its unique metal specificity: S335T and I340N mutations completely abolished Mn2+ and Cd2+ transport activity. The EEXXH metal-binding motif in TMD5 (distinct from the HEXXH motif in most ZIP transporters) is critical for ZIP8's unique affinity for Mn and Cd; replacing EEXXH with HEXXH abolished Mn and Cd transport. The A391T variant only slightly reduced transport activity. Site-directed mutagenesis, stable expression in DT40 cells, 54Mn and 109Cd radioisotope uptake assays Biochemical and biophysical research communications High 35636252
2023 Systematic replacement of differentially conserved residues in ZIP8 identified a conditional selectivity filter operative only in the outward-facing conformation. A quadruple variant (Q180H/E343H/C310A/N357H) largely reduced Cd2+, Fe2+, and Mn2+ transport while increasing Zn2+ selectivity, revealing the molecular basis of substrate specificity in ZIP8. Rational mutagenesis, transport activity assays, molecular modeling, covariance analysis, computational studies Communications biology High 37495662
2024 SLC39A8 is localized to the apical membrane of intestinal epithelial cells and mediates 54Mn uptake in intestinal organoid monolayer cultures. Slc39a8-IEC KO mice showed markedly decreased blood and organ Mn and impaired intestinal Mn absorption. Transcriptomic analysis identified alkaline ceramidase 1 (ACER1) as a downstream effector; ACER1 inhibition attenuated colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Intestinal epithelial cell-specific Slc39a8 knockout mice, radiotracer 54Mn absorption studies, intestinal organoid monolayer 54Mn uptake, immunofluorescence localization, RNA-seq, ACER1 inhibitor treatment in colitis model Nature communications High 38839750
2024 Slc39a8 neuron-specific knockout (Slc39a8-NSKO) mice displayed markedly decreased brain Mn levels and impaired brain 54Mn uptake by radiotracers, with cerebellar morphological defects including abnormal Purkinje cell dendritic arborization, reduced neurogenesis, increased apoptosis in the cerebellar external granular layer, and motor dysfunction. RNA-seq identified downregulation of cAMP signaling pathway genes; ZIP8 was required for optimal transcriptional response to cAMP-mediated signaling. Neuron-specific Slc39a8 conditional knockout, 54Mn radiotracer brain uptake, histology of cerebellum, Purkinje cell morphology analysis, neurogenesis and apoptosis assays, RNA-seq, cAMP signaling assays JCI insight High 39435657
2021 TGF-β1 induces ZIP8 expression in vascular endothelial cells via the ALK5-Smad2/3 signaling pathway, with Smad3-mediated induction associated with p38 MAPK, thereby increasing intracellular cadmium accumulation and cytotoxicity. TGF-β1 treatment of vascular endothelial cells, ALK5 inhibition, Smad2/3 pathway analysis, p38 MAPK inhibition, cadmium accumulation and cytotoxicity assays, ZIP8 expression analysis International journal of molecular sciences Medium 35008873
2021 Cadmium induces ZIP8 expression in vascular endothelial cells via both NF-κB and JNK signaling; JNK stabilizes NF-κB in the nucleus after cadmium-activated NF-κB nuclear translocation, resulting in ZIP8 induction that enhances cadmium cytotoxicity. NF-κB and JNK inhibitor experiments, ZIP8 overexpression in vascular endothelial cells, nuclear NF-κB localization assay, cadmium accumulation and cytotoxicity assays Toxicology and applied pharmacology Medium 34822840
2018 ZIP8 overexpression induces morphological changes in fibroblasts with F-actin reorganization, increased proliferation and migration, and upregulation of NF-κB and Snail2 transcription factors (and their targets COL1A2 and E-cadherin). ZIP8 knockout in HAP1 cells increases cell-cell adhesion and also modulates NF-κB and Snail2. ZIP8 overexpression in MEF cells, ZIP8 knockout in HAP1 cells, BAC-transgenic ZIP8 mouse lungs, F-actin staining, migration/proliferation assays, NF-κB and Snail2 expression analysis Metallomics : integrated biometal science Medium 29927450
