Zhao Liang, Gao Qing, Hu Kaifeng, Lu Shaoying
Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi, People's Republic of China.
Department of Nursing, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
Biochem Genet. 2025 Apr 25. doi: 10.1007/s10528-025-11117-z.
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.
苦参碱是一种天然生物碱，具有广泛的药理作用，如抗菌、抗炎、抗氧化和抗肿瘤作用。然而，苦参碱治疗动脉粥样硬化（AS）的分子机制尚未完全明确。体外培养人脐静脉内皮细胞（HUVECs），用100μg/mL氧化型低密度脂蛋白（ox-LDL）处理构建AS细胞模型，再用不同浓度的苦参碱处理细胞。结果显示，苦参碱可减轻ox-LDL处理诱导的HUVECs活力下降和铁死亡增加。随后，发现苦参碱靶向再生蛋白家族成员1α（REG1A），并抑制ox-LDL处理的HUVECs中REG1A的表达水平。REG1A过表达减弱了苦参碱对ox-LDL处理的HUVECs中PI3K/Akt/mTOR通路激活和铁死亡的改善作用。此外，磷脂酰肌醇-3激酶（PI3K）信号抑制剂LY294002和铁死亡诱导剂Erastin均可逆转苦参碱处理对ox-LDL处理的HUVECs铁死亡的缓解作用。体内实验结果表明，苦参碱治疗可抑制高脂饮食诱导的载脂蛋白E（ApoE）小鼠主动脉铁死亡，并减轻动脉组织损伤。综上所述，苦参碱通过靶向REG1A抑制铁死亡以激活PI3K/Akt/mTOR通路，从而减轻AS小鼠的主动脉内皮损伤和脂质斑块形成，提示苦参碱在AS治疗中具有潜在价值。
