{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T03:59:59Z","timestamp":1760587199349,"version":"3.41.2"},"reference-count":28,"publisher":"The Company of Biologists","issue":"7","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009877","name":"University of Michigan-Dearborn","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009877","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>The brain is the most metabolically active organ in the body and has a high demand for iron. Iron deficiency impairs brain function and is linked to various neurological disorders. To maintain iron homeostasis, astrocytes respond to iron levels and signal brain microvascular endothelial cells (BMVECs), which regulate iron import into the brain. However, the specific signaling molecules released by astrocytes remain largely unknown. In this study, we addressed this by performing a global proteomic analysis of the secretome of primary mouse astrocytes cultured under iron-deficient conditions. Quantitative mass spectrometry demonstrated significant remodeling of the astrocyte secretome in response to iron deficiency, affecting critical pathways related to metabolic reprogramming, stress responses, and cellular communication. We identified specific secreted factors with potential roles in paracrine signaling, with their secretion supported by prediction analysis. Our analysis also revealed novel condition-specific proteins. These findings provide new insights into astrocyte communication under iron stress and its potential influence on iron availability at the blood\u2013brain barrier. This study establishes a foundation for future investigations into astrocyte-secreted factors and their roles in neurological diseases associated with iron dysregulation.<\/jats:p>","DOI":"10.1242\/bio.062057","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T06:41:31Z","timestamp":1751352091000},"source":"Crossref","is-referenced-by-count":1,"title":["Astrocyte secretome remodeling under iron deficiency: potential implications for brain iron homeostasis"],"prefix":"10.1242","volume":"14","author":[{"given":"Mariam","family":"Duhaini","sequence":"first","affiliation":[{"name":"University of Michigan-Dearborn Department of Natural Sciences , , 4901 Evergreen Road, Dearborn, MI 48128 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Habiba S.","family":"Shamroukh","sequence":"additional","affiliation":[{"name":"University of Michigan-Dearborn Department of Natural Sciences , , 4901 Evergreen Road, Dearborn, MI 48128 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Michigan-Dearborn Department of Natural Sciences , , 4901 Evergreen Road, Dearborn, MI 48128 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1242-9990","authenticated-orcid":false,"given":"Kalyan C.","family":"Kondapalli","sequence":"additional","affiliation":[{"name":"University of Michigan-Dearborn Department of Natural Sciences , , 4901 Evergreen Road, Dearborn, MI 48128 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"2025070912233839600_BIO062057C1","doi-asserted-by":"publisher","first-page":"1533033818764470","DOI":"10.1177\/1533033818764470","article-title":"High-dose deferoxamine treatment disrupts intracellular iron homeostasis, reduces growth, and induces apoptosis in metastatic and nonmetastatic breast cancer cell lines","volume":"17","author":"Bajbouj","year":"2018","journal-title":"Technol. Cancer Res. Treat."},{"key":"2025070912233839600_BIO062057C2","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1146\/annurev.nutr.23.020102.075739","article-title":"Iron status and neural functioning","volume":"23","author":"Beard","year":"2003","journal-title":"Annu. Rev. Nutr."},{"key":"2025070912233839600_BIO062057C3","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1093\/protein\/gzh037","article-title":"Feature-based prediction of non-classical and leaderless protein secretion","volume":"17","author":"Bendtsen","year":"2004","journal-title":"Protein Eng. Des. Sel."},{"key":"2025070912233839600_BIO062057C4","doi-asserted-by":"publisher","first-page":"4293","DOI":"10.1074\/jbc.M116.769240","article-title":"Na(+)\/H(+) exchanger 9 regulates iron mobilization at the blood-brain barrier in response to iron starvation","volume":"292","author":"Beydoun","year":"2017","journal-title":"J. Biol. Chem."},{"key":"2025070912233839600_BIO062057C5","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1038\/icb.2010.64","article-title":"MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis","volume":"88","author":"Buschow","year":"2010","journal-title":"Immunol. Cell Biol."},{"key":"2025070912233839600_BIO062057C6","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/1471-2105-14-128","article-title":"Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool","volume":"14","author":"Chen","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"2025070912233839600_BIO062057C7","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/978-1-60761-977-2_4","article-title":"Reactome knowledgebase of human biological pathways and processes","volume":"694","author":"D'Eustachio","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"2025070912233839600_BIO062057C8","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1007\/s10534-016-9952-2","article-title":"Iron uptake and transport across physiological barriers","volume":"29","author":"Duck","year":"2016","journal-title":"Biometals"},{"key":"2025070912233839600_BIO062057C9","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/nmeth1019","article-title":"Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry","volume":"4","author":"Elias","year":"2007","journal-title":"Nat. Methods"},{"key":"2025070912233839600_BIO062057C10","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1093\/nar\/30.7.1575","article-title":"An efficient algorithm for large-scale detection of protein families","volume":"30","author":"Enright","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"2025070912233839600_BIO062057C11","doi-asserted-by":"publisher","first-page":"D325","DOI":"10.1093\/nar\/gkaa1113","article-title":"The