Icariin alleviates ferroptosis‐related atherosclerosis by promoting autophagy in xo‐LDL‐induced vascular endothelial cell injury and atherosclerotic mice

Abstract

Vascular endothelial cells (VECs) are located between the blood plasma and the vascular tissue, and the ferroptosis (iron‐dependent programmed cell death) of VECs can lead to a range of cardiovascular diseases. Icariin is the main active ingredient of Epimedium brevicornum Maxim., which can improve endothelial cell dysfunction. In the present study, the protective effects of icariin on oxidised low‐density lipoprotein (ox‐LDL)‐treated VECs and high‐fat diet‐fed Apolipoprotein E‐deficient mice were investigated. Inflammatory fibrosis in tissues and inflammatory factors in serum and cell supernatants were detected, and mitochondrial membrane potential and the expression levels of ferroptosis‐associated proteins were also detected. The results revealed that icariin reduced the endothelial atherosclerotic plaque area and collagen fibres in aortic sinus tissue, and increased the viability and mitochondrial membrane potential, whereas it reduced the reactive oxygen species levels of VECs. The nucleation of transcription factor EB (TFEB) and subsequent autophagy were negatively associated with ferroptosis in endothelial cells, and the more prominent the autophagy, the lower the levels of ferroptosis. Furthermore, by co‐treating the cells with icariin and the two autophagy inhibitors, Bafilomycin A1 (blocking autophagosome and lysosome fusion) and 3‐methyladenine (blocking autophagosome formation), respectively, the promoting effects of icariin on autophagy were found to be mediated through the process of autophagosome–lysosome fusion. In in vivo experiments, icariin reduced ferroptosis, alleviated atherosclerotic lesions and increased the rate of TFEB nucleation. Additionally, it was found that ARG304, THR308 and GLN311 were the optimal binding sites for the interaction between icariin and TFEB. Taken together, these results suggest that the fusion of autophagosomes and lysosomes promoted by icarrin enhances autophagy and thus reduces ferroptosis. Therefore, icariin may be a potential candidate for the prevention of ferroptosis of VECs and, thus, for the treatment of cardiovascular diseases.

Icariin Supplementation Suppresses the Markers of Ferroptosis and Attenuates the Progression of Nonalcoholic Steatohepatitis in Mice Fed a Methionine Choline-Deficient Diet

“…Additionally, targeting ALOX12 blocked NASH progression in mice treated with ML355, an enzymatic inhibitor of ALOX12 [35]. The inhibitory effects of icariin on ferroptosis have been reported in various disease models, including hypoxia/reoxygenation-induced myocardial injury [36], atherosclerosis [37], and prostate cancer [38]. This study demonstrates the inhibitory effects of icariin on ferroptosis in liver diseases.…”

Icariin‑curcumol promotes ferroptosis in prostate cancer cells through Nrf2/HO‑1 signaling

“…Specifically, curcumol can inhibit the endogenous production of ferroptosis in tumor cells and increase the concentration of free ferroptosis in the cytoplasm. These free ferroptosis can participate in the production of excessive ROS, thereby triggering autophagy and apoptosis in cells and inducing ferroptosis in tumor cells ( 38 ). Icariin and curcumol both have the ability to promote apoptosis in cells ( 27 ).…”

Ferroptosis: a potential target for the treatment of atherosclerosis

“…Icariin is a bioactive compound with both antioxidant and anti-inflammatory properties. Icariin inhibits ferroptosis and alleviates atherosclerosis by promoting autophagy in ApoE mice [160] .…”