{"gene":"SLC39A14","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2005,"finding":"ZIP14 (SLC39A14) is a plasma membrane-localized glycoprotein that functions as a zinc influx transporter in a temperature-dependent manner. The LZT metalloprotease motif (HEXPHEXGD) in transmembrane domain V is relevant to zinc transport, though ZIP14 lacks the initial histidine yet retains transport activity.","method":"Overexpression in cells with functional zinc transport assay (temperature-dependence), glycosylation analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, functional assay in overexpression system with glycosylation characterization, but limited mechanistic depth","pmids":["15642354"],"is_preprint":false},{"year":2005,"finding":"IL-6 upregulates ZIP14 expression in liver, and this ZIP14 induction drives hepatic zinc import and contributes to hypozincemia during acute-phase inflammatory response. ZIP14 localizes to the plasma membrane of hepatocytes and increases zinc uptake when transfected into HEK cells.","method":"IL-6 knockout mouse model (turpentine inflammation, LPS), immunohistochemistry, transfection with 65Zn accumulation and fluorescent Zn probe, metallothionein mRNA induction","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model plus in vitro functional assays, multiple orthogonal methods, replicated across conditions","pmids":["15863613"],"is_preprint":false},{"year":2006,"finding":"ZIP14 mediates cellular uptake of non-transferrin-bound iron (NTBI) as Fe2+ (inhibited by bathophenanthroline sulfonate, a cell-impermeant ferrous chelator) and zinc; overexpression in HEK 293H and Sf9 cells increases 65Zn and 59Fe uptake; siRNA knockdown in AML12 hepatocytes reduces both iron and zinc uptake.","method":"Overexpression in HEK 293H and Sf9 cells with radioisotope uptake (65Zn, 59Fe); siRNA knockdown in hepatocytes; ferrous chelator inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell systems (overexpression and knockdown), radioisotope transport assays, ferrous-specific chelator, replicated across labs","pmids":["16950869"],"is_preprint":false},{"year":2008,"finding":"ZIP14A and ZIP14B (arising from alternative splicing of exons 4A/4B) function as metal/bicarbonate symporters transporting Cd2+, Mn2+, and Zn2+. ZIP14B has higher affinity than ZIP14A for Cd2+ (Km=0.14 vs 1.1 µM) and Mn2+ (Km=4.4 vs 18.2 µM). Uptake is dependent on extracellular HCO3-. ZIP14 is glycosylated and localizes to the apical surface of polarized MDCK cells.","method":"Stable retroviral-infected mouse fetal fibroblast cultures; transient transfection in MDCK polarized epithelial cells; kinetic uptake assays with Cd, Mn, Zn; HCO3- dependence; glycosylation analysis; subcellular localization","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — detailed kinetic characterization of two splice isoforms, multiple substrates, bicarbonate symporter mechanism established, localization confirmed in polarized cells","pmids":["18270315"],"is_preprint":false},{"year":2008,"finding":"HFE (hereditary hemochromatosis protein) decreases ZIP14 protein levels post-translationally (without changing ZIP14 mRNA), shortening its half-life, thereby reducing both transferrin-bound and non-transferrin-bound iron uptake in HepG2 cells. ZIP14 knockdown abolishes HFE's effect on NTBI uptake.","method":"HFE overexpression in HepG2 and HeLa cells; siRNA knockdown of ZIP14; protein half-life/turnover assays; NTBI uptake assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal epistasis (HFE expression + ZIP14 knockdown), protein stability assays, multiple cell lines, consistent results","pmids":["18524764"],"is_preprint":false},{"year":2009,"finding":"IL-1β upregulates ZIP14 expression and zinc transport in hepatocytes via inducible nitric oxide synthase (iNOS)-generated nitric oxide (NO). The NO donor SNAP increases Zip14 mRNA and transcriptional activity; ChIP showed AP-1 and RNA polymerase II association with Zip14 promoter after NO exposure; induction was absent in iNOS-/- hepatocytes.","method":"Primary hepatocyte culture with NO donor (SNAP); IL-1β treatment of WT and iNOS-/- hepatocytes; ChIP for AP-1 and RNA Pol II; zinc fluorophore transport assay; RT-PCR","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP mechanistic evidence, iNOS knockout epistasis, multiple orthogonal methods in single study","pmids":["19179618"],"is_preprint":false},{"year":2010,"finding":"ZIP14 mediates cellular assimilation of iron from transferrin (transferrin-bound iron, TBI) via endosomal localization. ZIP14 is detected at the plasma membrane and in endosomes containing internalized transferrin in HepG2 cells; siRNA knockdown reduces iron assimilation from transferrin by 50% without affecting transferrin uptake; ZIP14 can transport iron at pH 6.5 (the endosomal pH where iron dissociates from transferrin).","method":"Targeted knock-in FLAG-tagged ZIP14 in HepG2 cells; confocal immunofluorescence; siRNA knockdown; iron assimilation assays; pH-dependent transport assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous tagged protein, confocal co-localization with transferrin endosomes, siRNA knockdown with quantitative iron assay, pH-dependence mechanistic study","pmids":["20682781"],"is_preprint":false},{"year":2010,"finding":"SLC39A14/ZIP14 splicing is regulated by the Wnt/β-catenin pathway in colorectal cancer; β-catenin knockdown or dominant-negative TCF expression alters the exon 4A/4B isoform ratio. The splicing factors SRSF1 and its kinase SRPK1 mediate this regulation, with SRSF1 binding preferentially to exon 4B.","method":"β-catenin siRNA knockdown, dominant-negative TCF overexpression in DLD1 and Ls174T cells; siRNA knockdown of SRPK1 and SRSF1; exon array and RT-PCR; in silico splicing factor binding analysis","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations in multiple cell lines, but pathway placement relies partly on in silico prediction for SRSF1 binding site","pmids":["20938052"],"is_preprint":false},{"year":2011,"finding":"ZIP14 is a broad-scope metal-ion transporter that specifically transports Fe2+ (not Fe3+), with K0.5 ≈ 2 µM; transport is saturable, temperature-dependent, pH-sensitive, Ca2+-dependent, stimulated by HCO3-, and inhibited by Co2+, Mn2+, Zn2+. ZIP14 also transports Cd2+, Mn2+, Zn2+ (K0.5 ≈ 2 µM for Zn2+) but not Cu (I or II). The inhibition profiles and Ca2+ dependence differ between Fe2+ and Zn2+ transport.","method":"Xenopus laevis oocyte heterologous expression system; radioisotope transport assays (55Fe, 109Cd, 54Mn, 65Zn, 64Cu); kinetic analysis; temperature, pH, ion dependence assays","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous electrophysiological/transport reconstitution in Xenopus oocytes with full kinetic characterization, multiple substrates, multiple orthogonal parameters","pmids":["21653899"],"is_preprint":false},{"year":2011,"finding":"SLC39A14/ZIP14 controls GPCR-mediated cAMP-CREB signaling by suppressing basal phosphodiesterase (PDE) activity. Zip14 KO mice show reduced cAMP due to increased PDE activity, causing impaired GPCR signaling in growth plate, pituitary, and liver, resulting in growth retardation and impaired gluconeogenesis.","method":"Slc39a14 knockout mouse model; cAMP measurement; PDE activity assay; CREB phosphorylation analysis; growth and gluconeogenesis phenotyping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with defined molecular phenotype (PDE activity, cAMP), but mechanistic link between zinc transport and PDE inhibition inferred rather than directly demonstrated","pmids":["21445361"],"is_preprint":false},{"year":2012,"finding":"ZIP14 localizes to the basolateral membrane of enterocytes and is present in endosomes; it is involved in endosomal trafficking of zinc. Zip14 KO mice show zinc trapped in endosomes and reduced threonine phosphorylation of tight junction protein occludin, impairing intestinal barrier function.","method":"Plasma membrane fractionation; endosome isolation; FluoZin-3AM fluorescence for endosomal zinc; intestinal permeability assays (FITC-dextran); occludin phosphorylation; claudin 1/2 expression","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation with functional consequence (barrier function), but single lab","pmids":["25428902"],"is_preprint":false},{"year":2012,"finding":"ZIP14 mediates hepatic zinc uptake during liver regeneration, inhibiting PTP1B phosphatase activity through increased intracellular zinc, which in turn enhances c-Met phosphorylation and hepatocyte proliferation. Zip14 KO mice fail to show increased hepatic zinc or hepatocyte proliferation after partial hepatectomy.","method":"Partial hepatectomy in WT and Zip14 KO mice; Zip14-overexpressing AML12 hepatocytes; PTP1B activity assay; c-Met phosphorylation; proliferation markers (PCNA, CyclinD1, Ki67); hepatic zinc measurement","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model plus cell overexpression with enzymatic (PTP1B) and signaling (c-Met phosphorylation) readouts, multiple orthogonal methods","pmids":["22374166"],"is_preprint":false},{"year":2012,"finding":"ZIP8 and ZIP14 both mediate apical uptake of Cd2+ and Mn2+ in kidney proximal tubule cells; siRNA knockdown of either reduces uptake from the apical membrane. ZIP8 and ZIP14 are expressed in the S3 segment of proximal tubules.","method":"siRNA knockdown of ZIP8, ZIP14, DMT1 in proximal tubule cell Transwell culture; apical/basolateral metal uptake assays; in situ hybridization","journal":"Metallomics : integrated biometal science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA in polarized cell culture with directional transport readout, but ZIP14 role partially overlapping with ZIP8","pmids":["22534978"],"is_preprint":false},{"year":2012,"finding":"ZIP14 in the Xenopus oocyte system mediates electroneutral divalent cation/bicarbonate symport (confirmed by electrogenicity studies using a potassium gradient). ZIP14A and ZIP14B show distinct metal-ion inhibition patterns for Cd and Zn uptake.","method":"Xenopus oocyte expression; Km/Vmax determination; electrogenicity studies with potassium gradient; competitive inhibition with 10 divalent cations","journal":"Metallomics : integrated biometal science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted transport in Xenopus oocytes with electrophysiological confirmation of electroneutrality, single lab but rigorous","pmids":["23090441"],"is_preprint":false},{"year":2012,"finding":"ZIP14 mediates zinc uptake in macrophages in response to LPS; Zip14 knockdown attenuates cytokine production, indicating ZIP14 has a buffering role in macrophage inflammatory responses. LPS induction of ZIP14 depends on calcium signaling, GC-rich DNA binding, and NF-κB downregulation.","method":"LPS treatment of primary human macrophages; siRNA knockdown; cytokine mRNA (RT-qPCR) and protein measurement; pharmacological inhibitors of calcium signaling and NF-κB","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary human macrophages with siRNA knockdown and cytokine readout, single lab","pmids":["23052185"],"is_preprint":false},{"year":2013,"finding":"ZIP14 protein is localized to the basolateral membrane of hepatocytes and to acinar cells of the pancreas; its protein levels are upregulated in iron-loaded animals (post-translationally, as mRNA does not change with iron status), while DMT1 is regulated oppositely.","method":"Confocal immunofluorescence microscopy; immunoblotting; qRT-PCR in iron-deficient, adequate, and overloaded rats; hypotransferrinemic mice","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunofluorescence localization with iron-status manipulation, but post-translational regulation inferred from protein/mRNA discordance, single lab","pmids":["23349308"],"is_preprint":false},{"year":2014,"finding":"ZIP14 undergoes endocytosis, membrane extraction, deglycosylation, and proteasomal degradation via a pathway independent of ER-associated protein degradation (ERAD). Iron inhibits membrane extraction of internalized ZIP14, resulting in higher steady-state levels. N-linked glycosylation at N102 is required for efficient membrane extraction and iron-sensitive degradation of ZIP14.","method":"Inhibitor studies (proteasome inhibitors, retrograde trafficking inhibitors, bafilomycin); glycosylation mutants (N102 substitution); pulse-chase and protein stability assays; endocytosis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis (N102), multiple inhibitors distinguishing pathways, mechanistic dissection of a novel degradation pathway","pmids":["24927598"],"is_preprint":false},{"year":2014,"finding":"IL-6 upregulates ZIP14 in SH-SY5Y neuronal cells, increasing Mn2+ uptake; siRNA knockdown of ZIP14 reduces Mn2+ uptake. IL-6 also downregulates ZnT10, reducing Mn excretion. Combined effect enhances Mn accumulation in neuronal cells.","method":"siRNA knockdown of ZIP14, ZIP8, ZnT10 in SH-SY5Y cells; IL-6 treatment; Mn uptake assays; mRNA and protein quantification","journal":"Metallomics : integrated biometal science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with quantitative Mn uptake, single lab, two transporters examined","pmids":["24576911"],"is_preprint":false},{"year":2015,"finding":"SLC39A14 ablation in mice markedly reduces NTBI uptake by liver and pancreas. In hemochromatosis mouse models (Hfe-/- and Hfe2-/-), Slc39a14 deficiency greatly diminishes hepatic and pancreatic iron loading and prevents iron deposition in hepatocytes and pancreatic acinar cells.","method":"Slc39a14 KO mice