Gene Ontology resource: enriching a GOld mine","volume":"49","author":"Gene Ontology Consortium","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2025070912233839600_BIO062057C12","doi-asserted-by":"publisher","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: new perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2025070912233839600_BIO062057C13","doi-asserted-by":"publisher","first-page":"W212","DOI":"10.1093\/nar\/gkz446","article-title":"ChEA3: transcription factor enrichment analysis by orthogonal omics integration","volume":"47","author":"Keenan","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2025070912233839600_BIO062057C14","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s10534-012-9538-6","article-title":"Mechanistic analysis of iron accumulation by endothelial cells of the BBB","volume":"25","author":"Mccarthy","year":"2012","journal-title":"Biometals"},{"key":"2025070912233839600_BIO062057C15","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s12964-014-0065-7","article-title":"Activation of C6 glioblastoma cell ceruloplasmin expression by neighboring human brain endothelia-derived interleukins in an in vitro blood-brain barrier model system","volume":"12","author":"McCarthy","year":"2014","journal-title":"Cell Commun. Signal"},{"key":"2025070912233839600_BIO062057C16","doi-asserted-by":"publisher","first-page":"31","DOI":"10.3389\/fnmol.2015.00031","article-title":"Mechanisms and regulation of iron trafficking across the capillary endothelial cells of the blood-brain barrier","volume":"8","author":"McCarthy","year":"2015","journal-title":"Front. Mol. Neurosci."},{"key":"2025070912233839600_BIO062057C17","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/s41423-020-00541-3","article-title":"Macrophages and the maintenance of homeostasis","volume":"18","author":"Mosser","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"2025070912233839600_BIO062057C18","doi-asserted-by":"publisher","first-page":"4417","DOI":"10.1074\/jbc.M705146200","article-title":"Cell surface levels of organellar Na+\/H+ exchanger isoform 6 are regulated by interaction with RACK1","volume":"283","author":"Ohgaki","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2025070912233839600_BIO062057C19","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.1002\/(SICI)1522-2683(19991201)20:18&lt;3551::AID-ELPS3551&gt;3.0.CO;2-2","article-title":"Probability-based protein identification by searching sequence databases using mass spectrometry data","volume":"20","author":"Perkins","year":"1999","journal-title":"Electrophoresis"},{"key":"2025070912233839600_BIO062057C20","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1080\/1028415X.2020.1740862","article-title":"Iron-deficient diet induces distinct protein profile related to energy metabolism in the striatum and hippocampus of adult rats","volume":"25","author":"Pino","year":"2022","journal-title":"Nutr. Neurosci."},{"key":"2025070912233839600_BIO062057C21","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s12868-019-0507-7","article-title":"Iron concentrations in neurons and glial cells with estimates on ferritin concentrations","volume":"20","author":"Reinert","year":"2019","journal-title":"BMC Neurosci."},{"key":"2025070912233839600_BIO062057C22","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nrn3453","article-title":"Iron metabolism in the CNS: implications for neurodegenerative diseases","volume":"14","author":"Rouault","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"2025070912233839600_BIO062057C23","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1002\/pmic.200900437","article-title":"Scaffold: a bioinformatic tool for validating MS\/MS-based proteomic studies","volume":"10","author":"Searle","year":"2010","journal-title":"Proteomics"},{"key":"2025070912233839600_BIO062057C24","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/jcbfm.2014.168","article-title":"A novel model for brain iron uptake: introducing the concept of regulation","volume":"35","author":"Simpson","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2025070912233839600_BIO062057C28","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1038\/nprot.2006.468","article-title":"In-gel digestion for mass spectrometric characterization of proteins and proteomes","volume":"1","author":"Shevchenko","year":"2006","journal-title":"Nat Protoc."},{"key":"2025070912233839600_BIO062057C25","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2025070912233839600_BIO062057C26","doi-asserted-by":"publisher","first-page":"D609","DOI":"10.1093\/nar\/gkae1010","article-title":"UniProt: the universal protein knowledgebase in 2025","volume":"53","author":"Uniprot Consortium","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"2025070912233839600_BIO062057C27","doi-asserted-by":"publisher","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function","volume":"38","author":"Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res."}],"container-title":["Biology Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/bio\/article-pdf\/doi\/10.1242\/bio.062057\/3654615\/bio062057.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/bio\/article-pdf\/doi\/10.1242\/bio.062057\/3655872\/bio062057.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/bio\/article-pdf\/doi\/10.1242\/bio.062057\/3655872\/bio062057.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T16:23:42Z","timestamp":1752078222000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/bio\/article\/14\/7\/bio062057\/368526\/Astrocyte-secretome-remodeling-under-iron"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,9]]},"references-count":28,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7,15]]}},"URL":"https:\/\/doi.org\/10.1242\/bio.062057","relation":{},"ISSN":["2046-6390"],"issn-type":[{"type":"electronic","value":"2046-6390"}],"subject":[],"published":{"date-parts":[[2025,7,9]]},"article-number":"bio062057"}}