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However, the relationship between iron overload and cell type\u2010specific fates remains largely unclear. Here, iron deposition and neuronal loss are reported within the perilesional cortex of three patients with ischemic stroke at both acute and subacute stages. It is identified that ischemia\/reperfusion\u2010induced iron overload triggers ferroptosis predominantly in neurons and to a lesser extent in astrocytes, whereas most astrocytes undergo reactive proliferation. Mechanistically, the reduced or elevated Nrf2\/GPX4 and SLC7A11 levels in neurons or astrocytes, respectively, account for these distinct iron overload\u2010induced cellular fates. Moreover, iron overload promotes astrogliosis by enhancing the transcriptional activities of several proliferation\u2010related genes. Using mice with partial knockout of the transferrin receptor 1 (TfR1) gene\n                    <jats:italic>Tfrc<\/jats:italic>\n                    , astrocyte\u2010specific\n                    <jats:italic>Tfrc<\/jats:italic>\n                    knockdown, and conditional astrocytic\n                    <jats:italic>Cpt1a<\/jats:italic>\n                    partial knockout (to induce fatty acid metabolism disorders), it is revealed that increased TfR1 palmitoylation and clathrin\u2010mediated endocytosis drive astrocytic iron overload. Notably, ischemia\/reperfusion\u2010induced elevation of palmitic acid is associated with enhanced TfR1 palmitoylation. Treatment with antioxidants or iron chelators mitigates ischemic brain injury. Together, these findings provide a comprehensive framework linking ischemia\/reperfusion\u2010induced iron overload to cell type\u2010specific fates. TfR1 palmitoylation emerges as a potential target for ischemic stroke therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202507384","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T10:13:16Z","timestamp":1762423996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Iron Overload Mediates the Differential Cell Fate of Astrocytes from Neurons and Its Regulatory Mechanisms in Ischemic Stroke"],"prefix":"10.1002","volume":"13","author":[{"given":"Yi","family":"Guo","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases Department of Pharmacology, College of Pharmaceutical Sciences Soochow University  Suzhou Jiangsu 215123 China"},{"name":"Department of Neurology Suzhou Ninth People's Hospital Suzhou Ninth Hospital 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