Matrine Alleviates Atherosclerosis by Targeting REG1A and Activating the PI3K/AKT/mTOR Pathway to Inhibit Endothelial Cell Ferroptosis

Matrine, a natural alkaloid, has a wide range of pharmacological effects, such as antibacterial, anti-inflammatory, anti-oxidation, and anti-tumor. However, the molecular mechanism of matrine in the treatment of atherosclerosis (AS) is not fully understood. Human umbilical vein endothelial cells (HUVECs) were treated with 100 μg/mL ox-LDL to construct an AS cell model in vitro, and the cells were treated with matrine at different concentrations. Our results showed that matrine alleviated the decrease of HUVEC viability and the increase of ferroptosis induced by ox-LDL treatment. Subsequently, we found that matrine targeted regenerating family member 1 alpha (REG1A) and inhibited the expression level of REG1A in ox-LDL treated HUVECs. Overexpression of REG1A attenuated the improvement of matrine on activation of the PI3K/Akt/mTOR pathway and ferroptosis in ox-LDL treated HUVECs. In addition, both LY294002 (an inhibitor of the PI3K signaling) and Erastin (an inducer of ferroptosis) reversed the alleviation of matrine treatment on ferroptosis in ox-LDL treated HUVECs. The results in vivo showed that matrine treatment inhibited high-fat diet-induced aortic ferroptosis in ApoE^-/- mice and alleviated arterial tissue lesions. In summary, matrine inhibits ferroptosis by targeting REG1A to activate PI3K/Akt/mTOR pathway, thereby alleviating aortic endothelial injury and lipid plaque formation in AS mice, suggesting that matrine has potential value for the treatment of AS.