2018 ZIP8 overexpression sensitizes mouse embryonic fibroblasts to cisplatin, while ZIP8 knockout in HAP1 leukemia cells confers cisplatin resistance. Cisplatin is not a direct ZIP8 substrate. ZIP8 regulates the anti-apoptotic protein Bcl-2: overexpression decreases Bcl-2 and increases cleaved Caspase-3, while loss of ZIP8 elevates Bcl-2. ZIP8 overexpression and knockout cell lines, cisplatin sensitivity assays, Bcl-2 and cleaved Caspase-3 Western blot, transgenic mouse tissue analysis Toxicology and applied pharmacology Medium 30342059
2020 In human fibroblast-like synoviocytes, TNF-α and IL-1α treatment increases ZIP8 and ZIP14 expression via HIF-1α activation (blocked by echinomycin, an HIF-1α inhibitor), leading to increased basal intracellular Zn2+ concentration. ZIP8 functional expression in HEK cells increased basal [Zn2+]i, and elevated Zn2+ intrinsically activated the TRPA1 channel. Cytokine stimulation of synoviocytes, HIF-1α inhibitor (echinomycin), NF-κB P65 and HIF-1α overexpression, fluorescent Zn2+ indicators, TRPA1 activity measurements, ZIP8 expression in HEK cells International journal of molecular sciences Medium 34198528
2024 SLC39A8 knockdown in aortic valve interstitial cells reduced intracellular Mn2+ concentration and decreased SOD2 expression and activity, exacerbating ferroptosis and osteogenic differentiation. Nesfatin-1 treatment elevated ZIP8 expression, increased Mn2+, and activated SOD2 to suppress ferroptosis. siRNA knockdown of ZIP8 in AVICs, Mn2+ concentration measurement, SOD2 activity assay, osteogenic differentiation assay, ferroptosis markers (GPX4, GSH) Free radical biology & medicine Medium 38851518
2023 ZIP8 KO mice exhibited elevated spleen iron and decreased serum iron, indicating a role for ZIP8 in systemic iron recycling. ZIP8 is expressed on lung distal airspace epithelial cells and transports iron from the airway into lung tissue. LPS-induced inflammation upregulated ZIP8 expression in the lung, but ZIP8 deletion did not significantly worsen LPS-induced acute lung injury or Klebsiella pneumoniae infection outcomes. Global inducible ZIP8 KO mouse, iron quantification in tissues, LPS-induced acute lung injury model, Klebsiella pneumoniae infection model Blood advances Medium 36260707

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. The Journal of biological chemistry 328 22898811
2014 Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis. Cell 304 24529376
2006 ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Molecular pharmacology 292 16638970
2013 ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB. Cell reports 287 23403290
2008 Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Molecular pharmacology 277 18270315
2015 SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation. American journal of human genetics 247 26637979
2005 Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proceedings of the National Academy of Sciences of the United States of America 240 15722412
2009 Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-gamma expression in activated human T cells. Journal of leukocyte biology 188 19401385
2015 Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8. American journal of human genetics 181 26637978
2012 Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells. Metallomics : integrated biometal science 166 22534978
2007 Cd2+ versus Zn2+ uptake by the ZIP8 HCO3--dependent symporter: kinetics, electrogenicity and trafficking. Biochemical and biophysical research communications 141 18037372
2017 Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity. The Journal of clinical investigation 136 28481222
2008 The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia. American journal of physiology. Lung cellular and molecular physiology 131 18390834
2002 Mycobacterium bovis BCG cell wall and lipopolysaccharide induce a novel gene, BIGM103, encoding a 7-TM protein: identification of a new protein family having Zn-transporter and Zn-metalloprotease signatures. Genomics 126 12504855
2016 A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition. Gastroenterology 116 27492617
2019 SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside. Human genomics 93 31521203
2016 A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders. Journal of inherited metabolic disease 90 27995398
