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.