2.3 Dysregulation of lipid metabolism leads to ferroptosis
Neuronal cells are prone to ferroptosis caused by iron-dependent lipid ROS accumulation, mainly because the brain is rich in polyunsaturated fatty acids (PUFAs), which are susceptible to lipoxygenases and reactive oxygen species (ROS) to generate lipid peroxides46. PUFAs, especially arachidonic acid (AA) and adrenic acid (ADA) are highly susceptible to oxidation and subsequently lead to the accumulation of lipid peroxides (LOOH) and ROS 47. Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lyso-phosphatidylcholine acyltransferase-3 (LPCAT3), as promoters of the esterification of AA and ADA into PE, play an important role in the formation of AA/ADA-PE48,49. AA/AdA-PE is converted to the harmful PE-AA-OOH or PE-ADA-OOH by lipoxygenase (LOXs) through enzymatic or non-enzymatic lipid peroxidation, resulting in the formation of large amounts of lipid peroxides, which leads to the destruction of membrane integrity and ferroptosis 50,51.
ACSL4 is widely expressed in brain tissue, and as a potential target of miR-347 after cerebral ischemia, it is upregulated with over-expression of miR-347 after cerebral ischemia in mice, inducing neuronal death52. Some studies have proposed that upregulation of thrombin after acute cerebral ischemia reperfusion can promote arachidonic acid mobilization by not affecting intracellular Fe2+ level, and then catalyzed esterification by ACSL4 stimulates ferroptosis signal transduction, leading to ferroptosis of neuronal cells. The results of this study strongly suggest that antithrombin therapy may be beneficial to post-stroke reperfusion by inhibiting ferroptosis4. It is worth further study. ACSL4 also promotes the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6(IL-6), and interleukin-1β (IL-1β) by microglia, which further exacerbates brain injury by promoting the inflammatory response after AIS53. It was found that ACSL4 expression was increased in a mouse model of ischemic stroke, and inhibition of ACSL4 with rosiglitazone significantly improved neurological function and reduced infarct volume 72 h after stroke39. These studies suggest that ACSL4 may be a novel regulator of neuronal death and neuroinflammation, and intervention of ACSL4 expression may be a potential therapeutic target for ischemic stroke. However, there are still few related studies in this field, so more studies should be conducted in the future to reveal the specific mechanism of action of ACSL4 in the occurrence of ferroptosis in patients with ischemic stroke.
LOXs are key enzymes in the induction of ferroptosis54. There are several subtypes of LOXs, of which 12/15-LOX is a particular subtype. The study found that after focal ischemia, 12/15-LOX was increased in neurons and endothelial cells. Overexpression of 12/15-LOX leads to neuronal death in the brain and disruption of the blood-cerebrospinal fluid barrier, and the use of 12/15-LOX inhibitors can improve neurological function and reduce cerebral edema55. And research has found that 12/15-LOX is up-regulated following global cerebral ischemia, and contributes to neuronal injury. Either gene knockout or treatment with the 12/15-LOX inhibitor LOXBlock-1 reduce injury and improve neurological outcome56. These findings suggest that increased expression of 12/15-LOX is involved in neuronal cell death after cerebral ischemia, and its inhibitor may be a novel therapeutic approach for alleviating cerebral ischemia injury. However, whether 12/15-LOX is involved in post-AIS neuronal cell death mainly by mediating ferroptosis remains unclear and deserves further study.