Role of Ferroptosis in Cerebral Ischemia-Reperfusion Injury
Download PDF
$currentUrl="http://$_SERVER[HTTP_HOST]$_SERVER[REQUEST_URI]"

Keywords

Ferroptosis
Ischemic stroke
Reperfusion injury
Targeted therapy

DOI

10.26689/jcnr.v9i5.10590

Submitted : 2025-05-07
Accepted : 2025-05-22
Published : 2025-06-06

Abstract

Ferroptosis is a novel form of non-apoptotic cell death that has been widely studied in recent years and is involved in a variety of pathophysiological processes. The core treatment goal of ischemic stroke is to restore blood flow as early as possible, while the pathological mechanism of reperfusion injury after restoring blood flow is complex, involving oxidative stress, calcium overload, and inflammatory response. In recent years, more and more studies have found that ferroptosis mediation is involved in the occurrence and development of cerebral ischemia-reperfusion injury. This paper elaborates on the concept, mechanisms, and regulation of ferroptosis, detailing its role in cerebral ischemia-reperfusion injury and potential inhibition strategies. The aim is to deepen the understanding of ferroptosis in this pathological process and provide insights for possible targeted therapies.

References

Barthels D, Das H, 2020, Current Advances in Ischemic Stroke Research and Therapies. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1866(4): 165260.

Rabinstein AA, 2020, Update on Treatment of Acute Ischemic Stroke. Continuum: Lifelong Learning in Neurology, 26(2): 268–286.

Li ZZ, Zhang DC, 2020, Research Progress on the Mechanisms Related to Cerebral Ischemia-Reperfusion Injury. Journal of Hebei North University (Medical Edition), 10(6): 60–63.

Yan HF, Zou T, Tuo QZ, et al., 2021, Ferroptosis: Mechanisms and Links With Diseases. Signal Transduction and Targeted Therapy, 6(1): 49.

Wu MY, Yiang GT, Liao WT, et al., 2018, Current Mechanistic Concepts in Ischemia and Reperfusion Injury. Cellular Physiology and Biochemistry, 46(4): 1650–1667.

Shi XH, Mang J, Xu ZX, 2022, Research Progress on Cell Death Patterns in Cerebral Ischemia-Reperfusion Injury. Journal of Jilin University (Medicine Edition), 48(6): 1635–1643.

Galluzzi L, Vitale I, Aaronson SA, et al., 2018, Molecular Mechanisms of Cell Death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death and Differentiation, 25(3): 486–541.

Zhang LY, Li FR, Wang C, et al., 2019, Emerging Roles of p53 in Ferroptosis and Its Potential Application. Chinese Journal of Pathophysiology, 35(12): 2299–2304.

Fang KM, Cheng FC, Huang YL, et al., 2013, Trace Element, Antioxidant Activity, and Lipid Peroxidation Levels in Brain Cortex of Gerbils After Cerebral Ischemic Injury. Biological Trace Element Research, 152: 66–74.

Tuo Q, Lei P, Jackman K, et al., 2017, Tau-Mediated Iron Export Prevents Ferroptotic Damage After Ischemic Stroke. Molecular Psychiatry, 22(11): 1520–1530.

She X, Lan B, Tian H, et al., 2020, Cross Talk Between Ferroptosis and Cerebral Ischemia. Frontiers in Neuroscience, 14: 776.

Zille M, Karuppagounder SS, Chen Y, et al., 2017, Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis. Stroke, 48(4): 1033–1043.

Dixon SJ, Lemberg KM, Lamprecht MR, et al., 2012, Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell, 149(5): 1060–1072.

Bertrand RL, 2017, Iron Accumulation, Glutathione Depletion, and Lipid Peroxidation Must Occur Simultaneously During Ferroptosis and Are Mutually Amplifying Events. Medical Hypotheses, 101: 69–74.

Xu Y, Li K, Zhao Y, et al., 2023, Role of Ferroptosis in Stroke. Cellular and Molecular Neurobiology, 43(1): 205–222.

Degregorio-Rocasolano N, Marti-Sistac O, Gasull T, 2019, Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis. Frontiers in Neuroscience, 13: 85.

Wang Y, Wu S, Li Q, et al., 2023, Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes. Advanced Science, 10(24): 2300325.

Liu B, Qian DH, 2023, Research and Progress on the Role of Ferroptosis in Pancreatic Cancer. China Journal of General Surgery, 32(3): 434–440.

Rochette L, Dogon G, Rigal E, et al., 2022, Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis. International Journal of Molecular Sciences, 24(1): 449.

Vogt AS, Arsiwala T, Mohsen M, et al., 2021, On Iron Metabolism and Its Regulation. International Journal of Molecular Sciences, 22(9): 4591.

Dutt S, Hamza I, Bartnikas TB, 2022, Molecular Mechanisms of Iron and Heme Metabolism. Annual Review of Nutrition, 42(1): 311–335.

Baenziger O, Martin E, Steinlin M, et al., 1993, Early Pattern Recognition in Severe Perinatal Asphyxia: A Prospective MRI Study. Neuroradiology, 35: 437–442.

Park UJ, Lee YA, Won SM, et al., 2011, Blood-Derived Iron Mediates Free Radical Production and Neuronal Death in the Hippocampal CA1 Area Following Transient Forebrain Ischemia in Rat. Acta Neuropathologica, 121: 459–473.

Degregorio-Rocasolano N, Marti Sistac O, Gasull T, 2019, Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis. Frontiers in Neuroscience, 13: 85.

Tuo Q, Lei P, Jackman K, et al., 2017, Tau-Mediated Iron Export Prevents Ferroptotic Damage After Ischemic Stroke. Molecular Psychiatry, 22(11): 1520–1530.

