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

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

  • Adv Sci (Weinh). 2025 Nov 6:e07384. doi: 10.1002/advs.202507384.
Yi Guo 1 2,  Yue Wang 1,  Yong Ni 1 3,  Bin Bo 4,  Jinzhi He 1,  Yongming Zhu 1,  Aiping Qin 5,  Xianyong Zhou 1,  Huaping Du 2,  Yuan Liu 2,  Tianyao Wang 6,  Yudu Li 7 8 9,  Yibo Zhao 7,  Zengai Chen 6,  Zhipei Liang 7 10,  Yao Li 4 11,  Yuan Xu 2,  Huiling Zhang 1 2
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Neurology, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou, 215200, China.
  • 3 Department of Pain and Suzhou Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, China.
  • 4 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.
  • 5 Department of Pharmacy, Jiangsu Health Vocational College, Nanjing, Jiangsu, 210000, China.
  • 6 Radiology Department, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, 200000, China.
  • 7 Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
  • 8 Department of Bioengineering University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
  • 9 National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
  • 10 Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
  • 11 Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai, 200000, China.
PMID: 41195589 DOI: 10.1002/advs.202507384
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.

Keywords

TfR1 palmitoylation; astrocytes; iron overload; ischemic stroke; neuron.

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