{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T18:41:59Z","timestamp":1776710519204,"version":"3.51.2"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P01CA245705"],"award-info":[{"award-number":["P01CA245705"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["TL1-TR002016"],"award-info":[{"award-number":["TL1-TR002016"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Iron is essential for normal physiological function, yet dysregulation of iron metabolism is increasingly recognized as a hallmark of cancers such as glioblastoma (GBM). Recent clinical evidence suggests that systemic iron deficiency anemia (IDA) negatively impacts GBM outcomes in a sex-dependent manner, but the mechanisms linking systemic iron availability to tumor iron metabolism remain poorly understood. Here, we interrogate the impact of systemic iron through dietary modulation (control, iron deficiency (ID), and high iron diets), stratified by sex, on tumor iron handling and GBM outcomes utilizing an immune competent (C57BL\/6) GBM (GL261) mouse model. Subsequently, we analyzed clinical samples to evaluate translational value. In the preclinical study, we show that iron deficiency decreased survival in males but conferred a slight survival advantage in females, consistent with prior clinical trends. Among circulating iron markers, only ferritin light chain (FTL), but not ferritin heavy chain (FTH) or serum iron, positively correlated with survival in males but not females. In the brain, contralateral iron levels reflected dietary iron status in males but not females, further supporting sex-dependent regulation of local and circulating iron. Notably, tumor iron content remained unchanged in males but was significantly elevated in ID female tumors, complemented by increased transferrin receptor (TfR1) and FTH expression. In clinical GBM samples, we observed non-statistically significant but similar survival trends across varying iron and ferritin levels, suggesting potential translational relevance of our exploratory model. These findings demonstrate that systemic iron availability exerts a sex-specific effect on tumor iron handling, highlighting a critical relationship between systemic and tumor iron regulation in GBM.<\/jats:p>","DOI":"10.1371\/journal.pone.0347520","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T17:46:41Z","timestamp":1776707201000},"page":"e0347520","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic iron availability differentially shapes tumor and brain iron handling in a sex-dependent manner in glioblastoma"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9090-4403","authenticated-orcid":true,"given":"Emily","family":"Tufano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kondaiah","family":"Palsa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecka O.","family":"Serpa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy B.","family":"Helmuth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2549-7400","authenticated-orcid":true,"given":"Gabriela","family":"Remit-Berthet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Mills-Huffnagle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathias","family":"Kant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurosman","family":"Sahu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0481-8240","authenticated-orcid":true,"given":"James R.","family":"Connor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"issue":"4","key":"pone.0347520.ref001","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines10040806","article-title":"The hallmarks of glioblastoma: Heterogeneity, intercellular crosstalk and molecular signature of invasiveness and progression","volume":"10","author":"F Torrisi","year":"2022","journal-title":"Biomedicines"},{"issue":"1","key":"pone.0347520.ref002","article-title":"Tumor microenvironment in glioblastoma: Current and emerging concepts","volume":"5","author":"P Sharma","year":"2023","journal-title":"Neurooncol Adv"},{"issue":"1","key":"pone.0347520.ref003","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12883-022-03047-9","article-title":"Clinical characteristics and prognosis of Glioblastoma patients with infratentorial recurrence","volume":"23","author":"D Kawauchi","year":"2023","journal-title":"BMC Neurol"},{"key":"pone.0347520.ref004","doi-asserted-by":"crossref","DOI":"10.1093\/neuonc\/noac202","article-title":"CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019","volume":"24","author":"QT Ostrom","year":"2022","journal-title":"Neuro Oncol"},{"issue":"6","key":"pone.0347520.ref005","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nrd.2016.248","article-title":"Targeting iron metabolism in drug discovery and delivery","volume":"16","author":"BJ Crielaard","year":"2017","journal-title":"Nat Rev Drug Discov"},{"issue":"4","key":"pone.0347520.ref006","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ccell.2015.09.002","article-title":"Preferential iron trafficking characterizes glioblastoma stem-like cells","volume":"28","author":"DL Schonberg","year":"2015","journal-title":"Cancer Cell"},{"key":"pone.0347520.ref007","doi-asserted-by":"crossref","first-page":"134777","DOI":"10.1016\/j.ijbiomac.2024.134777","article-title":"Advancing glioblastoma treatment through iron metabolism: A focus on TfR1 and Ferroptosis innovations","volume":"278","author":"MD Caverzan","year":"2024","journal-title":"Int J