Ecdysterone Alleviates Atherosclerosis by Inhibiting <scp>NCF2</scp> and Inhibiting Ferroptosis Mediated by the <scp>PI3K</scp>/Akt/Nrf2 Pathway

Ecdysterone (Ecd), an active ingredient in trianthema, has a strong anti-inflammatory effect. This study aimed to explore the potential mechanism by which Ecd improves atherosclerosis (AS). Here, we systematically investigated the mechanism of Ecd in human umbilical vein endothelial cells (HUVECs) treated with oxidised low-density lipoprotein (ox-LDL). In ox-LDL-treated HUVECs, Ecd promoted HUVEC viability as well as inhibited ferroptosis and the secretion of inflammatory factors (TNF-α, IL-6 and IL-1β). In addition, Ecd inhibited the expression of neutrophil cytoplasmic factor 2 (NCF2) and triggered the PI3K/AKT/Nrf2 signalling pathway, thereby alleviating the increase of ferroptosis in ox-LDL-treated HUVECs. More importantly, we constructed an AS mouse model by feeding ApoE^-/- mice with a high-fat diet and found that Ecd treatment alleviated vasculopathy and arterial ferroptosis and inhibited the secretion of inflammatory factors in vivo, which could be reversed by overexpression of NCF2. Overall, this study showed that the protective effect of Ecd on AS is mainly achieved by inhibiting NCF2 and activating the PI3K/Akt/Nrf2 pathway to inhibit ferroptosis. Therefore, Ecd may be an effective drug to improve AS by inhibiting ferroptosis-induced inflammation.