2.1 Disorder of iron metabolism leads to ferroptosis
Iron is an important participant and regulator in the normal
physiological activity of the brain and is abundant in brain tissue15,16. Physiologically, the brain is protected from
whole-body iron fluctuations due to the protection provided by the
blood-brain barrier (BBB) 17. Under normal
circumstances, BBB endothelial cells through the transferrin receptor -
transferrin (TFR - TF) compounds mediated endocytosis of inactive iron
intake
(Fe3+)18,
then through the Six-transmembrane epithelial antigen of prostate 3
(STEAP3) convert Fe3+ to free iron
(Fe2+). Fe2+ is transported from
endosomes by divalent metal transporter 1 (DMT1) and exported to the
extracellular space of the brain by active transport or exocytosis
mediated by ferroportin (FPN)19,20, and can also be
stored in ferritin or the labile iron pool (LIP)21,
which is involved in lipid ROS production. Studies have shown that BBB
capillary endothelial cells can store and release iron in a regulated
manner, thus acting as an iron reservoir for the brain22. Under acute ischemic conditions, microglia are
overactivated by ischemic stimuli, resulting in disruption of the BBB23, and free iron and ferritin enter the brain
parenchyma when the BBB is disrupted. Studies have shown that the
expressions of TFR1 and DMT1 can be significantly increased, and the
expression level of FPN can be decreased in the middle cerebral artery
ischemia model of MCAO rats24,25, indicating that the
ability of intracellular iron uptake is enhanced and the ability of iron
efflux is weakened after cerebral ischemia, which will eventually lead
to intracellular iron overload. In addition, in the MCAO rat model, the
assembly of cytoplasmic NCOA4 protein in neurons is significantly
increased to recognize ferritin and transport it to lysosome for
degradation, resulting in a significant increase in the concentration of
free iron in neurons26. Knockdown of the NCOA4gene can reduce the uptake of ferritin, avoid the accumulation of free
iron and eliminate the accumulation of reactive oxygen species, thereby
interfering with ferroptosis 27. This suggests that
NCOA4-mediated ferritin autophagy is one of the additional key
mechanisms mediating ferroptosis in AIS. Therefore, any form of induced
iron transport imbalance, autophagic degradation of ferritin, and
impairment of the blood-brain barrier will lead to iron overload in the
brain. Excessive intracellular Fe2+ can not only
generate ROS through the Fenton reaction but also participate in the
synthesis of lipoxygenase and then catalyze lipid
peroxidation28,29. Lethal accumulation of
intracellular lipid peroxides as well as reactive oxygen species
promotes nuclear, protein, and membrane damage that ultimately mediates
cell death. Studies have shown that the increase of intracellular free
iron is positively correlated with the degree of neuronal damage after
ischemic stroke30, which directly affects the recovery
of cerebral nerve function. In the early stages of ischemia-reperfusion,
iron overload increases the risk of bleeding transformation after early
tPA administration, accelerates ischemia-induced elevation of serum
matrix metalloproteinase-9, and enhances lipid peroxidation, thereby
increasing the likelihood of adverse outcomes31. A
clinical trial reports that the use of the iron-chelating agent
deferoxamine to reduce systemic iron levels within 1-3 days of ischemic
stroke may be beneficial for short-term outcomes in patients with acute
ischemic stroke10. It has also been proposed that the
use of ferroptosis inhibitors liproxstatin-1 and ferrostatin-1 can
reduce neurological dysfunction and cerebral infarct size in MCAO mice32. Therefore, rational application of ferroptosis
inhibitors such as deferoxamine to reduce the iron content in the brain
after AIS can reduce neuronal death and promote the recovery of
neurological function after ischemic stroke.