journal article·2026-01Open access

Iron Overload Mediates the Differential Cell Fate of Astrocytes from Neurons and Its Regulatory Mechanisms in Ischemic Stroke

Yi Guo, Yue Wang, Yong Ni, Bin Bo, Jinzhi He, Yongming Zhu, Aiping Qin, Xianyong Zhou, Huaping Du, Yuan Liu, Tianyao Wang, Yudu Li, Yibo Zhao, Zengai Chen, Zhipei Liang, Yao Li, Yuan Xu, Huiling Zhang

Advanced Science· Volume 13· Issue 4

Abstract

Abstract Iron accumulation and ferroptosis occur in the brain following ischemic stroke. However, the relationship between iron overload and cell type‐specific 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‐induced 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‐induced cellular fates. Moreover, iron overload promotes astrogliosis by enhancing the transcriptional activities of several proliferation‐related genes. Using mice with partial knockout of the transferrin receptor 1 (TfR1) gene Tfrc , astrocyte‐specific Tfrc knockdown, and conditional astrocytic Cpt1a partial knockout (to induce fatty acid metabolism disorders), it is revealed that increased TfR1 palmitoylation and clathrin‐mediated endocytosis drive astrocytic iron overload. Notably, ischemia/reperfusion‐induced 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‐induced iron overload to cell type‐specific fates. TfR1 palmitoylation emerges as a potential target for ischemic stroke therapy.
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Research context

OpenAlex topics: Ferroptosis and cancer prognosis · Iron Metabolism and Disorders · Neuroinflammation and Neurodegeneration Mechanisms

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

Department of Neurology Suzhou Ninth People's Hospital Suzhou Ninth Hospital Affiliated to Soochow University Soochow University Suzhou 215200 China

Department of Pain and Suzhou Clinical Research Center of Neurological Disease the Second Affiliated Hospital of Soochow University Suzhou Jiangsu 215000 China

National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy (NERC‐AMRT) School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200000 China

Department of Pharmacy Jiangsu Health Vocational College Nanjing Jiangsu 210000 China

Radiology Department Renji Hospital Shanghai Jiao Tong University of Medicine Shanghai 200000 China

Beckman Institute for Advanced Science and Technology University of Illinois at Urbana‐Champaign Urbana IL 61801 USA

Department of Bioengineering University of Illinois at Urbana‐Champaign Urbana IL 61801 USA

National Center for Supercomputing Applications University of Illinois at Urbana‐Champaign Urbana IL 61801 USA

Department of Electrical and Computer Engineering University of Illinois at Urbana‐Champaign Urbana IL 61801 USA

Institute of Medical Robotics Shanghai Jiao Tong University Shanghai 200000 China

Funding

National Natural Science Foundation of China · Qinglan Project of Jiangsu Province of China

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