2012 ZIP8 zinc transporter: indispensable role for both multiple-organ organogenesis and hematopoiesis in utero. PloS one 90 22563477
2006 Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line. American journal of physiology. Cell physiology 86 17108009
2022 The ZIP8/SIRT1 axis regulates alveolar progenitor cell renewal in aging and idiopathic pulmonary fibrosis. The Journal of clinical investigation 82 35389887
2018 Functional analysis of SLC39A8 mutations and their implications for manganese deficiency and mitochondrial disorders. Scientific reports 80 29453449
2013 MicroRNA-488 regulates zinc transporter SLC39A8/ZIP8 during pathogenesis of osteoarthritis. Journal of biomedical science 79 23688035
2020 The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis. International journal of molecular sciences 66 32392784
2008 Zinc transporters ZnT1 (Slc30a1), Zip8 (Slc39a8), and Zip10 (Slc39a10) in mouse red blood cells are differentially regulated during erythroid development and by dietary zinc deficiency. The Journal of nutrition 65 18936201
2017 SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy. Genetics in medicine : official journal of the American College of Medical Genetics 62 28749473
2017 Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition. PloS one 61 28056086
2020 The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation. Scientific reports 59 32753748
2012 Cadmium-mediated toxicity of lung epithelia is enhanced through NF-κB-mediated transcriptional activation of the human zinc transporter ZIP8. American journal of physiology. Lung cellular and molecular physiology 57 22345571
2012 ZIP14 and ZIP8 zinc/bicarbonate symporters in Xenopus oocytes: characterization of metal uptake and inhibition. Metallomics : integrated biometal science 56 23090441
2019 Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 51 30806852
2009 The role of ZIP8 down-regulation in cadmium-resistant metallothionein-null cells. Journal of applied toxicology : JAT 50 19194888
2017 The highly pleiotropic gene SLC39A8 as an opportunity to gain insight into the molecular pathogenesis of schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 49 28557351
2016 A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity. Human molecular genetics 49 27466201
2018 Zinc transporter Slc39a8 is essential for cardiac ventricular compaction. The Journal of clinical investigation 45 29337306
2020 A missense variant in SLC39A8 confers risk for Crohn's disease by disrupting manganese homeostasis and intestinal barrier integrity. Proceedings of the National Academy of Sciences of the United States of America 42 33139556
2019 The solute carriers ZIP8 and ZIP14 regulate manganese accumulation in brain microvascular endothelial cells and control brain manganese levels. The Journal of biological chemistry 42 31699897
2011 High sensitivity of RBL-2H3 cells to cadmium and manganese: an implication of the role of ZIP8. Metallomics : integrated biometal science 41 21509381
2015 Recent Positive Selection Drives the Expansion of a Schizophrenia Risk Nonsynonymous Variant at SLC39A8 in Europeans. Schizophrenia bulletin 39 26006263
2015 Reciprocal activation of hypoxia-inducible factor (HIF)-2α and the zinc-ZIP8-MTF1 axis amplifies catabolic signaling in osteoarthritis. Osteoarthritis and cartilage 39 26241779
2017 Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels. Experimental eye research 38 28057442
2011 Generation of a Slc39a8 hypomorph mouse: markedly decreased ZIP8 Zn²⁺/(HCO₃⁻)₂ transporter expression. Biochemical and biophysical research communications 38 21658371
2016 Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8). Toxicology research 37 30090406
2022 The schizophrenia-associated variant in SLC39A8 alters protein glycosylation in the mouse brain. Molecular psychiatry 36 35260802
2008 Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8. Molecular pharmacology 36 18556457
2019 New Insights into the Roles of ZIP8, a Cadmium and Manganese Transporter, and Its Relation to Human Diseases. Biological & pharmaceutical bulletin 35 31257283
