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Here, a 3D tumoroid model is used to investigate the metabolic sensitivity of temozolomide (TMZ)\u2010resistant GBM cells to iron chelation by deferoxamine (DFO) and deferiprone (DFP). This work shows that TMZ\u2010resistant GBM cells acquire stem\u2010like characteristics, higher intracellular iron levels, higher expression of aconitase, and elevated reliance on oxidative phosphorylation and proteins associated with iron metabolism. Using a microphysiological model of GBM\u2010on\u2010a\u2010chip consisting of extracellular matrix (ECM)\u2010incorporated tumoroids, this work demonstrates that the combination of iron chelators with TMZ induces a synergistic effect on an in vitro tumoroid model of newly diagnosed and recurrent chemo\u2010resistant patient\u2010derived GBM and reduced their size and invasion. Investigating downstream metabolic variations reveal reduced intracellular iron, increased reactive oxygen species (ROS), upregulated hypoxia\u2010inducible factor\u20101\u03b1, reduced viability, increased autophagy, upregulated ribonucleotide reductase (RRM2), arrested proliferation, and induced cell death in normoxic TMZ\u2010resistant cells. Hypoxic cells, while showing similar results, display reduced responses to iron deficiency, less blebbing, and an induced autophagic flux, suggesting an adaptive mechanism associated with hypoxia. These findings show that co\u2010treatment with iron chelators and TMZ induces a synergistic effect, making this combination a promising GBM therapy.<\/jats:p>","DOI":"10.1002\/advs.202412505","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T07:03:23Z","timestamp":1745651003000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tumoroid Model Reveals Synergistic Impairment of Metabolism by Iron Chelators and Temozolomide in Chemo\u2010Resistant Patient\u2010derived Glioblastoma Cells"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5035-9244","authenticated-orcid":false,"given":"Meitham","family":"Amereh","sequence":"first","affiliation":[{"name":"Laboratory for Innovations in Micro Engineering (LiME) Department of Mechanical Engineering University of Victoria  Victoria BC V8P 5C2 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