crossed with Hfe-/- and Hfe2-/- mice; plasma NTBI uptake measurements; tissue iron quantification; histology","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with hemochromatosis models, in vivo NTBI uptake measurements, replicated across two disease models","pmids":["26028554"],"is_preprint":false},{"year":2015,"finding":"Prion protein (PrPC) functions as a ferrireductase partner for ZIP14 (and DMT1); coexpression of PrPC with ZIP14 in HepG2 cells increases uptake of Fe3+ (not Fe2+), suggesting PrPC reduces Fe3+ to Fe2+ for transport through ZIP14.","method":"PrPC knockout mice with 59Fe radiolabeling; HepG2 cell overexpression; ferric vs ferrous iron uptake assays; coexpression studies","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO and in vitro coexpression with mechanistic interpretation, but ferrireductase mechanism not directly proved by reconstitution","pmids":["25862412"],"is_preprint":false},{"year":2016,"finding":"ZIP14 is upregulated in cachectic skeletal muscles by TNF-α and TGF-β cytokines. ZIP14-mediated zinc uptake in muscle progenitor cells represses MyoD and Mef2c expression, blocking muscle-cell differentiation. In differentiated muscle cells, ZIP14-mediated zinc accumulation induces myosin heavy chain loss. Germline or muscle-specific Zip14 depletion reduces muscle atrophy in metastatic cancer models.","method":"Cancer cachexia mouse models (metastatic colon, lung, breast); germline and muscle-specific Zip14 KO; cytokine treatment (TNF-α, TGF-β); MyoD and Mef2c mRNA/protein; myosin heavy chain measurement; zinc measurement","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline and tissue-specific KO, cytokine induction, multiple cancer models, mechanistic link to MyoD/Mef2c suppression","pmids":["29875463"],"is_preprint":false},{"year":2016,"finding":"ZIP14 is localized on the plasma membrane of human β-cells (primary islets and βlox5 cell line) and mediates ~50% of NTBI uptake in these cells; siRNA knockdown of ZIP14 reduces NTBI uptake by 50% in both cell systems.","method":"siRNA knockdown in βlox5 cells and primary human islets; NTBI uptake assays; overexpression of ZIP14, ZIP8, DMT1; immunofluorescence","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown in two human cell systems (cell line and primary islets), quantitative iron uptake, but single lab","pmids":["27903581"],"is_preprint":false},{"year":2016,"finding":"ZIP14 undergoes sequential translocation from the plasma membrane to early and late endosomes during glucose uptake in hepatocytes. ZIP14-mediated zinc transport delivers zinc to endosomes where it supports activity of zinc-dependent insulin-degrading enzyme (IDE) and cathepsin D to regulate insulin receptor activity. Zip14 KO mice show zinc-deficient endosomes, impaired IDE/cathepsin D activity, enhanced insulin receptor signaling, increased glycogen synthesis, and impaired gluconeogenesis.","method":"Zip14 KO mouse hepatocytes; endosome fractionation; zinc measurement in endosomes; IDE and cathepsin D activity assays; insulin receptor phosphorylation; glycogen synthesis and gluconeogenesis assays; live cell imaging of ZIP14 localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — subcellular fractionation, enzymatic activity assays, KO model with specific metabolic phenotype, multiple orthogonal methods","pmids":["27703010"],"is_preprint":false},{"year":2017,"finding":"p53 interacts with ZIP14 protein, increases its ubiquitination, and promotes its degradation, thereby reducing ZIP14 protein levels post-translationally. Loss of p53 results in higher ZIP14 levels and increased NTBI uptake.","method":"Co-precipitation (p53-ZIP14 interaction); ubiquitination assay; p53 overexpression/knockdown; NTBI uptake assays; immunoblotting","journal":"Nutrients","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-precipitation showing direct interaction, ubiquitination assay, functional iron uptake consequence, single lab","pmids":["29292794"],"is_preprint":false},{"year":2017,"finding":"Hepatic ZIP14 mediates zinc import required for adaptation to ER stress; ZIP14-mediated zinc inhibits PTP1B activity to suppress apoptosis and steatosis. During ER stress, transcription factors ATF4 and ATF6α transcriptionally upregulate Zip14. Zip14 KO mice under ER stress show greater PTP1B activity, proapoptotic protein expression, and hepatic steatosis.","method":"Pharmacologic and HFD-induced ER stress in Zip14 KO mice; ATF4/ATF6α overexpression; PTP1B activity assay; apoptosis markers; steatosis quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse, transcription factor mechanistic studies, PTP1B enzyme activity assay, multiple ER stress models","pmids":["28673968"],"is_preprint":false},{"year":2017,"finding":"Slc39a14 global knockout mice develop markedly increased Mn in brain and extrahepatic tissues with motor deficits reversible by Na2CaEDTA chelation. Hepatocyte-specific Slc39a14 KO mice do not accumulate Mn in brain under normal conditions, indicating hepatocyte-autonomous loss of ZIP14 is insufficient to cause brain Mn accumulation; non-hepatic ZIP14 expression is required to prevent systemic Mn overload.","method":"Global and hepatocyte-specific (Alb-Cre) Slc39a14 KO mice; ICP-MS for tissue metal levels; motor deficit assays; chelation rescue","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific vs global KO genetic epistasis, chelation rescue, ICP-MS quantification, clearly distinguishes organ-specific roles","pmids":["28751976"],"is_preprint":false},{"year":2018,"finding":"ZIP14 mediates Mn2+ uptake in brain microvascular endothelial cells (BMVECs) at both apical (blood) and basal (brain) sides, supporting bidirectional Mn flux across the blood-brain barrier. Knockdown of ZIP14 (and ZIP8) reduces Mn uptake; uptake is pH-, bicarbonate-, and LPS-dependent.","method":"siRNA knockdown of ZIP8 and ZIP14 in BMVECs; surface protein biotinylation; 54Mn uptake; kinetic analysis; LPS treatment; apical/basolateral transport assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA, surface biotinylation, directional transport, single lab","pmids":["31699897"],"is_preprint":false},{"year":2018,"finding":"A dominant gain-of-function mutation (L441R) in ZIP14 prevents its trafficking to the plasma membrane and causes intracellular zinc accumulation, leading to hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts exhibit enhanced endosteal cortical bone formation with osteoporotic trabecular bone, causing Hyperostosis Cranialis Interna-like phenotype.","method":"Whole-exome sequencing (patient); conditional knock-in mouse (osteoblast-specific L438R); subcellular localization assay; zinc measurement; cAMP-CREB and NFAT signaling assays; bone histomorphometry","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knock-in mouse with defined signaling pathway activation, localization assay, intracellular zinc measurement, phenotypic validation","pmids":["29621230"],"is_preprint":false},{"year":2019,"finding":"Intestinal ZIP14 acts primarily as a basolateral transporter in enterocytes that mediates direct basolateral reuptake of freshly absorbed manganese, thereby restricting net absorptive manganese transport. Loss of intestinal ZIP14 impairs secretory (basolateral-to-apical) Mn transport and enhances absorptive (apical-to-basolateral) Mn transport. Intestine-specific Zip14 KO mice accumulate Mn in liver and brain.","method":"CaCo-2 Transwell model; ZIP14-deficient CaCo-2 cells (CRISPR); directional Mn transport assays; intestine-specific Zip14 KO mice; ICP-MS","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene KO in polarized epithelial model, directional transport assays, in vivo tissue-specific KO confirmation","pmids":["31028174"],"is_preprint":false},{"year":2019,"finding":"ZIP14 in brain microvascular endothelial cells has plasma membrane occupancy regulated by cytoplasmic Ca2+ via the Golgi Ca2+-ATPase SPCA1. RNAi knockdown of SPCA1 increases cytoplasmic Ca2+, which enhances membrane localization of ZIP14 and increases 54Mn2+ uptake; SPCA1 overexpression has opposite effects.","method":"Surface protein biotinylation; indirect immunofluorescence; GFP-tagged proteins; SPCA1 RNAi knockdown; Ca2+ chelation; 54Mn2+ uptake assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — surface biotinylation, RNAi, functional Mn uptake assay, Ca2+ manipulation, single lab","pmids":["35787370"],"is_preprint":false},{"year":2019,"finding":"ZIP14 is degraded in response to Mn exposure via a lysosomal pathway (blocked by bafilomycin A1, which increased ZIP14 in LAMP1-positive vesicles), providing a cytoprotective feedback mechanism to limit Mn uptake. ZIP14 is localized to the basolateral surface of polarized HepaRG hepatocytes.","method":"Western blot and immunofluorescence in polarized HepaRG cells; 54Mn uptake (time- and temperature-dependent); bafilomycin A1 inhibition; LAMP1 co-localization","journal":"Biometals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization, degradation pathway pharmacologic dissection, transport kinetics, single lab","pmids":["31541377"],"is_preprint":false},{"year":2020,"finding":"Zip14 deletion in skeletal muscle results in muscle wasting at basal steady state associated with increased p-Mef2c, Hspb7, p38 activation, and NF-κB binding to the Mef2c promoter. Zip14-mediated zinc uptake in muscle during LPS inflammation increases Atrogin1/MuRF1 and reduces MyoD (cachexia signatures). miR-675-3p and -5p induction by LPS is Zip14-dependent.","method":"Zip14 global KO mice; LPS-induced inflammation; microarray and qPCR; ChIP (NF-κB at Mef2c promoter); p38 phosphorylation; Atrogin1/MuRF1/MyoD protein levels","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with ChIP and pathway analysis, multiple markers, single lab","pmids":["32132660"],"is_preprint":false},{"year":2022,"finding":"Enterocyte-specific ZIP14 ablation reduces HDAC3 (and total HDAC) activity, leading to epigenetic dysregulation of tight junction and cytokine genes (claudin 1, 2, IL-6, IFNγ). NF-κB, STAT3, and CDX2 show increased binding to promoters of dysregulated genes. Zinc supplementation of organoids from ΔIECZip14 mice restores differential gene expression.","method":"Enterocyte-specific Zip14 KO mice; RNA sequencing; ChIP for NF-κB, STAT3, CDX2; HDAC activity assays; intestinal organoids with zinc supplementation","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO, ChIP for multiple transcription factors, HDAC enzymatic activity, organoid rescue with zinc, multiple orthogonal methods","pmids":["36537699"],"is_preprint":false},{"year":2022,"finding":"Combined intestinal and hepatic ZIP14 deletion (double KO) causes much greater manganese overload than single-tissue deletion alone, demonstrating that both intestinal and hepatic ZIP14 cooperate to maintain systemic Mn homeostasis.","method":"Intestine-specific, liver-specific, and double (intestine+liver) Zip14 KO mice; ICP-MS for tissue Mn","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple tissue-specific KO comparisons, ICP-MS quantification, genetic epistasis approach, single lab","pmids":["35742937"],"is_preprint":false},{"year":2023,"finding":"In pancreatic β cells, ZIP14 localizes on the endoplasmic reticulum (not plasma membrane) and functions as a negative regulator of glucose-stimulated insulin secretion by regulating intracellular zinc trafficking. β cell-specific Zip14 KO mice show greater glucose-stimulated insulin secretion, increased energy expenditure, and on HFD develop greater islet hyperplasia and compensatory hyperinsulinemia.","method":"β cell-specific Zip14 KO mice; ZIP14 localization by immunofluorescence (co-staining with ER marker); glucose-stimulated insulin secretion (in vivo, ex vivo islets, MIN6 cells); zinc measurement; metabolic phenotyping","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with ER localization confirmed by immunofluorescence, functional insulin secretion assays in multiple systems, metabolic phenotyping","pmids":["38019082"],"is_preprint":false},{"year":2024,"finding":"Enterocyte-specific ZIP14 deletion reduces cellular labile zinc, causing chromatin remodeling (closed chromatin at MHCII gene regulatory regions) and decreased expression of MHCII molecules and their master transactivator CIITA. Zinc supplementation of Zip14 KO organoids restores MHCII transcript levels.","method":"Enterocyte-specific Zip14 KO; RNA sequencing; ChIP with CIITA antibody; ATAC-seq; FluoZin-3 zinc measurement; organoid zinc supplementation rescue; western blot, immunohistochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ATAC-seq chromatin remodeling, ChIP, zinc measurement, organoid rescue, tissue-specific KO, multiple orthogonal methods","pmids":["39793074"],"is_preprint":false},{"year":2024,"finding":"In liver fibrosis, zinc supplementation increases ZIP14 expression via MTF1 transcription factor binding to the ZIP14 promoter and reduction of HDAC4 binding, establishing an epigenetic mechanism by which zinc regulates ZIP14 expression in hepatocytes.","method":"CCl4-induced liver fibrosis mouse model; ZnCl2 treatment; ChIP for MTF1 and HDAC4 at ZIP14 promoter; ZIP14 expression; intracellular zinc measurement","journal":"Biological trace element research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating TF-promoter interactions, in vivo fibrosis model, single lab","pmids":["38221603"],"is_preprint":false}],"current_model":"SLC39A14/ZIP14 is a plasma membrane- and endosome-localized metal-ion transporter that mediates cellular uptake of Fe2+, Zn2+, Mn2+, and Cd2+ via an electroneutral metal/bicarbonate symport mechanism; it is transcriptionally induced by IL-6 (via STAT3), IL-1β (via AP-1/nitric oxide), and ATF4/ATF6α (during ER stress), and is post-translationally regulated by iron (via a glycosylation-dependent proteasomal degradation pathway requiring N102 glycosylation), Mn exposure (lysosomal degradation), p53 (ubiquitination), and HFE (protein destabilization); in the liver ZIP14 drives NTBI and transferrin-derived iron uptake, suppresses PTP1B activity to promote c-Met signaling and hepatocyte proliferation, and delivers zinc to endosomes to regulate insulin receptor degradation and glucose homeostasis; in the intestine it localizes basolaterally to restrict Mn absorption and maintain intestinal barrier integrity through zinc-dependent HDAC activity and MHCII expression; in skeletal muscle, ZIP14-mediated zinc accumulation (induced by TNF-α/TGF-β in cancer) represses MyoD and Mef2c to block differentiation and cause cachexia; in pancreatic β cells ZIP14 is ER-localized and acts as a negative regulator of glucose-stimulated insulin secretion; loss-of-function mutations cause systemic hypermanganesemia with childhood-onset dystonia-parkinsonism due to failure to clear Mn from the circulation."