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As there is a growing interest in the role of iron in modulating key BBB proteins, this study assessed the effect of iron on the expression and function of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and claudin-5 in primary mouse brain endothelial cells (MBECs) and their abundance in mouse brain microvessel-enriched membrane fractions (MVEFs).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Following a 48\u00a0h treatment with ferric ammonium citrate (FAC, 250\u00a0\u00b5M), MBEC protein abundance (P-gp, BCRP and claudin-5) and mRNA (<jats:italic>abcb1a<\/jats:italic>, <jats:italic>abcg2<\/jats:italic>, and <jats:italic>cldn5)<\/jats:italic> were assessed by western blotting and RT-qPCR, respectively. Protein function was evaluated by assessing transport of substrates <jats:sup>3<\/jats:sup>H-digoxin (P-gp), <jats:sup>3<\/jats:sup>H-prazosin (BCRP) and <jats:sup>14<\/jats:sup>C-sucrose (paracellular permeability). C57BL\/6 mice received iron dextran (100\u00a0mg\/kg, intraperitoneally) over 4\u00a0weeks, and MVEF protein abundance and iron levels (in\u00a0MVEFs\u00a0and plasma) were quantified via western blotting and inductively coupled plasma-mass spectrometry (ICP-MS), respectively.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>FAC treatment reduced P-gp protein by 50% and <jats:italic>abcb1a<\/jats:italic> mRNA by 43%, without affecting <jats:sup>3<\/jats:sup>H-digoxin transport. FAC did not alter BCRP protein or function, but decreased <jats:italic>abcg2<\/jats:italic> mRNA by 59%. FAC reduced claudin-5 protein and <jats:italic>cldn5<\/jats:italic> mRNA by 65% and 70%, respectively, resulting in a 200% increase in <jats:sup>14<\/jats:sup>C-sucrose permeability. <jats:italic>In vivo<\/jats:italic>, iron dextran treatment significantly elevated plasma iron levels (2.2-fold) but did not affect brain MVEF iron content or alter P-gp, BCRP or claudin-5 protein abundance.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Iron overload modulates BBB transporters and junction proteins <jats:italic>in vitro<\/jats:italic>, highlighting potential implications for CNS drug delivery in neurodegenerative diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s11095-025-03826-2","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T21:28:02Z","timestamp":1739395682000},"page":"319-334","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ferric Ammonium Citrate Reduces Claudin-5 Abundance and Function in Primary Mouse Brain Endothelial Cells"],"prefix":"10.1007","volume":"42","author":[{"given":"Pranav","family":"Runwal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae","family":"Pyun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie A.","family":"Newman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celeste","family":"Mawal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley I.","family":"Bush","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liam M.","family":"Koehn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0983-7152","authenticated-orcid":false,"given":"Joseph A.","family":"Nicolazzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"3826_CR1","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.3389\/fnins.2019.01443","volume":"13","author":"N Yan","year":"2020","unstructured":"Yan N, Zhang J. 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