{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T12:49:39Z","timestamp":1782305379631,"version":"3.54.5"},"reference-count":60,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIAID","award":["R21AI152017"],"award-info":[{"award-number":["R21AI152017"]}]},{"name":"NIH","award":["2R01-DK091281"],"award-info":[{"award-number":["2R01-DK091281"]}]},{"name":"NIH","award":["1R01AI153314-01"],"award-info":[{"award-number":["1R01AI153314-01"]}]},{"name":"NIH","award":["1R01DK138456-01"],"award-info":[{"award-number":["1R01DK138456-01"]}]},{"name":"Swiss National Science Foundation Advanced Postdoctoral Mobility Grant","award":["177932"],"award-info":[{"award-number":["177932"]}]},{"name":"UCR-City of Hope CUBRI Award","award":["2016"],"award-info":[{"award-number":["2016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). Iron deficiency is the most frequent cause of anemia in IBD; however, the mechanisms involved are still poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), in regulating iron homeostasis. Proteomic analyses were performed on serum from IBD patients genotyped for the IBD-associated loss-of-function rs1893217 PTPN2 variant. Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) mice were analyzed for iron content, blood parameters, and expression of iron handling proteins. Iron absorption was assessed through radiotracer assays. Serum proteomic analyses revealed that the \u201ciron homeostasis signaling pathway\u201d was the main pathway downregulated in Crohn\u2019s disease (CD) patients carrying the PTPN2 risk allele, independent of disease activity. Ptpn2-KO mice showed characteristics of anemia, including reduced hemoglobin concentrations along with serum and tissue iron deficiency and elevated serum hepcidin levels vs. Ptpn2-WT and Het mice. 55Fe absorption via oral gavage was significantly impaired in Ptpn2-KO mice. Correspondingly, Ptpn2-KO mice showed reduced apical membrane expression of the iron transporter DMT1. CD patients with the PTPN2 loss-of-function rs1893217 variant display alterations in serum iron handling proteins. Loss of Ptpn2 in mice caused features of anemia, including iron deficiency associated with reduced apical membrane expression of DMT1. These findings identify an important role for PTPN2 in regulating systemic iron homeostasis.<\/jats:p>","DOI":"10.3390\/ijms26073356","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T06:52:56Z","timestamp":1743749576000},"page":"3356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["PTPN2 Regulates Iron Handling Protein Expression in Inflammatory Bowel Disease Patients and Prevents Iron Deficiency in Mice"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1719-1387","authenticated-orcid":false,"given":"Hillmin","family":"Lei","sequence":"first","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Shawki","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina N.","family":"Santos","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2030-0268","authenticated-orcid":false,"given":"Vinicius","family":"Canale","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1062-5189","authenticated-orcid":false,"given":"Salomon","family":"Manz","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"},{"name":"Department of Gastroenterology & Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1766-3751","authenticated-orcid":false,"given":"Meli\u2019sa S.","family":"Crawford","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pritha","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4498-0058","authenticated-orcid":false,"given":"Marianne R.","family":"Spalinger","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"},{"name":"Department of Gastroenterology & Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Scharl","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology & Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-0802","authenticated-orcid":false,"given":"Declan F.","family":"McCole","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S2468-1253(19)30333-4","article-title":"The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"5","author":"Alatab","year":"2020","journal-title":"Lancet Gastroenterol. 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