},"narrative":{"mechanistic_narrative":"SLC39A14/ZIP14 is a broad-scope divalent metal-ion transporter that mediates cellular uptake of Fe2+, Zn2+, Mn2+, and Cd2+ through an electroneutral metal/bicarbonate symport mechanism, operating at the plasma membrane and within endosomes to govern systemic metal homeostasis [PMID:18270315, PMID:21653899, PMID:23090441]. It transports ferrous (but not ferric) iron and is responsible for non-transferrin-bound iron uptake as well as assimilation of transferrin-derived iron at endosomal pH, with prion protein serving as a ferrireductase partner that supplies Fe2+ from Fe3+ [PMID:16950869, PMID:20682781, PMID:25862412]. In the liver, ZIP14 drives NTBI uptake and delivers zinc that inhibits PTP1B to enhance c-Met signaling and hepatocyte proliferation, supports adaptation to ER stress, and traffics through endosomes to supply zinc-dependent insulin-degrading enzyme and cathepsin D, thereby regulating insulin receptor turnover and glucose homeostasis [PMID:22374166, PMID:27703010, PMID:28673968]. ZIP14 expression is induced by inflammatory signals — IL-6 in liver, IL-1β via iNOS-derived nitric oxide and AP-1, and ATF4/ATF6α during ER stress — and is post-translationally controlled by iron through an N102-glycosylation-dependent membrane-extraction and proteasomal degradation pathway, by Mn through lysosomal degradation, by p53-mediated ubiquitination, and by HFE-mediated destabilization [PMID:15863613, PMID:19179618, PMID:24927598, PMID:26028554, PMID:29292794, PMID:28673968, PMID:31541377, PMID:18524764]. In the intestine ZIP14 localizes basolaterally to restrict net manganese absorption and to supply labile zinc that sustains HDAC activity, tight-junction integrity, and MHCII/CIITA expression, while in skeletal muscle ZIP14-mediated zinc accumulation represses MyoD and Mef2c to block myogenesis and drive cancer cachexia [PMID:31028174, PMID:36537699, PMID:39793074, PMID:29875463]. Loss of ZIP14 across intestinal, hepatic, and non-hepatic tissues causes systemic manganese overload with brain accumulation and motor deficits, and a dominant gain-of-function mutation trapping ZIP14 intracellularly causes a hyperostosis bone phenotype through cAMP-CREB/NFAT activation [PMID:28751976, PMID:31028174, PMID:35742937, PMID:29621230].","teleology":[{"year":2005,"claim":"Established ZIP14 as a functional plasma-membrane zinc influx transporter and linked it to inflammation-driven hypozincemia, defining a first physiological context.","evidence":"Overexpression zinc-transport assays plus IL-6 knockout mouse and hepatocyte transfection","pmids":["15642354","15863613"],"confidence":"High","gaps":["Did not establish substrate breadth beyond zinc","Transcription factor mediating IL-6 induction not yet defined"]},{"year":2006,"claim":"Showed ZIP14 transports non-transferrin-bound iron as Fe2+ in addition to zinc, expanding it from a zinc transporter to a multi-metal transporter.","evidence":"Radioisotope uptake in HEK293H and Sf9 overexpression and hepatocyte siRNA knockdown with ferrous chelator","pmids":["16950869"],"confidence":"High","gaps":["Did not determine kinetics or full metal selectivity","Did not address transferrin-bound iron pathway"]},{"year":2008,"claim":"Defined the transport mechanism as metal/bicarbonate symport and characterized two splice isoforms (ZIP14A/B) with distinct Cd2+/Mn2+ affinities, establishing the biochemical basis of substrate handling.","evidence":"Kinetic uptake assays of two isoforms in fibroblasts and polarized MDCK cells with HCO3- dependence","pmids":["18270315"],"confidence":"High","gaps":["Physiological roles of isoform differences not addressed","Electroneutrality not yet proven electrophysiologically"]},{"year":2008,"claim":"Identified HFE as a post-translational destabilizer of ZIP14 that reduces both TBI and NTBI uptake, connecting ZIP14 to hereditary hemochromatosis regulation.","evidence":"HFE overexpression plus ZIP14 siRNA epistasis and protein half-life assays in HepG2/HeLa cells","pmids":["18524764"],"confidence":"High","gaps":["Molecular mechanism of HFE-mediated destabilization not resolved","Direct HFE-ZIP14 interaction not demonstrated"]},{"year":2009,"claim":"Defined a second inflammatory induction route, showing IL-1β induces ZIP14 via iNOS-derived NO acting through AP-1 at the promoter.","evidence":"NO donor and iNOS-/- hepatocytes with ChIP for AP-1 and RNA Pol II","pmids":["19179618"],"confidence":"High","gaps":["Did not link induction to downstream metal-dependent function","AP-1 subunit identity not specified"]},{"year":2010,"claim":"Showed ZIP14 assimilates transferrin-derived iron from endosomes at acidic pH, revealing an endosomal arm of its iron-handling role beyond plasma-membrane NTBI uptake.","evidence":"FLAG knock-in HepG2 cells, confocal co-localization with transferrin endosomes, siRNA, pH-dependent transport","pmids":["20682781"],"confidence":"High","gaps":["Endosomal recruitment mechanism not defined","Quantitative contribution versus DMT1 not resolved"]},{"year":2010,"claim":"Connected ZIP14 isoform splicing to Wnt/β-catenin signaling via SRSF1/SRPK1 in colorectal cancer, linking transporter isoform choice to an oncogenic pathway.","evidence":"β-catenin and TCF perturbation plus SRSF1/SRPK1 knockdown and exon arrays in colon cancer lines","pmids":["20938052"],"confidence":"Medium","gaps":["SRSF1 binding partly in silico predicted","Functional metal-transport consequence of isoform switch not measured"]},{"year":2011,"claim":"Provided rigorous reconstituted kinetics establishing ZIP14 selectivity (Fe2+, Zn2+, Cd2+, Mn2+ but not Cu) and ion dependencies, giving a definitive biophysical substrate map.","evidence":"Xenopus oocyte heterologous expression with multi-isotope kinetic and ion-dependence analysis","pmids":["21653899"],"confidence":"High","gaps":["Structural basis of selectivity unknown","Differing Fe2+ vs Zn2+ inhibition profiles mechanistically unexplained"]},{"year":2011,"claim":"Linked ZIP14 to GPCR cAMP-CREB signaling via suppression of phosphodiesterase activity, implicating it in growth and gluconeogenesis phenotypes.","evidence":"Slc39a14 KO mice with cAMP, PDE activity, and CREB phosphorylation readouts","pmids":["21445361"],"confidence":"Medium","gaps":["Mechanistic link from zinc transport to PDE inhibition inferred not shown","Which PDE isoform involved unresolved"]},{"year":2012,"claim":"Established hepatic ZIP14 as a driver of regeneration by importing zinc to inhibit PTP1B and enhance c-Met signaling, defining a signaling-via-metal mechanism.","evidence":"Partial hepatectomy in Zip14 KO mice plus hepatocyte overexpression with PTP1B activity and c-Met phosphorylation","pmids":["22374166"],"confidence":"High","gaps":["Direct zinc-PTP1B inhibition in vivo not quantified","Endosomal versus cytosolic zinc pool not distinguished"]},{"year":2012,"claim":"Mapped intestinal and renal localization, showing basolateral enterocyte and apical proximal-tubule roles in metal transport, and demonstrated endosomal zinc trafficking required for barrier integrity.","evidence":"Fractionation, FluoZin imaging, permeability and occludin assays in Zip14 KO intestine; siRNA in proximal tubule Transwell","pmids":["25428902","22534978"],"confidence":"Medium","gaps":["Overlap with ZIP8 not fully resolved","Mechanism of occludin phosphorylation regulation not defined"]},{"year":2012,"claim":"Confirmed electroneutral divalent-cation/bicarbonate symport electrophysiologically and showed isoform-specific inhibition patterns, finalizing the transport mechanism.","evidence":"Xenopus oocyte electrogenicity studies with potassium gradient and competitive inhibition","pmids":["23090441"],"confidence":"High","gaps":["Stoichiometry of metal:bicarbonate not precisely fixed","Structural transporter model absent"]},{"year":2012,"claim":"Showed ZIP14 buffers macrophage inflammatory responses through LPS-induced zinc uptake, broadening its role to innate immunity.","evidence":"LPS treatment and siRNA in primary human macrophages with cytokine readouts and pathway inhibitors","pmids":["23052185"],"confidence":"Medium","gaps":["Direct transcription factor at promoter not pinned","Single lab"]},{"year":2013,"claim":"Demonstrated iron-status-dependent post-translational upregulation of ZIP14 protein (opposite to DMT1), establishing iron as a regulator of transporter abundance.","evidence":"Immunofluorescence and immunoblotting versus qRT-PCR across iron-status rat and hypotransferrinemic models","pmids":["23349308"],"confidence":"Medium","gaps":["Degradation mechanism not yet defined here","mRNA/protein discordance only correlative"]},{"year":2014,"claim":"Defined the iron-sensitive degradation pathway: endocytosis, N102-glycosylation-dependent membrane extraction, deglycosylation, and ERAD-independent proteasomal degradation, explaining iron-regulated ZIP14 stability.","evidence":"Inhibitor panels, N102 glycosylation mutants, pulse-chase and endocytosis assays","pmids":["24927598"],"confidence":"High","gaps":["Ubiquitin ligase mediating degradation not identified","How iron blocks membrane extraction mechanistically unknown"]},{"year":2014,"claim":"Extended IL-6 induction of ZIP14 to neuronal cells, where it raises Mn uptake while ZnT10 downregulation limits efflux, implicating ZIP14 in neuronal Mn accumulation.","evidence":"siRNA and IL-6 treatment with Mn uptake assays in SH-SY5Y cells","pmids":["24576911"],"confidence":"Medium","gaps":["In vivo neuronal relevance not tested","Transcription factor for neuronal IL-6 induction unspecified"]},{"year":2015,"claim":"Demonstrated in vivo that ZIP14 is the major route of hepatic/pancreatic NTBI loading and is required for iron deposition in hemochromatosis models, establishing it as a therapeutic node in iron overload.","evidence":"Slc39a14 KO crossed with Hfe-/- and Hfe2-/- mice with in vivo NTBI uptake and tissue iron histology","pmids":["26028554"],"confidence":"High","gaps":["Did not address extrahepatic iron handling","Contribution to systemic iron balance versus other transporters not quantified"]},{"year":2015,"claim":"Identified prion protein as a ferrireductase partner supplying Fe2+ to ZIP14, providing a mechanism for ferric iron utilization.","evidence":"PrPC KO mice and HepG2 coexpression with ferric versus ferrous uptake","pmids":["25862412"],"confidence":"Medium","gaps":["Ferrireductase activity not proven by reconstitution","Physical PrPC-ZIP14 interaction not shown"]},{"year":2016,"claim":"Revealed ZIP14-mediated endosomal zinc delivery controls insulin receptor degradation via IDE and cathepsin D, mechanistically connecting ZIP14 trafficking to glucose homeostasis.","evidence":"Zip14 KO hepatocytes with endosome fractionation, IDE/cathepsin D activity, insulin receptor signaling and metabolic assays","pmids":["27703010"],"confidence":"High","gaps":["Trigger for plasma-membrane-to-endosome translocation unresolved","Direct zinc loading of IDE not demonstrated structurally"]},{"year":2016,"claim":"Showed ZIP14 contributes ~50% of β-cell NTBI uptake, extending its iron role to islet cells.","evidence":"siRNA and overexpression with NTBI uptake in βlox5 cells and primary human islets","pmids":["27903581"],"confidence":"Medium","gaps":["Functional consequence for β-cell iron physiology not addressed","Single lab"]},{"year":2016,"claim":"Identified ZIP14 as a driver of cancer cachexia, where cytokine-induced zinc accumulation represses MyoD/Mef2c to block myogenesis, providing a metal-dependent atrophy mechanism.","evidence":"Germline and muscle-specific Zip14 KO across multiple metastatic cancer models with cytokine treatment and myogenic marker analysis","pmids":["29875463"],"confidence":"High","gaps":["How zinc represses MyoD/Mef2c mechanistically not fully defined","Therapeutic window in humans not addressed"]},{"year":2017,"claim":"Established ZIP14 as required for hepatic ER-stress adaptation, with ATF4/ATF6α driving its transcription and ZIP14-zinc suppressing PTP1B to limit apoptosis and steatosis.","evidence":"ER-stress Zip14 KO mice with ATF4/ATF6α overexpression, PTP1B activity, apoptosis and steatosis readouts","pmids":["28673968"],"confidence":"High","gaps":["Direct ATF binding sites on