Lei P, Ayton S, Finkelstein DI, et al., 2012, Tau Deficiency Induces Parkinsonism With Dementia by Impairing APP-Mediated Iron Export. Nature Medicine, 18(2): 291–295.

Tuo Q, Lei P, Jackman K, et al., 2017, Tau-Mediated Iron Export Prevents Ferroptotic Damage After Ischemic Stroke. Molecular Psychiatry, 22(11): 1520–1530.

Zhang HX, Zhang S, 2024, Research Progress on PITPNC1 Regulation of Lipid Metabolism and Ferroptosis in Tumor Cells. China Journal of General Surgery, 33(1): 131–137.

Yang WH, Huang Z, Wu J, et al., 2020, A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer. Molecular Cancer Research, 18(1): 79–90.

Zou Y, Li H, Graham ET, et al., 2020, Cytochrome P450 Oxidoreductase Contributes to Phospholipid Peroxidation in Ferroptosis. Nature Chemical Biology, 16(3): 302–309.

Gubern C, Camos S, Ballesteros I, et al., 2013, miRNA Expression Is Modulated Over Time After Focal Ischaemia: Up-Regulation of miR-347 Promotes Neuronal Apoptosis. The FEBS Journal, 280(23): 6233–6246.

Iaccarino G, Ciccarelli M, Sorriento D, et al., 2005, Ischemic Neoangiogenesis Enhanced by B2-Adrenergic Receptor Overexpression: A Novel Role for the Endothelial Adrenergic System. Circulation Research, 97(11): 1182–1189.

Jung JE, Karatas H, Liu Y, et al., 2015, STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury After Stroke. Journal of Cerebral Blood Flow and Metabolism, 35(12): 2043–2051.

Zheng Y, Liu Y, Karatas H, et al., 2019, Contributions of 12/15-Lipoxygenase to Bleeding in the Brain Following Ischemic Stroke. Advances in Experimental Medicine and Biology, 1161: 125–131.

Ursini F, Maiorino M, 2020, Lipid Peroxidation and Ferroptosis: The Role of GSH and GPx4. Free Radical Biology and Medicine, 152: 175–185.

Zhang L, Luo YL, Xiang Y, et al., 2024, Ferroptosis Inhibitors: Past, Present and Future. Frontiers in Pharmacology, 15: 1407335.

Zhu L, Zhu D, Ran J, et al., 2024, Autophagy Aggravates Multi-Walled Carbon Nanotube-Induced Ferroptosis by Suppressing PGC-1 Dependent-Mitochondrial Biogenesis in Lung Epithelial Cells. Chemico-Biological Interactions, 400: 111158.

Doll S, Freitas FP, Shah R, et al., 2019, FSP1 Is a Glutathione-Independent Ferroptosis Suppressor. Nature, 575(7784): 693–698.

Kraft VA, Bezjian CT, Pfeiffer S, et al., 2019, GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis Through Lipid Remodeling. ACS Central Science, 6(1): 41–53.

Zhang Y, Lu X, Tai B, et al., 2021, Ferroptosis and Its Multifaceted Roles in Cerebral Stroke. Frontiers in Cellular Neuroscience, 15: 615372.

Liu H, An N, Wang L, et al., 2023, Protective Effect of Xingnaojing Injection on Ferroptosis After Cerebral Ischemia Injury in MCAO Rats and SH-SY5Y Cells. Journal of Ethnopharmacology, 301: 115836.

Van Hoecke M, Prigent-Tessier A, Bertrand N, et al., 2005, Apoptotic Cell Death Progression After Photothrombotic Focal Cerebral Ischaemia: Effects of the Lipophilic Iron Chelator 2, 2-Dipyridyl. European Journal of Neuroscience, 22(5): 1045–1056.

Hanson LR, Roeytenberg A, Martinez PM, et al., 2009, Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke. The Journal of Pharmacology and Experimental Therapeutics, 330(3): 679–686.

Ding H, Yan CZ, Shi H, et al., 2011, Hepcidin Is Involved in Iron Regulation in the Ischemic Brain. PLoS One, 6(9): e25324.

Tu XK, Zhang HB, Shi SS, et al., 2016, 5-LOX Inhibitor Zileuton Reduces Inflammatory Reaction and Ischemic Brain Damage Through the Activation of PI3K/Akt Signaling Pathway. Neurochemical Research, 41: 2779–2787.

Xu Y, Liu Y, Li K, et al., 2022, COX-2/PGE2 Pathway Inhibits the Ferroptosis Induced by Cerebral Ischemia Reperfusion. Molecular Neurobiology, 59(3): 1619–1631.

Sun SJ, Tu H, Tang LJ, et al., 2020, Research Progress on Ferroptosis Inducers and Inhibitors. Chinese Journal of Pharmacology and Toxicology, 34(8): 623–633.

Lapchak P, Maher P, Schubert D, et al., 2007, Baicalein, an Antioxidant 12/15-Lipoxygenase Inhibitor Improves Clinical Rating Scores Following Multiple Infarct Embolic Strokes. Neuroscience, 150(3): 585–591.

Guan X, Li X, Yang X, et al., 2019, The Neuroprotective Effects of Carvacrol on Ischemia/Reperfusion-Induced Hippocampal Neuronal Impairment by Ferroptosis Mitigation. Life Sciences, 235: 116795.

Ingold I, Berndt C, Schmitt S, et al., 2018, Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell, 172(3): 409–422.

Lan B, Ge JW, Cheng SW, et al., 2020, Extract of Naotaifang, a Compound Chinese Herbal Medicine, Protects Neuron Ferroptosis Induced by Acute Cerebral Ischemia in Rats. Journal of Integrative Medicine, 18(4): 344–350.