Biol Macromol"},{"issue":"3","key":"pone.0347520.ref008","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0119647","article-title":"Risk of cancer in patients with iron deficiency anemia: A nationwide population-based study","volume":"10","author":"N Hung","year":"2015","journal-title":"PLoS One"},{"issue":"3","key":"pone.0347520.ref009","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1080\/01635589709514541","article-title":"Adenocarcinomas of the esophagus and gastric cardia: the role of diet","volume":"27","author":"ZF Zhang","year":"1997","journal-title":"Nutr Cancer"},{"issue":"1","key":"pone.0347520.ref010","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s44313-024-00030-w","article-title":"Functional iron deficiency anemia in patients with cancer","volume":"59","author":"JS Koh","year":"2024","journal-title":"Blood Res"},{"key":"pone.0347520.ref011","article-title":"Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and mineral nutrition information system","author":"J Murphy","year":"2011","journal-title":"Geneva: World Health Organization"},{"issue":"1","key":"pone.0347520.ref012","doi-asserted-by":"crossref","DOI":"10.1136\/bmjgast-2021-000759","article-title":"Iron deficiency anaemia: Pathophysiology, assessment, practical management","volume":"9","author":"A Kumar","year":"2022","journal-title":"BMJ Open Gastroenterol"},{"issue":"1","key":"pone.0347520.ref013","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1038\/s41598-024-52492-8","article-title":"Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival","volume":"14","author":"G Shenoy","year":"2024","journal-title":"Sci Rep"},{"key":"pone.0347520.ref014","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2024.42.16_suppl.e14029","article-title":"Analysis of transition metals in glioblastoma tumor and plasma samples","volume":"42","author":"G Shenoy","year":"2024","journal-title":"JCO"},{"issue":"1","key":"pone.0347520.ref015","article-title":"Mouse models of glioblastoma for the evaluation of novel therapeutic strategies","volume":"3","author":"AF Haddad","year":"2021","journal-title":"Neurooncol Adv"},{"issue":"12","key":"pone.0347520.ref016","doi-asserted-by":"crossref","first-page":"9691","DOI":"10.1007\/s00432-023-04864-2","article-title":"Uptake of H-ferritin by Glioblastoma stem cells and its impact on their invasion capacity","volume":"149","author":"B Pandya Shesh","year":"2023","journal-title":"J Cancer Res Clin Oncol"},{"key":"pone.0347520.ref017","doi-asserted-by":"crossref","first-page":"100872","DOI":"10.1016\/j.mam.2020.100872","article-title":"Regulation of iron homeostasis: Lessons from mouse models","volume":"75","author":"S Altamura","year":"2020","journal-title":"Mol Aspects Med"},{"issue":"11","key":"pone.0347520.ref018","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1093\/jn\/123.11.1939","article-title":"AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet","volume":"123","author":"PG Reeves","year":"1993","journal-title":"J Nutr"},{"issue":"1","key":"pone.0347520.ref019","article-title":"Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses","volume":"6","author":"KM Troike","year":"2023","journal-title":"Neurooncol Adv"},{"issue":"6","key":"pone.0347520.ref020","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/j.1349-7006.2006.00208.x","article-title":"Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy","volume":"97","author":"T Szatm\u00e1ri","year":"2006","journal-title":"Cancer Sci"},{"issue":"8","key":"pone.0347520.ref021","doi-asserted-by":"crossref","DOI":"10.3390\/nu11081885","article-title":"Iron and zinc homeostasis and interactions: Does enteric zinc excretion cross-talk with intestinal iron absorption","volume":"11","author":"P Kondaiah","year":"2019","journal-title":"Nutrients"},{"issue":"9","key":"pone.0347520.ref022","doi-asserted-by":"crossref","first-page":"429","DOI":"10.4103\/1947-2714.100998","article-title":"Western blot: technique, theory, and trouble shooting","volume":"4","author":"T Mahmood","year":"2012","journal-title":"N Am J Med Sci"},{"issue":"2","key":"pone.0347520.ref023","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/MOG.0b013e32831ef1cd","article-title":"Iron deficiency anemia: Diagnosis and management","volume":"25","author":"SF Clark","year":"2009","journal-title":"Curr Opin Gastroenterol"},{"issue":"1","key":"pone.0347520.ref024","doi-asserted-by":"crossref","DOI":"10.1096\/fj.202301596RR","article-title":"Brain iron acquisition depends on age and sex in iron-deficient mice","volume":"38","author":"K Palsa","year":"2024","journal-title":"FASEB J"},{"issue":"2","key":"pone.0347520.ref025","doi-asserted-by":"crossref","first-page":"102868","DOI":"10.1016\/j.jbc.2022.102868","article-title":"Exosomes are involved in iron transport from human blood-brain barrier endothelial cells and are modified by endothelial cell iron status","volume":"299","author":"K Palsa","year":"2023","journal-title":"J Biol Chem"},{"issue":"1","key":"pone.0347520.ref026","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12929-023-00934-2","article-title":"Apo- and holo-transferrin differentially interact with hephaestin and ferroportin in a novel mechanism of cellular iron release regulation","volume":"30","author":"SL Baringer","year":"2023","journal-title":"J Biomed Sci"},{"issue":"11","key":"pone.0347520.ref027","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1177\/0271678X18783372","article-title":"Endothelial