Zip14 promoter not mapped here","Relationship to inflammatory induction routes unresolved"]},{"year":2017,"claim":"Identified p53 as a binding partner promoting ZIP14 ubiquitination and degradation, adding a tumor-suppressor-linked layer of post-translational control over iron uptake.","evidence":"Co-precipitation, ubiquitination assay, p53 perturbation with NTBI uptake","pmids":["29292794"],"confidence":"Medium","gaps":["E3 ligase recruited by p53 not identified","Direct versus indirect interaction not fully resolved"]},{"year":2017,"claim":"Distinguished organ-specific Mn-clearance roles, showing global but not hepatocyte-specific Zip14 loss causes brain Mn accumulation, establishing that non-hepatic ZIP14 prevents systemic Mn overload and underlies the hypermanganesemia-dystonia disease.","evidence":"Global and hepatocyte-specific Slc39a14 KO mice with ICP-MS, motor assays, chelation rescue","pmids":["28751976"],"confidence":"High","gaps":["Identity of the critical non-hepatic tissue not yet pinpointed here","Mechanism of Mn excretion downstream of uptake not defined"]},{"year":2018,"claim":"Defined a dominant gain-of-function mutation (L441R) trapping ZIP14 intracellularly to cause zinc accumulation and cAMP-CREB/NFAT hyperactivation, producing a hyperostosis bone phenotype and revealing trafficking-dependent signaling control.","evidence":"Patient exome sequencing and osteoblast-specific L438R knock-in mice with localization, zinc, and signaling assays","pmids":["29621230"],"confidence":"High","gaps":["How intracellular zinc activates CREB/NFAT mechanistically unresolved","Relationship to loss-of-function Mn phenotype not integrated"]},{"year":2018,"claim":"Showed ZIP14 mediates bidirectional Mn flux across the blood-brain barrier with pH/bicarbonate/LPS dependence, situating it in CNS metal entry.","evidence":"siRNA, surface biotinylation, and directional 54Mn uptake in brain microvascular endothelial cells","pmids":["31699897"],"confidence":"Medium","gaps":["Net directional contribution in vivo not established","Overlap with ZIP8 not resolved"]},{"year":2019,"claim":"Identified intestinal basolateral ZIP14 as the gatekeeper restricting net Mn absorption, with loss causing hepatic and brain Mn accumulation.","evidence":"CRISPR ZIP14-deficient CaCo-2 Transwell directional transport and intestine-specific Zip14 KO mice with ICP-MS","pmids":["31028174"],"confidence":"High","gaps":["Coordination with hepatic clearance not yet tested","Mn re-secretion route into lumen not fully defined"]},{"year":2019,"claim":"Showed Mn-induced lysosomal degradation of ZIP14 provides cytoprotective feedback limiting Mn uptake, complementing the iron-sensitive proteasomal route.","evidence":"Bafilomycin inhibition, LAMP1 co-localization and Mn uptake in polarized HepaRG cells","pmids":["31541377"],"confidence":"Medium","gaps":["Trigger sensing Mn for lysosomal targeting unknown","Single lab"]},{"year":2019,"claim":"Demonstrated SPCA1-controlled cytoplasmic Ca2+ regulates ZIP14 plasma-membrane occupancy and Mn uptake, adding a calcium-dependent trafficking control.","evidence":"Surface biotinylation, SPCA1 RNAi, Ca2+ chelation and 54Mn uptake in brain endothelial cells","pmids":["35787370"],"confidence":"Medium","gaps":["Molecular link from Ca2+ to ZIP14 trafficking unknown","In vivo relevance untested"]},{"year":2020,"claim":"Showed ZIP14 has a basal homeostatic role in skeletal muscle, with deletion causing wasting via Mef2c/p38/NF-κB dysregulation and inflammatory zinc uptake driving atrophy gene signatures.","evidence":"Zip14 KO mice with LPS challenge, microarray, ChIP at Mef2c promoter, and atrophy marker analysis","pmids":["32132660"],"confidence":"Medium","gaps":["Reconciliation of basal protective role with cachexia-driving role incomplete","miRNA mechanism downstream not defined"]},{"year":2022,"claim":"Linked intestinal ZIP14-supplied zinc to HDAC3 activity and epigenetic control of barrier and cytokine genes, defining a zinc-to-chromatin axis in gut homeostasis.","evidence":"Enterocyte-specific Zip14 KO with RNA-seq, ChIP for NF-κB/STAT3/CDX2, HDAC activity, and zinc-rescue organoids","pmids":["36537699"],"confidence":"High","gaps":["How labile zinc tunes HDAC3 activity mechanistically unresolved","Causal chain to disease phenotype not fully mapped"]},{"year":2022,"claim":"Showed intestinal and hepatic ZIP14 cooperate, with double deletion causing far greater Mn overload than single-tissue loss, defining a multi-organ clearance system.","evidence":"Intestine-, liver-, and double-tissue Slc39a14 KO mice with ICP-MS","pmids":["35742937"],"confidence":"Medium","gaps":["Quantitative partition between organs not resolved","Single lab"]},{"year":2023,"claim":"Revealed a non-canonical ER-localized ZIP14 in pancreatic β cells acting as a negative regulator of glucose-stimulated insulin secretion, distinguishing it from plasma-membrane ZIP14 roles.","evidence":"β cell-specific Zip14 KO with ER co-localization, insulin secretion in vivo/ex vivo/MIN6, and metabolic phenotyping","pmids":["38019082"],"confidence":"High","gaps":["Mechanism by which ER zinc trafficking restrains secretion unresolved","Relationship to hepatic glucose roles not integrated"]},{"year":2024,"claim":"Connected intestinal ZIP14-supplied labile zinc to chromatin accessibility at MHCII loci and CIITA expression, extending the zinc-chromatin axis to mucosal immune gene regulation.","evidence":"Enterocyte-specific Zip14 KO with ATAC-seq, CIITA ChIP, zinc measurement and organoid zinc rescue","pmids":["39793074"],"confidence":"High","gaps":["Direct zinc-dependent factor controlling chromatin not identified","Functional immune consequence in vivo not fully tested"]},{"year":2024,"claim":"Defined a feedforward transcriptional loop in which zinc increases ZIP14 via MTF1 binding and HDAC4 release at the promoter in liver fibrosis.","evidence":"CCl4 fibrosis model with ZnCl2 treatment and ChIP for MTF1/HDAC4 at the ZIP14 promoter","pmids":["38221603"],"confidence":"Medium","gaps":["Causal contribution to fibrosis outcome not established","Single lab"]},{"year":null,"claim":"How ZIP14 trafficking between plasma membrane, endosomes, and ER is selected in a tissue-specific manner, and the structural basis of its metal selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the transporter exists in the corpus","Signals directing ER versus plasma-membrane localization across cell types unknown","The E3 ligases and sensors coupling iron/Mn levels to degradation are not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,3,6,8,13]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[3,8,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3,6,21,26]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,10,16,22]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[34]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,3,6,8,18,28]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,22,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,27]}],"complexes":[],"partners":["HFE","PRPC","TP53","PTP1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15043","full_name":"Metal cation symporter ZIP14","aliases":["LIV-1 subfamily of ZIP zinc transporter 4","LZT-Hs4","Solute carrier family 39 member 14","Zrt- and Irt-like protein 14","ZIP-14"],"length_aa":492,"mass_kda":54.2,"function":"Electroneutral transporter of the plasma membrane mediating the cellular uptake of the divalent metal cations zinc, manganese and iron that are important for tissue homeostasis, metabolism, development and immunity (PubMed:15642354, PubMed:27231142, PubMed:29621230). Functions as an energy-dependent symporter, transporting through the membranes an electroneutral complex composed of a divalent metal cation and two bicarbonate anions (By similarity). Beside these endogenous cellular substrates, can also import cadmium a non-essential metal which is cytotoxic and carcinogenic (By similarity). Controls the cellular uptake by the intestinal epithelium of systemic zinc, which is in turn required to maintain tight junctions and the intestinal permeability (By similarity). Modifies the activity of zinc-dependent phosphodiesterases, thereby indirectly regulating G protein-coupled receptor signaling pathways important for gluconeogenesis and chondrocyte differentiation (By similarity). Regulates insulin receptor signaling, glucose uptake, glycogen synthesis and gluconeogenesis in hepatocytes through the zinc-dependent intracellular catabolism of insulin (PubMed:27703010). Through zinc cellular uptake also plays a role in the adaptation of cells to endoplasmic reticulum stress (By similarity). Major manganese transporter of the basolateral membrane of intestinal epithelial cells, it plays a central role in manganese systemic homeostasis through intestinal manganese uptake (PubMed:31028174). Also involved in manganese extracellular uptake by cells of the blood-brain barrier (PubMed:31699897). May also play a role in manganese and zinc homeostasis participating in their elimination from the blood through the hepatobiliary excretion (By similarity). Also functions in the extracellular uptake of free iron. May also function intracellularly and mediate the transport from endosomes to cytosol of iron endocytosed by transferrin (PubMed:20682781). Plays a role in innate immunity by regulating the expression of cytokines by activated macrophages (PubMed:23052185)","subcellular_location":"Cell membrane; Apical cell membrane; Basolateral cell membrane; Early endosome membrane; Late endosome membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q15043/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC39A14","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC39A14","total_profiled":1310},"omim":[{"mim_id":"617013","title":"HYPERMANGANESEMIA WITH DYSTONIA 2; HMNDYT2","url":"https://www.omim.org/entry/617013"},{"mim_id":"613609","title":"HOMEOSTATIC IRON REGULATOR; HFE","url":"https://www.omim.org/entry/613609"},{"mim_id":"613280","title":"HYPERMANGANESEMIA WITH DYSTONIA 1; HMNDYT1","url":"https://www.omim.org/entry/613280"},{"mim_id":"608736","title":"SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 14; SLC39A14","url":"https://www.omim.org/entry/608736"},{"mim_id":"608374","title":"HEMOJUVELIN BMP CORECEPTOR; HJV","url":"https://www.omim.org/entry/608374"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":515.9},{"tissue":"pancreas","ntpm":235.9}],"url":"https://www.proteinatlas.org/search/SLC39A14"},"hgnc":{"alias_symbol":["KIAA0062","NET34","ZIP14","ZIP-14"],"prev_symbol":[]},"alphafold":{"accession":"Q15043","domains":[{"cath_id":"-","chopping":"49-75_91-143","consensus_level":"high","plddt":78.2918,"start":49,"end":143},{"cath_id":"-","chopping":"149-247_333-487","consensus_level":"high","plddt":88.4383,"start":149,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15043","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15043-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15043-F1-predicted_aligned_error_v6.png","plddt_mean":73.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC39A14","jax_strain_url":"https://www.jax.org/strain/search?query=SLC39A14"},"sequence":{"accession":"Q15043","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15043.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15043/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15043"}},"corpus_meta":[{"pmid":"16950869","id":"PMC_16950869","title":"Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16950869","citation_count":454,"is_preprint":false},{"pmid":"15863613","id":"PMC_15863613","title":"Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15863613","citation_count":443,"is_preprint":false},{"pmid":"18270315","id":"PMC_18270315","title":"Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter.","date":"2008","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18270315","citation_count":277,"is_preprint":false},{"pmid":"26028554","id":"PMC_26028554","title":"SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis.","date":"2015","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26028554","citation_count":193,"is_preprint":false},{"pmid":"21653899","id":"PMC_21653899","title":"Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron.","date":"2011","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21653899","citation_count":189,"is_preprint":false},{"pmid":"22534978","id":"PMC_22534978","title":"Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells.","date":"2012","source":"Metallomics : integrated biometal science","url":"https://pubmed.ncbi.nlm.nih.gov/22534978","citation_count":166,"is_preprint":false},{"pmid":"29875463","id":"PMC_29875463","title":"Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle.","date":"2018","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29875463","citation_count":150,"is_preprint":false},{"pmid":"23349308","id":"PMC_23349308","title":"ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders.","date":"2013","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/23349308","citation_count":147,"is_preprint":false},{"pmid":"15642354","id":"PMC_15642354","title":"Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15642354","citation_count":144,"is_preprint":false},{"pmid":"21445361","id":"PMC_21445361","title":"The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21445361","citation_count":143,"is_preprint":false},{"pmid":"23110240","id":"PMC_23110240","title":"Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia).","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23110240","citation_count":141,"is_preprint":false},{"pmid":"20682781","id":"PMC_20682781","title":"ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20682781","citation_count":135,"is_preprint":false},{"pmid":"29490098","id":"PMC_29490098","title":"The Multiple Faces of the Metal Transporter ZIP14 (SLC39A14).","date":"2018","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/29490098","citation_count":107,"is_preprint":false},{"pmid":"28751976","id":"PMC_28751976","title":"Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice.","date":"2017","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/28751976","citation_count":107,"is_preprint":false},{"pmid":"25428902","id":"PMC_25428902","title":"Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function.","date":"2014","source":"American journal of physiology. 