{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T16:32:53Z","timestamp":1769185973412,"version":"3.49.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Michigan Medical School Research Scouts Scholar program","award":["U096298"],"award-info":[{"award-number":["U096298"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: The hepcidin\u2013ferroportin (Fpn1) axis is central to intestinal iron absorption, and dysregulation of this axis underlies all known forms of iron disorders. Hemochromatosis, the most common iron overload disorder in humans, results from systemic iron accumulation due to decades of uncontrolled intestinal absorption. Despite major advances in medicine in recent years, strategies for iron overload management are still lagging as they primarily rely on iron chelation and repeated phlebotomies. Fpn1, the cellular iron exporter, is ubiquitously expressed and plays a critical role in maintaining systemic iron homeostasis. Methods: To investigate the specific contribution of intestinal Fpn1 to systemic iron overload, we employed a CRISPR-based adenoviral hepcidin knockout mediated mouse iron overload model, combined with intestine-specific deletion of Fpn1. Results: An initial time-dependent experiment establishes the efficiency of hepcidin knockout (KO) by as early as 1 week of adenovirus injection. At 2 weeks of injection, a perfect reciprocal relationship between hepcidin gene suppression and liver iron levels (5\u20137-fold induction from the baseline) was established. Finally, intestine-specific Fpn1 deletion effectively prevented iron accumulation in hepcidin KO mice, as evidenced by nearly 4-fold lower liver iron levels compared to hepcidin KO animals with intact intestinal Fpn1. Conclusions: In summary, our results demonstrate that ablation of intestinal Fpn1 is sufficient to attenuate systemic iron accumulation in this mouse model of hemochromatosis. These findings suggest that selective targeting of intestinal Fpn1 may represent a promising strategy for the management of iron overload.<\/jats:p>","DOI":"10.3390\/nu18020352","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T14:58:40Z","timestamp":1769180320000},"page":"352","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intestine-Specific Ferroportin Ablation Rescues from Systemic Iron Overload in Mice"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6125-1813","authenticated-orcid":false,"given":"Cristina","family":"Castillo","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"Gim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5652-1134","authenticated-orcid":false,"given":"Nupur K.","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1559S","DOI":"10.3945\/ajcn.117.155804","article-title":"Current understanding of iron homeostasis","volume":"106","author":"Anderson","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1146\/annurev-nutr-062320-112625","article-title":"Molecular Mechanisms of Iron and Heme Metabolism","volume":"42","author":"Dutt","year":"2022","journal-title":"Annu. Rev. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2016.12.034","article-title":"A Red Carpet for Iron Metabolism","volume":"168","author":"Muckenthaler","year":"2017","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.bbadis.2015.03.011","article-title":"An overview of molecular basis of iron metabolism regulation and the associated pathologies","volume":"1852","author":"Silva","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.cmet.2008.12.012","article-title":"Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency","volume":"9","author":"Shah","year":"2009","journal-title":"Cell Metab."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Nemeth, E., and Ganz, T. (2021). Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126493"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/bs.vh.2019.01.002","article-title":"Hepcidin-ferroportin axis in health and disease","volume":"110","author":"Ginzburg","year":"2019","journal-title":"Vitam. Horm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3324\/haematol.2019.232124","article-title":"Iron metabolism and iron disorders revisited in the hepcidin era","volume":"105","author":"Camaschella","year":"2020","journal-title":"Haematologica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1002\/hep4.2012","article-title":"Iron overload disorders","volume":"6","author":"Hsu","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.bbamcr.2006.05.013","article-title":"Hereditary hemochromatosis","volume":"1763","author":"Pietrangelo","year":"2006","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.cmet.2005.01.003","article-title":"The iron exporter ferroportin\/Slc40a1 is essential for iron homeostasis","volume":"1","author":"Donovan","year":"2005","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.cmet.2015.09.006","article-title":"Ironing out Ferroportin","volume":"22","author":"Drakesmith","year":"2015","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.bbamcr.2012.01.014","article-title":"Hepcidin and iron homeostasis","volume":"1823","author":"Ganz","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pantopoulos, K. (2018). Inherited Disorders of Iron Overload. Front. Nutr., 5.","DOI":"10.3389\/fnut.2018.00103"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1146\/annurev-med-050109-142444","article-title":"Hepcidin and disorders of iron metabolism","volume":"62","author":"Ganz","year":"2011","journal-title":"Annu. Rev. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.3324\/haematol.2017.170720","article-title":"Ferroportin disease: Pathogenesis, diagnosis and treatment","volume":"102","author":"Pietrangelo","year":"2017","journal-title":"Haematologica"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1182\/blood-2018-06-856500","article-title":"Anemia of inflammation","volume":"133","author":"Weiss","year":"2019","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1172\/JCI122359","article-title":"Hepatic hepcidin\/intestinal HIF-2alpha axis maintains iron absorption during iron deficiency and overload","volume":"129","author":"Schwartz","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1182\/blood.2021013452","article-title":"Modulation of the HIF2alpha-NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis","volume":"139","author":"Das","year":"2022","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.cmet.2019.10.005","article-title":"Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis","volume":"31","author":"Das","year":"2020","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E4922","DOI":"10.1073\/pnas.1314197110","article-title":"Intestinal HIF2alpha promotes tissue-iron accumulation in disorders of iron overload with anemia","volume":"110","author":"Anderson","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1136\/bmj.331.7521.903","article-title":"Standard deviations and standard errors","volume":"331","author":"Altman","year":"2005","journal-title":"bmj"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1002\/hem3.147","article-title":"The oral ferroportin inhibitor vamifeport prevents liver iron overload in a mouse model of hemochromatosis","volume":"8","author":"Nyffenegger","year":"2024","journal-title":"Hemasphere"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1080\/17474086.2021.1935854","article-title":"Oral ferroportin inhibitor vamifeport for improving iron homeostasis and erythropoiesis in beta-thalassemia: Current evidence and future clinical development","volume":"14","author":"Porter","year":"2021","journal-title":"Expert Rev. