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Pan, Y.;  Wang, X.;  Liu, X.;  Shen, L.;  Chen, Q.;  Shu, Q. Targeting Ferroptosis for Ischemia-Reperfusion Injury. Encyclopedia. Available online: (accessed on 27 May 2024).
Pan Y,  Wang X,  Liu X,  Shen L,  Chen Q,  Shu Q. Targeting Ferroptosis for Ischemia-Reperfusion Injury. Encyclopedia. Available at: Accessed May 27, 2024.
Pan, Yihang, Xueke Wang, Xiwang Liu, Lihua Shen, Qixing Chen, Qiang Shu. "Targeting Ferroptosis for Ischemia-Reperfusion Injury" Encyclopedia, (accessed May 27, 2024).
Pan, Y.,  Wang, X.,  Liu, X.,  Shen, L.,  Chen, Q., & Shu, Q. (2022, December 08). Targeting Ferroptosis for Ischemia-Reperfusion Injury. In Encyclopedia.
Pan, Yihang, et al. "Targeting Ferroptosis for Ischemia-Reperfusion Injury." Encyclopedia. Web. 08 December, 2022.
Targeting Ferroptosis for Ischemia-Reperfusion Injury

Ischemia-reperfusion (I/R) injury is a major challenge in perioperative medicine that contributes to pathological damage in various conditions, including ischemic stroke, myocardial infarction, acute lung injury, liver transplantation, acute kidney injury and hemorrhagic shock. I/R damage is often irreversible, and current treatments for I/R injury are limited. Ferroptosis, a type of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, has been implicated in multiple diseases, including I/R injury. Emerging evidence suggests that ferroptosis can serve as a therapeutic target to alleviate I/R injury, and pharmacological strategies targeting ferroptosis have been developed in I/R models.

ischemia-reperfusion injury ferroptosis iron antioxidant therapeutic strategies

1. Introduction

Ischemia-reperfusion (I/R) is a pathological condition characterized by the initial restriction of the blood supply to organs or tissues, followed by the restoration of blood flow and reoxygenation. Insufficient blood supply leads to tissue hypoxia and cellular metabolic imbalance, and subsequent reperfusion and reoxygenation cause excessive inflammatory responses and exacerbate ischemic tissue damage, which is known as I/R injury [1]. I/R injury is intrinsically associated with oxidative damage, and multiple pathological processes contribute to this damage, including impaired endothelial barrier function, mitochondrial dysfunction, activation of the cell death program, calcium overload, sterile inflammation and autoimmune responses [2]. However, the precise molecular mechanism of I/R injury has not been fully elucidated and targeted therapies are still limited. Overall, therapeutic strategies for this condition need to be developed, and examining new therapeutic targets to manage I/R injury is a top priority.
Cell death is a stable pathological indicator of I/R injury. Emerging evidence has revealed a novel therapeutic concept to target regulated cell death (RCD) to counteract I/R injury, although the role of RCD in I/R injury has only recently become apparent [3]. Different forms of RCD have been identified in I/R injury, including autophagy, necroptosis, apoptosis, pyroptosis, parthanatos and ferroptosis [2]. Recent studies suggest that targeting RCD exerts beneficial effects against I/R injury; in particular, RCD in parenchymal and endothelial cells is recognized as a promising intervention target. I/R injury leads to RCD of parenchymal and endothelial cells, and apoptosis, necroptosis and autophagy are the most common types [4]. Generally, regulating I/R-induced RCD has been recognized as a new therapeutic strategy against I/R injury, but effective interventions are rarely summarized.
Recently, ferroptosis, a form of RCD characterized by iron-dependent lipid peroxidation, glutathione (GSH) depletion and glutathione peroxidase 4 (GPX4) inactivation [5], has received great attention in I/R events [6]. Ferroptosis occurs during the reperfusion but not the ischemic phase, as the levels of two key enzymes in ferroptosis, GPX4 and long-chain-fatty-acid-CoA ligase 4 (ACSL4) in tissues were significantly regulated only during reperfusion, accompanied by elevated iron concentration and malondialdehyde (MDA) levels [7]. During the reperfusion phase, mitochondrial respiration is enhanced, which consequently triggers reactive oxygen species (ROS) explosion and ferroptosis [8]. Notably, decreased mitochondrial membrane potential (MMP) can be observed, which indicates increased mitochondrial outer membrane permeability, a characteristic of mitochondrial-mediated apoptosis [9]. Although caspases are activated during this process, interventions targeting apoptosis do not completely prevent cell death. Thus, although activated in I/R, apoptosis is not essential for subsequent cell death, suggesting the existence of other mechanisms governing cell death [10], such as ferroptosis. And indeed, mitochondria play a much more active role in ferroptosis than in apoptosis (17). Moreover, some morphological characteristics of mitochondria during I/R, including reduced mitochondrial volume, reduced or even lost mitochondrial cristae, and condensed mitochondrial membrane densities, are not associated with other forms of cell death, further emphasizing the relevance of ferroptosis [8].


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