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Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40818459","citation_count":5,"is_preprint":false},{"pmid":"36005133","id":"PMC_36005133","title":"Heterogeneous Immunolocalisation of Zinc Transporters ZIP6, ZIP10 and ZIP14 in Human Normo- and Asthenozoospermic Spermatozoa.","date":"2022","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36005133","citation_count":5,"is_preprint":false},{"pmid":"36501144","id":"PMC_36501144","title":"Long Noncoding RNA, MicroRNA, Zn Transporter Zip14 (Slc39a14) and Inflammation in Mice.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/36501144","citation_count":4,"is_preprint":false},{"pmid":"39793074","id":"PMC_39793074","title":"Deletion of metal transporter Zip14 reduces major histocompatibility complex II expression in murine small intestinal epithelial cells.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39793074","citation_count":4,"is_preprint":false},{"pmid":"36062189","id":"PMC_36062189","title":"Circ_000829 Plays an Anticancer Role in Renal Cell Carcinoma by Suppressing SRSF1-Mediated Alternative Splicing of SLC39A14.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36062189","citation_count":4,"is_preprint":false},{"pmid":"38439666","id":"PMC_38439666","title":"The mechanism by which piR-000699 targets SLC39A14 regulates ferroptosis in aging myocardial ischemia/reperfusion injury.","date":"2024","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/38439666","citation_count":4,"is_preprint":false},{"pmid":"38573932","id":"PMC_38573932","title":"Genetic control of MRI contrast using the manganese transporter Zip14.","date":"2024","source":"Magnetic resonance in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38573932","citation_count":3,"is_preprint":false},{"pmid":"37990424","id":"PMC_37990424","title":"ZIP14 Affects the Proliferation, Apoptosis, and Migration of Cervical Cancer Cells by Regulating the P38 MAPK Pathway.","date":"2024","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/37990424","citation_count":3,"is_preprint":false},{"pmid":"35887381","id":"PMC_35887381","title":"Transcriptional Regulation and Protein Localization of Zip10, Zip13 and Zip14 Transporters of Freshwater Teleost Yellow Catfish Pelteobagrus fulvidraco Following Zn Exposure in a Heterologous HEK293T Model.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35887381","citation_count":3,"is_preprint":false},{"pmid":"39519408","id":"PMC_39519408","title":"ZIP8 Is Upregulated in the Testis of Zip14-/- Mice.","date":"2024","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/39519408","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52172,"output_tokens":9968,"usd":0.153018,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20846,"output_tokens":9162,"usd":0.16664,"stage2_stop_reason":"end_turn"},"total_usd":0.319658,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"ZIP14 (SLC39A14) is a plasma membrane-localized glycoprotein that functions as a zinc influx transporter in a temperature-dependent manner. The LZT metalloprotease motif (HEXPHEXGD) in transmembrane domain V is relevant to zinc transport, though ZIP14 lacks the initial histidine yet retains transport activity.\",\n      \"method\": \"Overexpression in cells with functional zinc transport assay (temperature-dependence), glycosylation analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, functional assay in overexpression system with glycosylation characterization, but limited mechanistic depth\",\n      \"pmids\": [\"15642354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-6 upregulates ZIP14 expression in liver, and this ZIP14 induction drives hepatic zinc import and contributes to hypozincemia during acute-phase inflammatory response. ZIP14 localizes to the plasma membrane of hepatocytes and increases zinc uptake when transfected into HEK cells.\",\n      \"method\": \"IL-6 knockout mouse model (turpentine inflammation, LPS), immunohistochemistry, transfection with 65Zn accumulation and fluorescent Zn probe, metallothionein mRNA induction\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model plus in vitro functional assays, multiple orthogonal methods, replicated across conditions\",\n      \"pmids\": [\"15863613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ZIP14 mediates cellular uptake of non-transferrin-bound iron (NTBI) as Fe2+ (inhibited by bathophenanthroline sulfonate, a cell-impermeant ferrous chelator) and zinc; overexpression in HEK 293H and Sf9 cells increases 65Zn and 59Fe uptake; siRNA knockdown in AML12 hepatocytes reduces both iron and zinc uptake.\",\n      \"method\": \"Overexpression in HEK 293H and Sf9 cells with radioisotope uptake (65Zn, 59Fe); siRNA knockdown in hepatocytes; ferrous chelator inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell systems (overexpression and knockdown), radioisotope transport assays, ferrous-specific chelator, replicated across labs\",\n      \"pmids\": [\"16950869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ZIP14A and ZIP14B (arising from alternative splicing of exons 4A/4B) function as metal/bicarbonate symporters transporting Cd2+, Mn2+, and Zn2+. ZIP14B has higher affinity than ZIP14A for Cd2+ (Km=0.14 vs 1.1 µM) and Mn2+ (Km=4.4 vs 18.2 µM). Uptake is dependent on extracellular HCO3-. ZIP14 is glycosylated and localizes to the apical surface of polarized MDCK cells.\",\n      \"method\": \"Stable retroviral-infected mouse fetal fibroblast cultures; transient transfection in MDCK polarized epithelial cells; kinetic uptake assays with Cd, Mn, Zn; HCO3- dependence; glycosylation analysis; subcellular localization\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — detailed kinetic characterization of two splice isoforms, multiple substrates, bicarbonate symporter mechanism established, localization confirmed in polarized cells\",\n      \"pmids\": [\"18270315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HFE (hereditary hemochromatosis protein) decreases ZIP14 protein levels post-translationally (without changing ZIP14 mRNA), shortening its half-life, thereby reducing both transferrin-bound and non-transferrin-bound iron uptake in HepG2 cells. ZIP14 knockdown abolishes HFE's effect on NTBI uptake.\",\n      \"method\": \"HFE overexpression in HepG2 and HeLa cells; siRNA knockdown of ZIP14; protein half-life/turnover assays; NTBI uptake assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal epistasis (HFE expression + ZIP14 knockdown), protein stability assays, multiple cell lines, consistent results\",\n      \"pmids\": [\"18524764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-1β upregulates ZIP14 expression and zinc transport in hepatocytes via inducible nitric oxide synthase (iNOS)-generated nitric oxide (NO). The NO donor SNAP increases Zip14 mRNA and transcriptional activity; ChIP showed AP-1 and RNA polymerase II association with Zip14 promoter after NO exposure; induction was absent in iNOS-/- hepatocytes.\",\n      \"method\": \"Primary hepatocyte culture with NO donor (SNAP); IL-1β treatment of WT and iNOS-/- hepatocytes; ChIP for AP-1 and RNA Pol II; zinc fluorophore transport assay; RT-PCR\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP mechanistic evidence, iNOS knockout epistasis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19179618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ZIP14 mediates cellular assimilation of iron from transferrin (transferrin-bound iron, TBI) via endosomal localization. ZIP14 is detected at the plasma membrane and in endosomes containing internalized transferrin in HepG2 cells; siRNA knockdown reduces iron assimilation from transferrin by 50% without affecting transferrin uptake; ZIP14 can transport iron at pH 6.5 (the endosomal pH where iron dissociates from transferrin).\",\n      \"method\": \"Targeted knock-in FLAG-tagged ZIP14 in HepG2 cells; confocal immunofluorescence; siRNA knockdown; iron assimilation assays; pH-dependent transport assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous tagged protein, confocal co-localization with transferrin endosomes, siRNA knockdown with quantitative iron assay, pH-dependence mechanistic study\",\n      \"pmids\": [\"20682781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SLC39A14/ZIP14 splicing is regulated by the Wnt/β-catenin pathway in colorectal cancer; β-catenin knockdown or dominant-negative TCF expression alters the exon 4A/4B isoform ratio. The splicing factors SRSF1 and its kinase SRPK1 mediate this regulation, with SRSF1 binding preferentially to exon 4B.\",\n      \"method\": \"β-catenin siRNA knockdown, dominant-negative TCF overexpression in DLD1 and Ls174T cells; siRNA knockdown of SRPK1 and SRSF1; exon array and RT-PCR; in silico splicing factor binding analysis\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations in multiple cell lines, but pathway placement relies partly on in silico prediction for SRSF1 binding site\",\n      \"pmids\": [\"20938052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZIP14 is a broad-scope metal-ion transporter that specifically transports Fe2+ (not Fe3+), with K0.5 ≈ 2 µM; transport is saturable, temperature-dependent, pH-sensitive, Ca2+-dependent, stimulated by HCO3-, and inhibited by Co2+, Mn2+, Zn2+. ZIP14 also transports Cd2+, Mn2+, Zn2+ (K0.5 ≈ 2 µM for Zn2+) but not Cu (I or II). The inhibition profiles and Ca2+ dependence differ between Fe2+ and Zn2+ transport.\",\n      \"method\": \"Xenopus laevis oocyte heterologous expression system; radioisotope transport assays (55Fe, 109Cd, 54Mn, 65Zn, 64Cu); kinetic analysis; temperature, pH, ion dependence assays\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous electrophysiological/transport reconstitution in Xenopus oocytes with full kinetic characterization, multiple substrates, multiple orthogonal parameters\",\n      \"pmids\": [\"21653899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SLC39A14/ZIP14 controls GPCR-mediated cAMP-CREB signaling by suppressing basal phosphodiesterase (PDE) activity. Zip14 KO mice show reduced cAMP due to increased PDE activity, causing impaired GPCR signaling in growth plate, pituitary, and liver, resulting in growth retardation and impaired gluconeogenesis.\",\n      \"method\": \"Slc39a14 knockout mouse model; cAMP measurement; PDE activity assay; CREB phosphorylation analysis; growth and gluconeogenesis phenotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with defined molecular phenotype (PDE activity, cAMP), but mechanistic link between zinc transport and PDE inhibition inferred rather than directly demonstrated\",\n      \"pmids\": [\"21445361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZIP14 localizes to the basolateral membrane of enterocytes and is present in endosomes; it is involved in endosomal trafficking of zinc. Zip14 KO mice show zinc trapped in endosomes and reduced threonine phosphorylation of tight junction protein occludin, impairing intestinal barrier function.\",\n      \"method\": \"Plasma membrane fractionation; endosome isolation; FluoZin-3AM fluorescence for endosomal zinc; intestinal permeability assays (FITC-dextran); occludin phosphorylation; claudin 1/2 expression\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation with functional consequence (barrier function), but single lab\",\n      \"pmids\": [\"25428902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZIP14 mediates hepatic zinc uptake during liver regeneration, inhibiting PTP1B phosphatase activity through increased intracellular zinc, which in turn enhances c-Met phosphorylation and hepatocyte proliferation. Zip14 KO mice fail to show increased hepatic zinc or hepatocyte proliferation after partial hepatectomy.\",\n      \"method\": \"Partial hepatectomy in WT and Zip14 KO mice; Zip14-overexpressing AML12 hepatocytes; PTP1B activity assay; c-Met phosphorylation; proliferation markers (PCNA, CyclinD1, Ki67); hepatic zinc measurement\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model plus cell overexpression with enzymatic (PTP1B) and signaling (c-Met phosphorylation) readouts, multiple orthogonal methods\",\n      \"pmids\": [\"22374166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZIP8 and ZIP14 both mediate apical uptake of Cd2+ and Mn2+ in kidney proximal tubule cells; siRNA knockdown of either reduces uptake from the apical membrane. ZIP8 and ZIP14 are expressed in the S3 segment of proximal tubules.