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.