cells are critical regulators of iron transport in a model of the human blood-brain barrier","volume":"39","author":"B Chiou","year":"2019","journal-title":"J Cereb Blood Flow Metab"},{"issue":"1","key":"pone.0347520.ref028","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s12987-024-00590-0","article-title":"Blood-brain barrier permeability increases with the differentiation of glioblastoma cells in vitro","volume":"21","author":"S Digiovanni","year":"2024","journal-title":"Fluids Barriers CNS"},{"issue":"4","key":"pone.0347520.ref029","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/s12276-025-01436-x","article-title":"Transferrin receptors","volume":"57","author":"Q Guo","year":"2025","journal-title":"Exp Mol Med"},{"issue":"8","key":"pone.0347520.ref030","doi-asserted-by":"crossref","first-page":"911","DOI":"10.3727\/096504019X15516966905337","article-title":"miR-148-3p inhibits growth of glioblastoma targeting DNA methyltransferase-1 (DNMT1)","volume":"27","author":"Y Li","year":"2019","journal-title":"Oncol Res"},{"key":"pone.0347520.ref031","doi-asserted-by":"crossref","DOI":"10.1182\/blood-2024-210302","article-title":"miRNA-144\/451 regulates cell surface TfR1 expression in normal and \u03b2-thalassemic erythroblasts","volume":"144","author":"GE Christakopoulos","year":"2024","journal-title":"Blood"},{"issue":"2","key":"pone.0347520.ref032","doi-asserted-by":"crossref","DOI":"10.3171\/2021.11.FOCUS21556","article-title":"Syngeneic murine glioblastoma models: Reactionary immune changes and immunotherapy intervention outcomes","volume":"52","author":"V Letchuman","year":"2022","journal-title":"Neurosurg Focus"},{"key":"pone.0347520.ref033","doi-asserted-by":"crossref","first-page":"102376","DOI":"10.1016\/j.tranon.2025.102376","article-title":"Analysis of transition metal content in glioblastoma reveals association between iron and survival","volume":"55","author":"G Shenoy","year":"2025","journal-title":"Transl Oncol"},{"issue":"12","key":"pone.0347520.ref034","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1007\/s00066-011-1129-x","article-title":"Prognostic impact of hemoglobin level and other factors in patients with high-grade gliomas treated with postoperative radiochemotherapy and sequential chemotherapy based on temozolomide: a 10-year experience at a single institution","volume":"187","author":"GA C\u00e9faro","year":"2011","journal-title":"Strahlenther Onkol"},{"issue":"1","key":"pone.0347520.ref035","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0167-8140(99)00128-0","article-title":"Accelerated hyperfractionated radiotherapy in 149 patients with glioblastoma multiforme","volume":"53","author":"J Lutterbach","year":"1999","journal-title":"Radiother Oncol"},{"issue":"7","key":"pone.0347520.ref036","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.3390\/cancers16071393","article-title":"Dexamethasone in patients with glioblastoma: A systematic review and meta-analysis","volume":"16","author":"P Scheffler","year":"2024","journal-title":"Cancers (Basel)"},{"issue":"8","key":"pone.0347520.ref037","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1002\/jhm.70008","article-title":"Elevation in white blood cell count after corticosteroid use in noninfected hospitalized patients","volume":"20","author":"E Sullivan","year":"2025","journal-title":"J Hosp Med"},{"key":"pone.0347520.ref038","doi-asserted-by":"crossref","first-page":"0","DOI":"10.20892\/j.issn.2095-3941.2021.0037","article-title":"Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events","volume":"18","author":"W Zhang","year":"2021","journal-title":"Cancer Biol Med"},{"issue":"23","key":"pone.0347520.ref039","doi-asserted-by":"crossref","DOI":"10.3390\/molecules28237707","article-title":"New perspectives on circulating ferritin: its role in health and disease","volume":"28","author":"\u00d3 Fonseca","year":"2023","journal-title":"Molecules"},{"issue":"41","key":"pone.0347520.ref040","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":"AJ Schwartz","year":"2019","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0347520.ref041","doi-asserted-by":"crossref","first-page":"94","DOI":"10.3390\/ph11040094","article-title":"Anemia and iron deficiency in cancer patients: Role of iron replacement therapy","volume":"11","author":"F Busti","year":"2018","journal-title":"Pharmaceuticals (Basel)"},{"key":"pone.0347520.ref042","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1159\/000083128","article-title":"Cancer-related anemia: pathogenesis, prevalence and treatment","author":"G Birgeg\u00e5rd","year":"2005","journal-title":"Oncology"},{"key":"pone.0347520.ref043","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2147\/IJCTM.S187569","article-title":"Chemotherapy-induced anemia: Etiology, pathophysiology, and implications for contemporary practice","volume":"6","author":"E Bryer","year":"2018","journal-title":"IJCTM"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0347520","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T17:46:51Z","timestamp":1776707211000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0347520"}},"subtitle":[],"editor":[{"given":"Kostas","family":"Pantopoulos","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,20]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0347520","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,20]]}}}