\",\n      \"method\": \"siRNA knockdown of ZIP8, ZIP14, DMT1 in proximal tubule cell Transwell culture; apical/basolateral metal uptake assays; in situ hybridization\",\n      \"journal\": \"Metallomics : integrated biometal science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA in polarized cell culture with directional transport readout, but ZIP14 role partially overlapping with ZIP8\",\n      \"pmids\": [\"22534978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZIP14 in the Xenopus oocyte system mediates electroneutral divalent cation/bicarbonate symport (confirmed by electrogenicity studies using a potassium gradient). ZIP14A and ZIP14B show distinct metal-ion inhibition patterns for Cd and Zn uptake.\",\n      \"method\": \"Xenopus oocyte expression; Km/Vmax determination; electrogenicity studies with potassium gradient; competitive inhibition with 10 divalent cations\",\n      \"journal\": \"Metallomics : integrated biometal science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted transport in Xenopus oocytes with electrophysiological confirmation of electroneutrality, single lab but rigorous\",\n      \"pmids\": [\"23090441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZIP14 mediates zinc uptake in macrophages in response to LPS; Zip14 knockdown attenuates cytokine production, indicating ZIP14 has a buffering role in macrophage inflammatory responses. LPS induction of ZIP14 depends on calcium signaling, GC-rich DNA binding, and NF-κB downregulation.\",\n      \"method\": \"LPS treatment of primary human macrophages; siRNA knockdown; cytokine mRNA (RT-qPCR) and protein measurement; pharmacological inhibitors of calcium signaling and NF-κB\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary human macrophages with siRNA knockdown and cytokine readout, single lab\",\n      \"pmids\": [\"23052185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ZIP14 protein is localized to the basolateral membrane of hepatocytes and to acinar cells of the pancreas; its protein levels are upregulated in iron-loaded animals (post-translationally, as mRNA does not change with iron status), while DMT1 is regulated oppositely.\",\n      \"method\": \"Confocal immunofluorescence microscopy; immunoblotting; qRT-PCR in iron-deficient, adequate, and overloaded rats; hypotransferrinemic mice\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunofluorescence localization with iron-status manipulation, but post-translational regulation inferred from protein/mRNA discordance, single lab\",\n      \"pmids\": [\"23349308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZIP14 undergoes endocytosis, membrane extraction, deglycosylation, and proteasomal degradation via a pathway independent of ER-associated protein degradation (ERAD). Iron inhibits membrane extraction of internalized ZIP14, resulting in higher steady-state levels. N-linked glycosylation at N102 is required for efficient membrane extraction and iron-sensitive degradation of ZIP14.\",\n      \"method\": \"Inhibitor studies (proteasome inhibitors, retrograde trafficking inhibitors, bafilomycin); glycosylation mutants (N102 substitution); pulse-chase and protein stability assays; endocytosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis (N102), multiple inhibitors distinguishing pathways, mechanistic dissection of a novel degradation pathway\",\n      \"pmids\": [\"24927598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-6 upregulates ZIP14 in SH-SY5Y neuronal cells, increasing Mn2+ uptake; siRNA knockdown of ZIP14 reduces Mn2+ uptake. IL-6 also downregulates ZnT10, reducing Mn excretion. Combined effect enhances Mn accumulation in neuronal cells.\",\n      \"method\": \"siRNA knockdown of ZIP14, ZIP8, ZnT10 in SH-SY5Y cells; IL-6 treatment; Mn uptake assays; mRNA and protein quantification\",\n      \"journal\": \"Metallomics : integrated biometal science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with quantitative Mn uptake, single lab, two transporters examined\",\n      \"pmids\": [\"24576911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC39A14 ablation in mice markedly reduces NTBI uptake by liver and pancreas. In hemochromatosis mouse models (Hfe-/- and Hfe2-/-), Slc39a14 deficiency greatly diminishes hepatic and pancreatic iron loading and prevents iron deposition in hepatocytes and pancreatic acinar cells.\",\n      \"method\": \"Slc39a14 KO mice crossed with Hfe-/- and Hfe2-/- mice; plasma NTBI uptake measurements; tissue iron quantification; histology\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with hemochromatosis models, in vivo NTBI uptake measurements, replicated across two disease models\",\n      \"pmids\": [\"26028554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Prion protein (PrPC) functions as a ferrireductase partner for ZIP14 (and DMT1); coexpression of PrPC with ZIP14 in HepG2 cells increases uptake of Fe3+ (not Fe2+), suggesting PrPC reduces Fe3+ to Fe2+ for transport through ZIP14.\",\n      \"method\": \"PrPC knockout mice with 59Fe radiolabeling; HepG2 cell overexpression; ferric vs ferrous iron uptake assays; coexpression studies\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO and in vitro coexpression with mechanistic interpretation, but ferrireductase mechanism not directly proved by reconstitution\",\n      \"pmids\": [\"25862412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZIP14 is upregulated in cachectic skeletal muscles by TNF-α and TGF-β cytokines. ZIP14-mediated zinc uptake in muscle progenitor cells represses MyoD and Mef2c expression, blocking muscle-cell differentiation. In differentiated muscle cells, ZIP14-mediated zinc accumulation induces myosin heavy chain loss. Germline or muscle-specific Zip14 depletion reduces muscle atrophy in metastatic cancer models.\",\n      \"method\": \"Cancer cachexia mouse models (metastatic colon, lung, breast); germline and muscle-specific Zip14 KO; cytokine treatment (TNF-α, TGF-β); MyoD and Mef2c mRNA/protein; myosin heavy chain measurement; zinc measurement\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline and tissue-specific KO, cytokine induction, multiple cancer models, mechanistic link to MyoD/Mef2c suppression\",\n      \"pmids\": [\"29875463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZIP14 is localized on the plasma membrane of human β-cells (primary islets and βlox5 cell line) and mediates ~50% of NTBI uptake in these cells; siRNA knockdown of ZIP14 reduces NTBI uptake by 50% in both cell systems.\",\n      \"method\": \"siRNA knockdown in βlox5 cells and primary human islets; NTBI uptake assays; overexpression of ZIP14, ZIP8, DMT1; immunofluorescence\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown in two human cell systems (cell line and primary islets), quantitative iron uptake, but single lab\",\n      \"pmids\": [\"27903581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZIP14 undergoes sequential translocation from the plasma membrane to early and late endosomes during glucose uptake in hepatocytes. ZIP14-mediated zinc transport delivers zinc to endosomes where it supports activity of zinc-dependent insulin-degrading enzyme (IDE) and cathepsin D to regulate insulin receptor activity. Zip14 KO mice show zinc-deficient endosomes, impaired IDE/cathepsin D activity, enhanced insulin receptor signaling, increased glycogen synthesis, and impaired gluconeogenesis.\",\n      \"method\": \"Zip14 KO mouse hepatocytes; endosome fractionation; zinc measurement in endosomes; IDE and cathepsin D activity assays; insulin receptor phosphorylation; glycogen synthesis and gluconeogenesis assays; live cell imaging of ZIP14 localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — subcellular fractionation, enzymatic activity assays, KO model with specific metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"27703010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p53 interacts with ZIP14 protein, increases its ubiquitination, and promotes its degradation, thereby reducing ZIP14 protein levels post-translationally. Loss of p53 results in higher ZIP14 levels and increased NTBI uptake.\",\n      \"method\": \"Co-precipitation (p53-ZIP14 interaction); ubiquitination assay; p53 overexpression/knockdown; NTBI uptake assays; immunoblotting\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-precipitation showing direct interaction, ubiquitination assay, functional iron uptake consequence, single lab\",\n      \"pmids\": [\"29292794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hepatic ZIP14 mediates zinc import required for adaptation to ER stress; ZIP14-mediated zinc inhibits PTP1B activity to suppress apoptosis and steatosis. During ER stress, transcription factors ATF4 and ATF6α transcriptionally upregulate Zip14. Zip14 KO mice under ER stress show greater PTP1B activity, proapoptotic protein expression, and hepatic steatosis.\",\n      \"method\": \"Pharmacologic and HFD-induced ER stress in Zip14 KO mice; ATF4/ATF6α overexpression; PTP1B activity assay; apoptosis markers; steatosis quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse, transcription factor mechanistic studies, PTP1B enzyme activity assay, multiple ER stress models\",\n      \"pmids\": [\"28673968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Slc39a14 global knockout mice develop markedly increased Mn in brain and extrahepatic tissues with motor deficits reversible by Na2CaEDTA chelation. Hepatocyte-specific Slc39a14 KO mice do not accumulate Mn in brain under normal conditions, indicating hepatocyte-autonomous loss of ZIP14 is insufficient to cause brain Mn accumulation; non-hepatic ZIP14 expression is required to prevent systemic Mn overload.\",\n      \"method\": \"Global and hepatocyte-specific (Alb-Cre) Slc39a14 KO mice; ICP-MS for tissue metal levels; motor deficit assays; chelation rescue\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific vs global KO genetic epistasis, chelation rescue, ICP-MS quantification, clearly distinguishes organ-specific roles\",\n      \"pmids\": [\"28751976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZIP14 mediates Mn2+ uptake in brain microvascular endothelial cells (BMVECs) at both apical (blood) and basal (brain) sides, supporting bidirectional Mn flux across the blood-brain barrier. Knockdown of ZIP14 (and ZIP8) reduces Mn uptake; uptake is pH-, bicarbonate-, and LPS-dependent.\",\n      \"method\": \"siRNA knockdown of ZIP8 and ZIP14 in BMVECs; surface protein biotinylation; 54Mn uptake; kinetic analysis; LPS treatment; apical/basolateral transport assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA, surface biotinylation, directional transport, single lab\",\n      \"pmids\": [\"31699897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A dominant gain-of-function mutation (L441R) in ZIP14 prevents its trafficking to the plasma membrane and causes intracellular zinc accumulation, leading to hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts exhibit enhanced endosteal cortical bone formation with osteoporotic trabecular bone, causing Hyperostosis Cranialis Interna-like phenotype.\",\n      \"method\": \"Whole-exome sequencing (patient); conditional knock-in mouse (osteoblast-specific L438R); subcellular localization assay; zinc measurement; cAMP-CREB and NFAT signaling assays; bone histomorphometry\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knock-in mouse with defined signaling pathway activation, localization assay, intracellular zinc measurement, phenotypic validation\",\n      \"pmids\": [\"29621230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Intestinal ZIP14 acts primarily as a basolateral transporter in enterocytes that mediates direct basolateral reuptake of freshly absorbed manganese, thereby restricting net absorptive manganese transport. Loss of intestinal ZIP14 impairs secretory (basolateral-to-apical) Mn transport and enhances absorptive (apical-to-basolateral) Mn transport. Intestine-specific Zip14 KO mice accumulate Mn in liver and brain.\",\n      \"method\": \"CaCo-2 Transwell model; ZIP14-deficient CaCo-2 cells (CRISPR); directional Mn transport assays; intestine-specific Zip14 KO mice; ICP-MS\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene KO in polarized epithelial model, directional transport assays, in vivo tissue-specific KO confirmation\",\n      \"pmids\": [\"31028174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZIP14 in brain microvascular endothelial cells has plasma membrane occupancy regulated by cytoplasmic Ca2+ via the Golgi Ca2+-ATPase SPCA1. RNAi knockdown of SPCA1 increases cytoplasmic Ca2+, which enhances membrane localization of ZIP14 and increases 54Mn2+ uptake; SPCA1 overexpression has opposite effects.\",\n      \"method\": \"Surface protein biotinylation; indirect immunofluorescence; GFP-tagged proteins; SPCA1 RNAi knockdown; Ca2+ chelation; 54Mn2+ uptake assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — surface biotinylation, RNAi, functional Mn uptake assay, Ca2+ manipulation, single lab\",\n      \"pmids\": [\"35787370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZIP14 is degraded in response to Mn exposure via a lysosomal pathway (blocked by bafilomycin A1, which increased ZIP14 in LAMP1-positive vesicles), providing a cytoprotective feedback mechanism to limit Mn uptake. ZIP14 is localized to the basolateral surface of polarized HepaRG hepatocytes.