4. Conclusion and prospect
The occurrence of cerebrovascular events is the result of many factors. It is closely associated with various diseases, such as atherosclerosis, atrial fibrillation, diabetes mellitus, hypertension, obstructive sleep apnea, and so on. Comorbidities are the hallmark of stroke, which can both increase the incidence of stroke and worsen the outcome. More and more studies have shown that ferroptosis is not only involved in the occurrence and progression of AIS but also involved in the chronic pathogenesis of AIS risk factors.
This article mainly reviews the mechanism of ferroptosis in the occurrence and development of acute ischemic stroke. By introducing the relationship between ferroptosis and AS, AF, HF, DM, OSA, and the specific mechanism of ferroptosis after acute ischemic stroke, it is further explained that ferroptosis plays a very important role in the occurrence and development of AIS. At the same time, the following thoughts are also triggered: (1) Although this paper describes the correlation between ferroptosis and AIS risk factors, the research on the mechanism of ferroptosis and AIS risk factors is limited, and the specific mechanism of ferroptosis is not clear, which is worthy of further research by scientists. (2) Smoking, alcohol consumption, and hyperlipidemia are also common risk factors for AIS. In future studies, we can establish an acute ischemic stroke model in mice with AIS risk factors, study the specific mechanism of neuronal ferroptosis, and find targeted drugs and inhibitors to observe the impact on the prognosis and treatment of AIS. (3) At least two or more types of programmed cell death may occur in the occurrence and development of AIS. Therefore, only targeting ferroptosis may not achieve the desired effect, and in the future, multiple targets combined with cell death methods such as apoptosis, autophagy, and necrosis can effectively treat the disease. (4) So far, there is no clinical trial of inhibitors of ferroptosis for the treatment of ischemic stroke. This field needs further exploration and more population-based data are needed to determine whether the prognosis of AIS patients can be improved by inhibiting ferroptosis. With the deepening of research, inhibition of ferroptosis is likely to become an effective strategy for the treatment of ischemic stroke.
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Figure 1 Mechanism and regulation of ferroptosis in acute ischemic stroke
Related regulatory mechanisms of iron metabolism: damage of the blood-brain barrier, imbalance of iron transport, and NCOA4-mediated ferritin autophagy can lead to iron overload and induce the Fenton reaction to produce a large number of ROS. Lipid metabolism related regulatory mechanisms: The increased expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipoxygenases (LOXs) induced lipid peroxidation. Amino acid metabolism related regulatory mechanisms: The expression of solute carrier family 7 member 11(SLC7A11) was inhibited and the synthesis of glutathione (GSH) was restricted. The decreased content of glutathione peroxidase 4 (GPX4) eventually led to excessive accumulation of lipid peroxide. Polyunsaturated fatty acids (PUFAs); prostaglandin-endoperoxide synthase 2 (PTGS2); cyclooxygenase-2 (COX2); arachidonic acid (AA); adrenic acid (AdA); lyso-phosphatidylcholine acyltransferase-3 (LPCAT3); lipid peroxide (L-OOH); Phospholipids-H (L-OH); solute carrier family 3 member A2 (SLC3A2); glutathione- cysteine ligase (GCL); glutathione synthase (GSS); oxidized glutathione (GSSH); transferrin (TF); transferrin receptor1 (TFR1); Divalent metal transporter 1 (DMT1); Six-transmembrane epithelial antigen of prostate 3 (STEAP3); labile iron pool (LIP); ferroportin (FPN)
Figure 2 Atherosclerosis associated ferroptosis hub gene
TP53 , MAPK1 , STAT3 , HMOX1 and PTGS2may be the key hub genes of AS-associated ferroptosis.
Figure 3 Atrial fibrillation risk factors regulate ferroptosis and affect atrial fibrillation susceptibility
Alcohol consumption, obesity, and sepsis are risk factors for atrial fibrillation, which can participate in the regulation of ferroptosis and affect the susceptibility to atrial fibrillation.