2009 Involvement of DNA hypermethylation in down-regulation of the zinc transporter ZIP8 in cadmium-resistant metallothionein-null cells. Toxicology and applied pharmacology 34 19699220
2024 Inhibition of Slc39a14/Slc39a8 reduce vascular calcification via alleviating iron overload induced ferroptosis in vascular smooth muscle cells. Cardiovascular diabetology 32 38812011
2018 Hepatic ZIP8 deficiency is associated with disrupted selenium homeostasis, liver pathology, and tumor formation. American journal of physiology. Gastrointestinal and liver physiology 32 29927321
2021 Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia. Journal of immunology (Baltimore, Md. : 1950) 31 34380651
2016 Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite uptake. Oncotarget 30 27166256
2024 The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease. Nature communications 29 38839750
2021 Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling. Translational psychiatry 28 33608496
2014 Tissue-Specific Induction of Mouse ZIP8 and ZIP14 Divalent Cation/Bicarbonate Symporters by, and Cytokine Response to, Inflammatory Signals. International journal of toxicology 27 24728862
2013 Oral cadmium in mice carrying 5 versus 2 copies of the Slc39a8 gene: comparison of uptake, distribution, metal content, and toxicity. International journal of toxicology 27 24345748
2014 Cellular localization and developmental changes of Zip8, Zip14 and transferrin receptor 1 in the inner ear of rats. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 26 25007852
2023 Identification of ZIP8-induced ferroptosis as a major type of cell death in monocytes under sepsis conditions. Redox biology 25 38103342
2019 Induction of the metal transporter ZIP8 by interferon gamma in intestinal epithelial cells: Potential role of metal dyshomeostasis in Crohn's disease. Biochemical and biophysical research communications 24 31151823
2018 Secreted α-Klotho maintains cartilage tissue homeostasis by repressing NOS2 and ZIP8-MMP13 catabolic axis. Aging 23 29920476
2017 Elemental Ingredients in the Macrophage Cocktail: Role of ZIP8 in Host Response to Mycobacterium tuberculosis. International journal of molecular sciences 23 29120360
2019 Manganese Uptake by A549 Cells is Mediated by Both ZIP8 and ZIP14. Nutrients 22 31261654
2022 Divalent Metal Uptake and the Role of ZIP8 in Host Defense Against Pathogens. Frontiers in cell and developmental biology 21 35832795
2019 Manganese influx and expression of ZIP8 is essential in primary myoblasts and contributes to activation of SOD2. Metallomics : integrated biometal science 21 31086870
2021 ZIP8 exacerbates collagen-induced arthritis by increasing pathogenic T cell responses. Experimental & molecular medicine 20 33795795
2012 ZIP8 expression in human proximal tubule cells, human urothelial cells transformed by Cd+2 and As+3 and in specimens of normal human urothelium and urothelial cancer. Cancer cell international 20 22550998
2021 Clinical, molecular and glycophenotype insights in SLC39A8-CDG. Orphanet journal of rare diseases 19 34246313
2017 Progressive silencing of the zinc transporter Zip8 (Slc39a8) in chronic cadmium-exposed lung epithelial cells. Acta biochimica et biophysica Sinica 19 28338971
2013 Suppression of ZIP8 expression is a common feature of cadmium-resistant and manganese-resistant RBL-2H3 cells. Metallomics : integrated biometal science 19 23598904
2022 Effects of individual amino acid mutations of zinc transporter ZIP8 on manganese- and cadmium-transporting activity. Biochemical and biophysical research communications 17 35636252
2021 TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells. International journal of molecular sciences 17 35008873
2020 Localization of ZIP14 and ZIP8 in HIBCPP Cells. Brain sciences 17 32784388
2020 MicroRNA-25-3p therapy for intervertebral disc degeneration by targeting the IL-1β/ZIP8/MTF1 signaling pathway with a novel thermo-responsive vector. Annals of translational medicine 17 33313245
2018 Knockdown of zinc transporter ZIP8 expression inhibits neuroblastoma progression and metastasis in vitro. Molecular medicine reports 17 29749445
2021 HIF-1α Dependent Upregulation of ZIP8, ZIP14, and TRPA1 Modify Intracellular Zn2+ Accumulation in Inflammatory Synoviocytes. International journal of molecular sciences 16 34198528