\",\n      \"method\": \"Western blot and immunofluorescence in polarized HepaRG cells; 54Mn uptake (time- and temperature-dependent); bafilomycin A1 inhibition; LAMP1 co-localization\",\n      \"journal\": \"Biometals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization, degradation pathway pharmacologic dissection, transport kinetics, single lab\",\n      \"pmids\": [\"31541377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Zip14 deletion in skeletal muscle results in muscle wasting at basal steady state associated with increased p-Mef2c, Hspb7, p38 activation, and NF-κB binding to the Mef2c promoter. Zip14-mediated zinc uptake in muscle during LPS inflammation increases Atrogin1/MuRF1 and reduces MyoD (cachexia signatures). miR-675-3p and -5p induction by LPS is Zip14-dependent.\",\n      \"method\": \"Zip14 global KO mice; LPS-induced inflammation; microarray and qPCR; ChIP (NF-κB at Mef2c promoter); p38 phosphorylation; Atrogin1/MuRF1/MyoD protein levels\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with ChIP and pathway analysis, multiple markers, single lab\",\n      \"pmids\": [\"32132660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Enterocyte-specific ZIP14 ablation reduces HDAC3 (and total HDAC) activity, leading to epigenetic dysregulation of tight junction and cytokine genes (claudin 1, 2, IL-6, IFNγ). NF-κB, STAT3, and CDX2 show increased binding to promoters of dysregulated genes. Zinc supplementation of organoids from ΔIECZip14 mice restores differential gene expression.\",\n      \"method\": \"Enterocyte-specific Zip14 KO mice; RNA sequencing; ChIP for NF-κB, STAT3, CDX2; HDAC activity assays; intestinal organoids with zinc supplementation\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO, ChIP for multiple transcription factors, HDAC enzymatic activity, organoid rescue with zinc, multiple orthogonal methods\",\n      \"pmids\": [\"36537699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Combined intestinal and hepatic ZIP14 deletion (double KO) causes much greater manganese overload than single-tissue deletion alone, demonstrating that both intestinal and hepatic ZIP14 cooperate to maintain systemic Mn homeostasis.\",\n      \"method\": \"Intestine-specific, liver-specific, and double (intestine+liver) Zip14 KO mice; ICP-MS for tissue Mn\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple tissue-specific KO comparisons, ICP-MS quantification, genetic epistasis approach, single lab\",\n      \"pmids\": [\"35742937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In pancreatic β cells, ZIP14 localizes on the endoplasmic reticulum (not plasma membrane) and functions as a negative regulator of glucose-stimulated insulin secretion by regulating intracellular zinc trafficking. β cell-specific Zip14 KO mice show greater glucose-stimulated insulin secretion, increased energy expenditure, and on HFD develop greater islet hyperplasia and compensatory hyperinsulinemia.\",\n      \"method\": \"β cell-specific Zip14 KO mice; ZIP14 localization by immunofluorescence (co-staining with ER marker); glucose-stimulated insulin secretion (in vivo, ex vivo islets, MIN6 cells); zinc measurement; metabolic phenotyping\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with ER localization confirmed by immunofluorescence, functional insulin secretion assays in multiple systems, metabolic phenotyping\",\n      \"pmids\": [\"38019082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Enterocyte-specific ZIP14 deletion reduces cellular labile zinc, causing chromatin remodeling (closed chromatin at MHCII gene regulatory regions) and decreased expression of MHCII molecules and their master transactivator CIITA. Zinc supplementation of Zip14 KO organoids restores MHCII transcript levels.\",\n      \"method\": \"Enterocyte-specific Zip14 KO; RNA sequencing; ChIP with CIITA antibody; ATAC-seq; FluoZin-3 zinc measurement; organoid zinc supplementation rescue; western blot, immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ATAC-seq chromatin remodeling, ChIP, zinc measurement, organoid rescue, tissue-specific KO, multiple orthogonal methods\",\n      \"pmids\": [\"39793074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In liver fibrosis, zinc supplementation increases ZIP14 expression via MTF1 transcription factor binding to the ZIP14 promoter and reduction of HDAC4 binding, establishing an epigenetic mechanism by which zinc regulates ZIP14 expression in hepatocytes.\",\n      \"method\": \"CCl4-induced liver fibrosis mouse model; ZnCl2 treatment; ChIP for MTF1 and HDAC4 at ZIP14 promoter; ZIP14 expression; intracellular zinc measurement\",\n      \"journal\": \"Biological trace element research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating TF-promoter interactions, in vivo fibrosis model, single lab\",\n      \"pmids\": [\"38221603\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC39A14/ZIP14 is a plasma membrane- and endosome-localized metal-ion transporter that mediates cellular uptake of Fe2+, Zn2+, Mn2+, and Cd2+ via an electroneutral metal/bicarbonate symport mechanism; it is transcriptionally induced by IL-6 (via STAT3), IL-1β (via AP-1/nitric oxide), and ATF4/ATF6α (during ER stress), and is post-translationally regulated by iron (via a glycosylation-dependent proteasomal degradation pathway requiring N102 glycosylation), Mn exposure (lysosomal degradation), p53 (ubiquitination), and HFE (protein destabilization); in the liver ZIP14 drives NTBI and transferrin-derived iron uptake, suppresses PTP1B activity to promote c-Met signaling and hepatocyte proliferation, and delivers zinc to endosomes to regulate insulin receptor degradation and glucose homeostasis; in the intestine it localizes basolaterally to restrict Mn absorption and maintain intestinal barrier integrity through zinc-dependent HDAC activity and MHCII expression; in skeletal muscle, ZIP14-mediated zinc accumulation (induced by TNF-α/TGF-β in cancer) represses MyoD and Mef2c to block differentiation and cause cachexia; in pancreatic β cells ZIP14 is ER-localized and acts as a negative regulator of glucose-stimulated insulin secretion; loss-of-function mutations cause systemic hypermanganesemia with childhood-onset dystonia-parkinsonism due to failure to clear Mn from the circulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC39A14/ZIP14 is a broad-scope divalent metal-ion transporter that mediates cellular uptake of Fe2+, Zn2+, Mn2+, and Cd2+ through an electroneutral metal/bicarbonate symport mechanism, operating at the plasma membrane and within endosomes to govern systemic metal homeostasis [#3, #8, #13]. It transports ferrous (but not ferric) iron and is responsible for non-transferrin-bound iron uptake as well as assimilation of transferrin-derived iron at endosomal pH, with prion protein serving as a ferrireductase partner that supplies Fe2+ from Fe3+ [#2, #6, #19]. In the liver, ZIP14 drives NTBI uptake and delivers zinc that inhibits PTP1B to enhance c-Met signaling and hepatocyte proliferation, supports adaptation to ER stress, and traffics through endosomes to supply zinc-dependent insulin-degrading enzyme and cathepsin D, thereby regulating insulin receptor turnover and glucose homeostasis [#11, #22, #24]. ZIP14 expression is induced by inflammatory signals — IL-6 in liver, IL-1\\u03b2 via iNOS-derived nitric oxide and AP-1, and ATF4/ATF6\\u03b1 during ER stress — and is post-translationally controlled by iron through an N102-glycosylation-dependent membrane-extraction and proteasomal degradation pathway, by Mn through lysosomal degradation, by p53-mediated ubiquitination, and by HFE-mediated destabilization [#1, #5, #16, #18, #23, #24, #30, #4]. In the intestine ZIP14 localizes basolaterally to restrict net manganese absorption and to supply labile zinc that sustains HDAC activity, tight-junction integrity, and MHCII/CIITA expression, while in skeletal muscle ZIP14-mediated zinc accumulation represses MyoD and Mef2c to block myogenesis and drive cancer cachexia [#28, #32, #35, #20]. Loss of ZIP14 across intestinal, hepatic, and non-hepatic tissues causes systemic manganese overload with brain accumulation and motor deficits, and a dominant gain-of-function mutation trapping ZIP14 intracellularly causes a hyperostosis bone phenotype through cAMP-CREB/NFAT activation [#25, #28, #33, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established ZIP14 as a functional plasma-membrane zinc influx transporter and linked it to inflammation-driven hypozincemia, defining a first physiological context.\",\n      \"evidence\": \"Overexpression zinc-transport assays plus IL-6 knockout mouse and hepatocyte transfection\",\n      \"pmids\": [\"15642354\", \"15863613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish substrate breadth beyond zinc\", \"Transcription factor mediating IL-6 induction not yet defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed ZIP14 transports non-transferrin-bound iron as Fe2+ in addition to zinc, expanding it from a zinc transporter to a multi-metal transporter.\",\n      \"evidence\": \"Radioisotope uptake in HEK293H and Sf9 overexpression and hepatocyte siRNA knockdown with ferrous chelator\",\n      \"pmids\": [\"16950869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine kinetics or full metal selectivity\", \"Did not address transferrin-bound iron pathway\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the transport mechanism as metal/bicarbonate symport and characterized two splice isoforms (ZIP14A/B) with distinct Cd2+/Mn2+ affinities, establishing the biochemical basis of substrate handling.\",\n      \"evidence\": \"Kinetic uptake assays of two isoforms in fibroblasts and polarized MDCK cells with HCO3- dependence\",\n      \"pmids\": [\"18270315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological roles of isoform differences not addressed\", \"Electroneutrality not yet proven electrophysiologically\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified HFE as a post-translational destabilizer of ZIP14 that reduces both TBI and NTBI uptake, connecting ZIP14 to hereditary hemochromatosis regulation.\",\n      \"evidence\": \"HFE overexpression plus ZIP14 siRNA epistasis and protein half-life assays in HepG2/HeLa cells\",\n      \"pmids\": [\"18524764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of HFE-mediated destabilization not resolved\", \"Direct HFE-ZIP14 interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a second inflammatory induction route, showing IL-1\\u03b2 induces ZIP14 via iNOS-derived NO acting through AP-1 at the promoter.\",\n      \"evidence\": \"NO donor and iNOS-/- hepatocytes with ChIP for AP-1 and RNA Pol II\",\n      \"pmids\": [\"19179618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link induction to downstream metal-dependent function\", \"AP-1 subunit identity not specified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed ZIP14 assimilates transferrin-derived iron from endosomes at acidic pH, revealing an endosomal arm of its iron-handling role beyond plasma-membrane NTBI uptake.\",\n      \"evidence\": \"FLAG knock-in HepG2 cells, confocal co-localization with transferrin endosomes, siRNA, pH-dependent transport\",\n      \"pmids\": [\"20682781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endosomal recruitment mechanism not defined\", \"Quantitative contribution versus DMT1 not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected ZIP14 isoform splicing to Wnt/\\u03b2-catenin signaling via SRSF1/SRPK1 in colorectal cancer, linking transporter isoform choice to an oncogenic pathway.\",\n      \"evidence\": \"\\u03b2-catenin and TCF perturbation plus SRSF1/SRPK1 knockdown and exon arrays in colon cancer lines\",\n      \"pmids\": [\"20938052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SRSF1 binding partly in silico predicted\", \"Functional metal-transport consequence of isoform switch not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided rigorous reconstituted kinetics establishing ZIP14 selectivity (Fe2+, Zn2+, Cd2+, Mn2+ but not Cu) and ion dependencies, giving a definitive biophysical substrate map.\",\n      \"evidence\": \"Xenopus oocyte heterologous expression with multi-isotope kinetic and ion-dependence analysis\",\n      \"pmids\": [\"21653899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of selectivity unknown\", \"Differing Fe2+ vs Zn2+ inhibition profiles mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked ZIP14 to GPCR cAMP-CREB signaling via suppression of phosphodiesterase activity, implicating it in growth and gluconeogenesis phenotypes.\",\n      \"evidence\": \"Slc39a14 KO mice with cAMP, PDE activity, and CREB phosphorylation readouts\",\n      \"pmids\": [\"21445361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from zinc transport to PDE inhibition inferred not shown\", \"Which PDE isoform involved unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established hepatic ZIP14 as a driver of regeneration by importing zinc to inhibit PTP1B and enhance c-Met signaling, defining a signaling-via-metal mechanism.\",\n      \"evidence\": \"Partial hepatectomy in Zip14 KO mice plus hepatocyte overexpression with PTP1B activity and c-Met phosphorylation\",\n      \"pmids\": [\"22374166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct zinc-PTP1B inhibition in vivo not quantified\", \"Endosomal versus cytosolic zinc pool not distinguished\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped intestinal and renal localization, showing basolateral enterocyte and apical proximal-tubule roles in metal transport, and demonstrated endosomal zinc trafficking required for barrier integrity.