Wang Shuai, Song Xiaoliang, Gao Hui, Zhang Yi, Zhou Xin, Wang Fengrong
Liaoning University of Traditional Chinese Medicine, Shenyang, China.
Department of Cardiology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China.
Appl Biochem Biotechnol. 2025 Mar 22. doi: 10.1007/s12010-025-05214-3.
Targeting endothelial cell ferroptosis is a potential approach for the treatment of atherosclerosis (AS). 6-Gingerol (6-Gin) is an active substance in ginger that is beneficial for improving AS. We conducted this study to explore whether 6-Gin mediated AS progression by regulating ferroptosis of endothelial cells. ApoE-/- mice were fed a high-fat diet to establish AS mouse model. Additionally, oxidized low-density lipoprotein (ox-LDL) was used to treat human umbilical vein endothelial cells (HUVECs) to generate injured cell model. Ferroptosis was evaluated by propidium iodide staining assay, western blot, and detecting iron, glutathione, malonaldehyde, and reactive oxygen species levels. The results showed that ox-LDL inhibited the proliferation and induced inflammation and ferroptosis of HUVECs, which was reversed by 6-Gin treatment. Moreover, 6-Gin upregulated HO-1 and NQO1 levels and promoted nuclear translocation of NRF2 in ox-LDL-treated HUVECs. ATRA, an NRF2 inhibitor, abrogated the promotion of proliferation and the inhibition of inflammation and ferroptosis induced by 6-Gin. Additionally, 6-Gin alleviated AS and suppressed ferroptosis in vivo. In conclusion, 6-Gin inhibited endothelial cell ferroptosis by inactivating the NRF2/HO-1 pathway, thereby improving abnormal lipid metabolism in AS mice. These findings suggest that 6-Gin may be a novel therapeutic drug for AS.
靶向内皮细胞铁死亡是治疗动脉粥样硬化（AS）的一种潜在方法。6-姜酚（6-Gin）是生姜中的一种活性物质，对改善AS有益。我们开展本研究以探究6-Gin是否通过调节内皮细胞铁死亡来介导AS进展。给载脂蛋白E基因敲除（ApoE-/-）小鼠喂食高脂饮食以建立AS小鼠模型。此外，用氧化型低密度脂蛋白（ox-LDL）处理人脐静脉内皮细胞（HUVECs）以构建损伤细胞模型。通过碘化丙啶染色试验、蛋白质印迹法以及检测铁、谷胱甘肽、丙二醛和活性氧水平来评估铁死亡。结果显示，ox-LDL抑制HUVECs的增殖并诱导其炎症反应和铁死亡，而6-Gin处理可逆转这些作用。此外，6-Gin上调ox-LDL处理的HUVECs中血红素加氧酶-1（HO-1）和醌氧化还原酶1（NQO1）的水平，并促进核因子E2相关因子2（NRF2）的核转位。全反式维甲酸（ATRA），一种NRF2抑制剂，可消除6-Gin对增殖的促进作用以及对炎症和铁死亡的抑制作用。此外，6-Gin在体内减轻了AS并抑制了铁死亡。总之，6-Gin通过使NRF2/HO-1通路失活来抑制内皮细胞铁死亡，从而改善AS小鼠的脂质代谢异常。这些研究结果表明，6-Gin可能是一种治疗AS的新型药物。
