3.1.1 Ferroptosis is involved in endothelial dysfunction in AS
An important mechanism by which ferroptosis occurs is iron overload.
Studies have found that chronic iron overload can exacerbate the
atherosclerotic process, which is associated with oxidative stress and
vascular endothelial dysfunction 58,59. A clinical
trial has reported that iron levels increase in carotid atherosclerotic
lesions compared to normal healthy human endothelium and are further
elevated in advanced AS, inducing oxidative stress and inflammatory
responses60. Induced oxidative stress is mainly
manifested by excessively stored iron leading to peroxidative damage in
the inner wall of the artery by increasing the production of oxygen free
radicals, which further aggravates AS. Inflammatory response induction
mainly shows that with the progression of the disease, long-term iron
overload leads to the increase and dominance of M1 macrophages, which
can secrete pro-inflammatory factor TNF-α, etc61.
Blood vessels infiltrated by long-term inflammatory factors are prone to
the aggregation and oxidation of LDL, promoting the formation of foam
cells and the deposition of atherosclerotic plaques. In turn, it
promotes the development of AS and ferroptosis of macrophages in
plaques62. Administration of ferroptosis inhibitor
ferrostatin-1 significantly ameliorated ROS-induced lipid peroxidation
and endothelial dysfunction, thereby attenuating atherosclerotic
lesions11. A recent study demonstrated for the first
time that ionizing radiation can induce ferroptosis in endothelial cells
through NCOA4-mediated ferritin autophagy to promote plaque progression
in AS. At the same time, this study also proposed that the knockdown of
NCOA4 has a therapeutic effect in alleviating ionizing radiation-induced
ferroptosis in endothelial cells63. The above studies
suggest that ferroptosis is involved in endothelial dysfunction and
plays an important role in the occurrence and development of AS.