\",\n      \"evidence\": \"Fractionation, FluoZin imaging, permeability and occludin assays in Zip14 KO intestine; siRNA in proximal tubule Transwell\",\n      \"pmids\": [\"25428902\", \"22534978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overlap with ZIP8 not fully resolved\", \"Mechanism of occludin phosphorylation regulation not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed electroneutral divalent-cation/bicarbonate symport electrophysiologically and showed isoform-specific inhibition patterns, finalizing the transport mechanism.\",\n      \"evidence\": \"Xenopus oocyte electrogenicity studies with potassium gradient and competitive inhibition\",\n      \"pmids\": [\"23090441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of metal:bicarbonate not precisely fixed\", \"Structural transporter model absent\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed ZIP14 buffers macrophage inflammatory responses through LPS-induced zinc uptake, broadening its role to innate immunity.\",\n      \"evidence\": \"LPS treatment and siRNA in primary human macrophages with cytokine readouts and pathway inhibitors\",\n      \"pmids\": [\"23052185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcription factor at promoter not pinned\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated iron-status-dependent post-translational upregulation of ZIP14 protein (opposite to DMT1), establishing iron as a regulator of transporter abundance.\",\n      \"evidence\": \"Immunofluorescence and immunoblotting versus qRT-PCR across iron-status rat and hypotransferrinemic models\",\n      \"pmids\": [\"23349308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation mechanism not yet defined here\", \"mRNA/protein discordance only correlative\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the iron-sensitive degradation pathway: endocytosis, N102-glycosylation-dependent membrane extraction, deglycosylation, and ERAD-independent proteasomal degradation, explaining iron-regulated ZIP14 stability.\",\n      \"evidence\": \"Inhibitor panels, N102 glycosylation mutants, pulse-chase and endocytosis assays\",\n      \"pmids\": [\"24927598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase mediating degradation not identified\", \"How iron blocks membrane extraction mechanistically unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended IL-6 induction of ZIP14 to neuronal cells, where it raises Mn uptake while ZnT10 downregulation limits efflux, implicating ZIP14 in neuronal Mn accumulation.\",\n      \"evidence\": \"siRNA and IL-6 treatment with Mn uptake assays in SH-SY5Y cells\",\n      \"pmids\": [\"24576911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo neuronal relevance not tested\", \"Transcription factor for neuronal IL-6 induction unspecified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo that ZIP14 is the major route of hepatic/pancreatic NTBI loading and is required for iron deposition in hemochromatosis models, establishing it as a therapeutic node in iron overload.\",\n      \"evidence\": \"Slc39a14 KO crossed with Hfe-/- and Hfe2-/- mice with in vivo NTBI uptake and tissue iron histology\",\n      \"pmids\": [\"26028554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address extrahepatic iron handling\", \"Contribution to systemic iron balance versus other transporters not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified prion protein as a ferrireductase partner supplying Fe2+ to ZIP14, providing a mechanism for ferric iron utilization.\",\n      \"evidence\": \"PrPC KO mice and HepG2 coexpression with ferric versus ferrous uptake\",\n      \"pmids\": [\"25862412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ferrireductase activity not proven by reconstitution\", \"Physical PrPC-ZIP14 interaction not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed ZIP14-mediated endosomal zinc delivery controls insulin receptor degradation via IDE and cathepsin D, mechanistically connecting ZIP14 trafficking to glucose homeostasis.\",\n      \"evidence\": \"Zip14 KO hepatocytes with endosome fractionation, IDE/cathepsin D activity, insulin receptor signaling and metabolic assays\",\n      \"pmids\": [\"27703010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for plasma-membrane-to-endosome translocation unresolved\", \"Direct zinc loading of IDE not demonstrated structurally\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed ZIP14 contributes ~50% of \\u03b2-cell NTBI uptake, extending its iron role to islet cells.\",\n      \"evidence\": \"siRNA and overexpression with NTBI uptake in \\u03b2lox5 cells and primary human islets\",\n      \"pmids\": [\"27903581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for \\u03b2-cell iron physiology not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified ZIP14 as a driver of cancer cachexia, where cytokine-induced zinc accumulation represses MyoD/Mef2c to block myogenesis, providing a metal-dependent atrophy mechanism.\",\n      \"evidence\": \"Germline and muscle-specific Zip14 KO across multiple metastatic cancer models with cytokine treatment and myogenic marker analysis\",\n      \"pmids\": [\"29875463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How zinc represses MyoD/Mef2c mechanistically not fully defined\", \"Therapeutic window in humans not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established ZIP14 as required for hepatic ER-stress adaptation, with ATF4/ATF6\\u03b1 driving its transcription and ZIP14-zinc suppressing PTP1B to limit apoptosis and steatosis.\",\n      \"evidence\": \"ER-stress Zip14 KO mice with ATF4/ATF6\\u03b1 overexpression, PTP1B activity, apoptosis and steatosis readouts\",\n      \"pmids\": [\"28673968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ATF binding sites on Zip14 promoter not mapped here\", \"Relationship to inflammatory induction routes unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified p53 as a binding partner promoting ZIP14 ubiquitination and degradation, adding a tumor-suppressor-linked layer of post-translational control over iron uptake.\",\n      \"evidence\": \"Co-precipitation, ubiquitination assay, p53 perturbation with NTBI uptake\",\n      \"pmids\": [\"29292794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase recruited by p53 not identified\", \"Direct versus indirect interaction not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished organ-specific Mn-clearance roles, showing global but not hepatocyte-specific Zip14 loss causes brain Mn accumulation, establishing that non-hepatic ZIP14 prevents systemic Mn overload and underlies the hypermanganesemia-dystonia disease.\",\n      \"evidence\": \"Global and hepatocyte-specific Slc39a14 KO mice with ICP-MS, motor assays, chelation rescue\",\n      \"pmids\": [\"28751976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the critical non-hepatic tissue not yet pinpointed here\", \"Mechanism of Mn excretion downstream of uptake not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a dominant gain-of-function mutation (L441R) trapping ZIP14 intracellularly to cause zinc accumulation and cAMP-CREB/NFAT hyperactivation, producing a hyperostosis bone phenotype and revealing trafficking-dependent signaling control.\",\n      \"evidence\": \"Patient exome sequencing and osteoblast-specific L438R knock-in mice with localization, zinc, and signaling assays\",\n      \"pmids\": [\"29621230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How intracellular zinc activates CREB/NFAT mechanistically unresolved\", \"Relationship to loss-of-function Mn phenotype not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed ZIP14 mediates bidirectional Mn flux across the blood-brain barrier with pH/bicarbonate/LPS dependence, situating it in CNS metal entry.\",\n      \"evidence\": \"siRNA, surface biotinylation, and directional 54Mn uptake in brain microvascular endothelial cells\",\n      \"pmids\": [\"31699897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Net directional contribution in vivo not established\", \"Overlap with ZIP8 not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified intestinal basolateral ZIP14 as the gatekeeper restricting net Mn absorption, with loss causing hepatic and brain Mn accumulation.\",\n      \"evidence\": \"CRISPR ZIP14-deficient CaCo-2 Transwell directional transport and intestine-specific Zip14 KO mice with ICP-MS\",\n      \"pmids\": [\"31028174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination with hepatic clearance not yet tested\", \"Mn re-secretion route into lumen not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed Mn-induced lysosomal degradation of ZIP14 provides cytoprotective feedback limiting Mn uptake, complementing the iron-sensitive proteasomal route.\",\n      \"evidence\": \"Bafilomycin inhibition, LAMP1 co-localization and Mn uptake in polarized HepaRG cells\",\n      \"pmids\": [\"31541377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger sensing Mn for lysosomal targeting unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated SPCA1-controlled cytoplasmic Ca2+ regulates ZIP14 plasma-membrane occupancy and Mn uptake, adding a calcium-dependent trafficking control.\",\n      \"evidence\": \"Surface biotinylation, SPCA1 RNAi, Ca2+ chelation and 54Mn uptake in brain endothelial cells\",\n      \"pmids\": [\"35787370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from Ca2+ to ZIP14 trafficking unknown\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed ZIP14 has a basal homeostatic role in skeletal muscle, with deletion causing wasting via Mef2c/p38/NF-\\u03baB dysregulation and inflammatory zinc uptake driving atrophy gene signatures.\",\n      \"evidence\": \"Zip14 KO mice with LPS challenge, microarray, ChIP at Mef2c promoter, and atrophy marker analysis\",\n      \"pmids\": [\"32132660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of basal protective role with cachexia-driving role incomplete\", \"miRNA mechanism downstream not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked intestinal ZIP14-supplied zinc to HDAC3 activity and epigenetic control of barrier and cytokine genes, defining a zinc-to-chromatin axis in gut homeostasis.\",\n      \"evidence\": \"Enterocyte-specific Zip14 KO with RNA-seq, ChIP for NF-\\u03baB/STAT3/CDX2, HDAC activity, and zinc-rescue organoids\",\n      \"pmids\": [\"36537699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How labile zinc tunes HDAC3 activity mechanistically unresolved\", \"Causal chain to disease phenotype not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed intestinal and hepatic ZIP14 cooperate, with double deletion causing far greater Mn overload than single-tissue loss, defining a multi-organ clearance system.\",\n      \"evidence\": \"Intestine-, liver-, and double-tissue Slc39a14 KO mice with ICP-MS\",\n      \"pmids\": [\"35742937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative partition between organs not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-canonical ER-localized ZIP14 in pancreatic \\u03b2 cells acting as a negative regulator of glucose-stimulated insulin secretion, distinguishing it from plasma-membrane ZIP14 roles.\",\n      \"evidence\": \"\\u03b2 cell-specific Zip14 KO with ER co-localization, insulin secretion in vivo/ex vivo/MIN6, and metabolic phenotyping\",\n      \"pmids\": [\"38019082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ER zinc trafficking restrains secretion unresolved\", \"Relationship to hepatic glucose roles not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected intestinal ZIP14-supplied labile zinc to chromatin accessibility at MHCII loci and CIITA expression, extending the zinc-chromatin axis to mucosal immune gene regulation.\",\n      \"evidence\": \"Enterocyte-specific Zip14 KO with ATAC-seq, CIITA ChIP, zinc measurement and organoid zinc rescue\",\n      \"pmids\": [\"39793074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct zinc-dependent factor controlling chromatin not identified\", \"Functional immune consequence in vivo not fully tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a feedforward transcriptional loop in which zinc increases ZIP14 via MTF1 binding and HDAC4 release at the promoter in liver fibrosis.\",\n      \"evidence\": \"CCl4 fibrosis model with ZnCl2 treatment and ChIP for MTF1/HDAC4 at the ZIP14 promoter\",\n      \"pmids\": [\"38221603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution to fibrosis outcome not established\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZIP14 trafficking between plasma membrane, endosomes, and ER is selected in a tissue-specific manner, and the structural basis of its metal selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the transporter exists in the corpus\", \"Signals directing ER versus plasma-membrane localization across cell types unknown\", \"The E3 ligases and sensors coupling iron/Mn levels to degradation are not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 3, 6, 8, 13]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [3, 8, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 6, 21, 26]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 10, 16, 22]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 3, 6, 8, 18, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 22, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HFE\", \"PrPC\", \"TP53\", \"PTP1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}