2021 Induction of ZIP8, a ZIP transporter, via NF-κB signaling by the activation of IκBα and JNK signaling in cultured vascular endothelial cells exposed to cadmium. Toxicology and applied pharmacology 16 34822840
2023 A mouse model characterizes the roles of ZIP8 in systemic iron recycling and lung inflammation and infection. Blood advances 14 36260707
2022 Deficiency in the zinc transporter ZIP8 impairs epithelia renewal and enhances lung fibrosis. The Journal of clinical investigation 14 35642632
2021 Brain Magnetic Resonance Imaging Phenome-Wide Association Study With Metal Transporter Gene SLC39A8. Frontiers in genetics 14 33790950
2023 Rational engineering of an elevator-type metal transporter ZIP8 reveals a conditional selectivity filter critically involved in determining substrate specificity. Communications biology 13 37495662
2022 Calcium and the Ca-ATPase SPCA1 modulate plasma membrane abundance of ZIP8 and ZIP14 to regulate Mn(II) uptake in brain microvascular endothelial cells. The Journal of biological chemistry 12 35787370
2021 SLC39A8/Zinc Suppresses the Progression of Clear Cell Renal Cell Carcinoma. Frontiers in oncology 12 33869056
2021 The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization. International journal of molecular sciences 12 34768831
2019 SLC39A8 missense variant is associated with Crohn's disease but does not have a major impact on gut microbiome composition in healthy subjects. PloS one 12 30703110
2016 Inhibitory effect of divalent metal cations on zinc uptake via mouse Zrt-/Irt-like protein 8 (ZIP8). Life sciences 12 27956349
2013 Zip1, Zip2, and Zip8 mRNA expressions were associated with growth hormone level during the growth hormone provocation test in children with short stature. Biological trace element research 12 23921484
2020 Functional Analysis of Two Zinc (Zn) Transporters (ZIP3 and ZIP8) Promoters and Their Distinct Response to MTF1 and RREB1 in the Regulation of Zn Metabolism. International journal of molecular sciences 11 32858813
2018 Role of ZIP8 in regulating cell morphology and NF-κB/Snail2 signaling. Metallomics : integrated biometal science 11 29927450
2024 Endothelial ZIP8 plays a minor role in BMP6 regulation by iron in mice. Blood 10 38518102
2024 Nesfatin-1 mitigates calcific aortic valve disease via suppressing ferroptosis mediated by GSH/GPX4 and ZIP8/SOD2 axes. Free radical biology & medicine 10 38851518
2018 Role of ZIP8 in regulation of cisplatin sensitivity through Bcl-2. Toxicology and applied pharmacology 10 30342059
2015 Zinc Supplementation in a Randomized Controlled Trial Decreased ZIP4 and ZIP8 mRNA Abundance in Peripheral Blood Mononuclear Cells of Adult Women. Nutrition and metabolic insights 10 26023281
2024 Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism. Inflammatory bowel diseases 9 38289995
2024 Expression of Manganese Transporters ZIP8, ZIP14, and ZnT10 in Brain Barrier Tissues. International journal of molecular sciences 9 39408669
2021 ZIP8 mediates the extracellular matrix degradation of nucleus pulposus cells via NF-κB signaling pathway. Biochemical and biophysical research communications 9 33677133
2024 Coumestrol facilitates apoptosis in colorectal cancer cells by interacting with ZIP8 protein via the ferroptosis pathway. Journal of Cancer 8 39006076
2024 Neuronal SLC39A8 deficiency impairs cerebellar development by altering manganese homeostasis. JCI insight 8 39435657
2023 The Regulation of ZIP8 by Dietary Manganese in Mice. International journal of molecular sciences 8 36983036
2022 The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance. Frontiers in physiology 8 35784893
2021 Knockdown of Circ_SLC39A8 protects against the progression of osteoarthritis by regulating miR-591/IRAK3 axis. Journal of orthopaedic surgery and research 8 33658057
2019 SLC39A8 is a risk factor for schizophrenia in Uygur Chinese: a case-control study. BMC psychiatry 8 31533672
2025 ZIP8 modulates ferroptosis to drive esophageal carcinoma progression. Cell death & disease 7 40328750

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