Emerging Role of Ferroptosis in the Pathogenesis of Ischemic Stroke: A New Therapeutic Target?

Abstract

Ischemic stroke is one of the main causes of high morbidity, mortality, and disability worldwide; however, the treatment methods are limited and do not always achieve satisfactory results. The pathogenesis of ischemic stroke is complex, defined by multiple mechanisms; among them, programmed death of neuronal cells plays a significant role. Ferroptosis is a novel type of regulated cell death characterized by iron redistribution or accumulation and increased lipid peroxidation in the membrane. Ferroptosis is implicated in many pathological conditions, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. In this review, we summarize current research findings on ferroptosis, including possible molecular mechanisms and therapeutic applications of ferroptosis regulators, with a focus on the involvement of ferroptosis in the pathogenesis and treatment of ischemic stroke. Understanding the role of ferroptosis in ischemic stroke will throw some light on the development of methods for diagnosis, treatment, and prevention of this devastating disease.

Neuroinflammation, Stem Cells, and Stroke

“…26 Targeting ferroptosis serves as a promising approach for treating ischemic stroke; however, the exact mechanisms linking ferroptosis and inflammation remain under investigation. 27 Indeed, microglial activation occurs within minutes after stroke. A defective microglial activation may increase infarction and apoptosis after stroke.…”

Identification of a ferroptosis-related gene pair biomarker with immune infiltration landscapes in ischemic stroke: a bioinformatics-based comprehensive study

“…Unlike the mitochondrial morphology of other types of cell death, the shrunken mitochondria, increased membrane densities, reduced or disappeared mitochondria crista along with intact nucleus can be observed in ferroptosis under transmission electron microscopy [ 6 – 8 ]. The possible molecular mechanisms of ferroptosis involve abnormal iron metabolism, lipid peroxidation, and some critical enzymes (like GPX4) [ 9 ]. Although ferroptosis is first formally put forward in tumors [ 10 ], a growing body of work has demonstrated that it is also related to ischemic events, such as in intestinal, lung, and renal [ 11 – 13 ].…”

Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Pulmonary Fibrosis

“…Recently, an iron-dependent and non-apoptotic regulatory cell death mechanism have been discovered and named ferroptosis ( Zhang et al, 2021 ). Ferroptosis is widely involved in the development of stroke, brain injury, and tumors ( Bu et al, 2021 ; Guan et al, 2021 ; Hu et al, 2021 ). However, iron is an essential reagent for normal physiological activities of cells, ferroptosis is distinguished from other forms of cell death such as apoptosis, necrosis, and autophagy by the lethal iron-dependent accumulation of lipid-based reactive oxygen species (ROS) ( Ye et al, 2019 ).…”