Progress of Ferroptosis in Ischemic Stroke and Therapeutic Targets

Abstract

Ferroptosis is an iron-dependent form of programmed cell death (PCD) and ischemic stroke (IS) has been confirmed to be closely related to ferroptosis. The mechanisms of ferroptosis were summarized into three interrelated aspects: iron metabolism, lipid peroxide metabolism, as well as glutathione and amino acid metabolism. What's more, the causal relationship between ferroptosis and IS has been elucidated by several processes. The disruption of the blood-brain barrier, the release of excitatory amino acids, and the inflammatory response after ischemic stroke all lead to the disorder of iron metabolism and the antioxidant system. Based on these statements, we reviewed the reported effects of compounds and drugs treating IS by modulating key molecules in ferroptosis. Through detailed analysis of the roles of these key molecules, we have also more clearly demonstrated the essential effect of ferroptosis in the occurrence of IS so as to provide new targets and ideas for the therapeutic targets of IS.

Keywords: Ferroptosis; Iron overload; Ischemic stroke; Lipid peroxidation.

Fig. 1

Cellular metabolic mechanism of ferroptosis. ACSL4, acyl-CoA synthetase long-chain family member 4; DMT1, divalent metal transporter 1; FPN, ferroportin; FT, ferritin; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, oxidized glutathione; LOX, lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3; NADP⁺, β-nicotinamide adenine dinucleotide phosphate; NADPH, nicotinamide adenine dinucleotide phosphate oxidase; PEs, phosphatidylethanolamines; PUFA, polyunsaturated fatty acid; ROS, reactive oxygen species; STEAT3, six-transmembrane epithelial antigen of prostate 3; TF, transferrin; TFR1, transferrin receptor 1; γ-GCS, γ-glutamyl cysteine synthetase

Fig. 2

Mechanisms of ferroptosis in ischemic stroke. BBB, blood–brain barrier; DMT1, divalent metal transporter 1; Glu, glutamate; GPX4, glutathione peroxidase 4; GSH, glutathione; IS, ischemic stroke; TFR1, transferrin receptor 1