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1146\/annurev-med-043021-032816","article-title":"Hepcidin and Iron in Health and Disease","volume":"74","author":"Nemeth","year":"2023","journal-title":"Annu. Rev. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1126\/science.1104742","article-title":"Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization","volume":"306","author":"Nemeth","year":"2004","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1096\/fj.14-251520","article-title":"Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice","volume":"28","author":"Aslam","year":"2014","journal-title":"FASEB J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1182\/blood.2023020504","article-title":"The iron chaperone poly(rC)-binding protein 1 regulates iron efflux through intestinal ferroportin in mice","volume":"142","author":"Wang","year":"2023","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14991","DOI":"10.1074\/jbc.RA119.009578","article-title":"A genetic mouse model of severe iron deficiency anemia reveals tissue-specific transcriptional stress responses and cardiac remodeling","volume":"294","author":"Schwartz","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C477","DOI":"10.1152\/ajpcell.00168.2009","article-title":"Iron supply determines apical\/basolateral membrane distribution of intestinal iron transporters DMT1 and ferroportin 1","volume":"298","author":"Nunez","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1053\/j.gastro.2011.03.007","article-title":"Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice","volume":"140","author":"Taylor","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/s42255-021-00406-7","article-title":"Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells","volume":"3","author":"Schwartz","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1126\/science.aau6481","article-title":"Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing","volume":"368","author":"Bessman","year":"2020","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1016\/j.cgh.2024.10.041","article-title":"Diagnosis and Treatment of Hemochromatosis","volume":"23","author":"Adams","year":"2025","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Katsarou, A., and Pantopoulos, K. (2018). Hepcidin Therapeutics. Pharmaceuticals, 11.","DOI":"10.3390\/ph11040127"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.14309\/ajg.0000000000000315","article-title":"ACG Clinical Guideline: Hereditary Hemochromatosis","volume":"114","author":"Kowdley","year":"2019","journal-title":"Am. J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.hoc.2013.11.004","article-title":"Modulation of hepcidin as therapy for primary and secondary iron overload disorders: Preclinical models and approaches","volume":"28","author":"Schmidt","year":"2014","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/ng1150","article-title":"Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis","volume":"34","author":"Nicolas","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4880","DOI":"10.1172\/JCI57693","article-title":"Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload","volume":"121","author":"Preza","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1182\/blood-2012-07-440743","article-title":"Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis","volume":"120","author":"Ramos","year":"2012","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1182\/blood-2017-11-737411","article-title":"Hepcidin agonists as therapeutic tools","volume":"131","author":"Casu","year":"2018","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/S2468-1253(23)00250-9","article-title":"Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: An open-label, multicentre, proof-of-concept phase 2 trial","volume":"8","author":"Kowdley","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.3324\/haematol.2022.282328","article-title":"Ferroportin inhibitor vamifeport ameliorates ineffective erythropoiesis in a mouse model of beta-thalassemia with blood transfusions","volume":"108","author":"Kalleda","year":"2023","journal-title":"Haematologica"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Vlasveld, L.T., Janssen, R., Bardou-Jacquet, E., Venselaar, H., Hamdi-Roze, H., Drakesmith, H., and Swinkels, D.W. (2019). Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features. Pharmaceuticals, 12.","DOI":"10.3390\/ph12030132"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1182\/blood-2013-08-522466","article-title":"Anti-hepcidin therapy for iron-restricted anemias","volume":"122","author":"Nemeth","year":"2013","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Poli, M., Asperti, M., Ruzzenenti, P., Regoni, M., and Arosio, P. (2014). Hepcidin antagonists for potential treatments of disorders with hepcidin excess. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00086"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4977","DOI":"10.1182\/blood-2011-03-345066","article-title":"Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats","volume":"118","author":"Theurl","year":"2011","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/ajh.27578","article-title":"A Recombinant Antibody Against ALK2 Promotes Tissue Iron Redistribution and Contributes to Anemia Resolution in a Mouse Model of Anemia of Inflammation","volume":"100","author":"Wang","year":"2025","journal-title":"Am. J. Hematol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1124\/mol.112.083428","article-title":"High-throughput screening of small molecules identifies hepcidin antagonists","volume":"83","author":"Fung","year":"2013","journal-title":"Mol. Pharmacol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/2\/352\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T15:01:25Z","timestamp":1769180485000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/2\/352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,22]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["nu18020352"],"URL":"https:\/\/doi.org\/10.3390\/nu18020352","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,22]]}}}