2.2 Disorder of amino acid metabolism leads to ferroptosis
System Xc- is a cystine/glutamic acid anti-transporter, which is composed of light chain SLC7A11 and heavy chain SLC3A2, and is an important intracellular antioxidant element. System Xc- exchanges glutamate and cystine inside and outside the cell in a 1:1 ratio33. Extracellular cystine is introduced into cells via SLC7A11, the light chain of System Xc-. The cystine that enters the cells is reduced to cysteine, and glutamic acid and glycine are added to produce glutathione (GSH) under the catalyst of cysteine ligase (GCL) and glutathione synthase (GSS), respectively. GSH is an important antioxidant, which can enhance the anti-lipid peroxidation activity of glutathione peroxidase 4 (GPX4). GPX4 can catalyze reduced GSH into oxidized glutathione (GSSG). Normally, reduced GSH accounts for the majority, and GPX4 takes GSH as the substrate to react with lipid peroxides to play an antioxidant role. Ultimately, it reduces the occurrence of lipid peroxidation and ferroptosis and protects cells from oxidative damage34.
After acute ischemic stroke, excess extracellular glutamate inhibits the activity of System Xc- by restricting cystine absorption, thereby affecting GSH synthesis35. In addition, acute ischemia and hypoxia can increase the expression of BACH1, ATF3, and p53 , and these factors can reduce the uptake of cystine by neurons by inhibiting the expression of System Xc- light chain SLC7A11, leading to a decrease in GSH synthesis36-38. Other studies have suggested that GPX4 protein expression and activity decreased after acute ischemic stroke 39. The abnormal function of these specific factors can lead to the accumulation of lipid peroxides in cells and eventually ferroptosis. The above results suggest that ferroptosis of cells caused by amino acid metabolism disorder after AIS is manifested in the following three aspects: (1) inhibition of System Xc-; (2) decreased glutathione synthesis; (3) The expression and activity of GPX4 were decreased. This suggests that ferroptosis can be inhibited by intervening in the above process, and related studies have used some drugs to intervene in the above process to inhibit the occurrence of ferroptosis. Some studies have shown that galangin and Naotaifang extracts can inhibit ferroptosis and reduce neuronal cell death by enhancing the expression of SLC7A11 and GPX424,40. Edaravone is an antioxidant protective agent that effectively inhibits ferroptosis caused by decreased GSH content caused by cystine deficiency41. Furthermore, in the rat ischemic stroke model, it was found that edaravone treatment reduced Fe2+, MDA, and LPO in the brain tissue, increased GSH content, and up-regulated GPX4 expression, suggesting that edaravone could inhibit ferroptosis and attenuate cerebral ischemia-reperfusion injury25. Edaravone is currently used in the treatment of acute ischemic stroke. Research shows that post-tMCAO selenium treatment significantly reduces cerebral infarct volume, oxidative stress, and ferroptosis and enhances post-tMCAO motor performance in the acute phase after stroke42. Carvacrol can inhibit ferroptosis by enhancing GPX4 expression, thereby rescuing hippocampal neuronal injury induced by reperfusion 43. Icariin has been shown to have a neuroprotective effect against acute ischemic stroke44. In a study of the action and mechanism of icariin as a synovitis therapeutic agent, it was found that icariin enhances cell survival in lipopolysaccharide-induced synoviocytes by suppressing ferroptosis via the Xc-/GPX4 axis45. However, there is still a lack of relevant studies on the effect of icariin on anti-ferroptosis to improve the prognosis of AIS. Therefore, regulating amino acid metabolism and GPX4 expression can reduce neuronal ferroptosis and promote brain injury recovery after AIS. In the future, more sensitive drugs can be developed to inhibit ferroptosis according to the specific mechanism of amino acid metabolism disorders, to improve the treatment and prognosis of AIS.