Xiang Ming, Lin Xiangdong, Chen Haiying
Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan, China.
Key Laboratory of TCM Heart and Lung Syndrome Differentiation & Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
Cell Biochem Biophys. 2025 Jul 28. doi: 10.1007/s12013-025-01831-1.
Coronary heart disease (CHD) is a disease caused by organic and functional coronary artery stenosis, resulting in a reduced oxygen supply to the heart. This study aimed to investigate the mechanism via which Luteolin regulates the Sirt1/Nrf2 pathway to inhibit ferroptosis in human umbilical vein endothelial cells (HUVEC) associated with CHD. An ox-LDL-induced HUVEC cell model with Sirt1 silencing and Luteolin treatment was established. The silencing efficiency of Sirt1 was validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. The results of molecular docking and DARTS experiments showed that Luteolin could effectively bind Sirt1. Subsequently, we measured the expression of Nrf2 and Sirt1, cell viability, MDA, GSH, Fe levels, lipid ROS content, expression of ferroptosis-related proteins GPX4, FTH, FTL, and cell migration parameters. The results showed that Luteolin could activate the Sirt1/Nrf2 axis and effectively inhibit ox-LDL-induced ferroptosis in HUVEC. Experimental results revealed that Luteolin could enhance HUVEC cell viability, decrease MDA, Fe, and ROS levels, increase GSH levels, promote the expression of HO-1, GPX4, FTH, FTL, inhibit the expression of ACSL4 and TFRC, and enhance the migration capability of HUVEC cells. Moreover, silencing Sirt1 reversed the effects of Luteolin on the activation of Sirt1 and Nrf2, confirming the dependence of these effects on the Sirt1/Nrf2 signaling pathway. In conclusion, this study indicates that Luteolin could inhibit ferroptosis in HUVEC in CHD by modulating the Sirt1/Nrf2 axis, providing a basis for further research on strategies for preventing and treating CHD and related diseases.
冠心病（CHD）是一种由冠状动脉器质性和功能性狭窄引起的疾病，导致心脏氧气供应减少。本研究旨在探讨木犀草素调节Sirt1/Nrf2通路以抑制与冠心病相关的人脐静脉内皮细胞（HUVEC）铁死亡的机制。建立了沉默Sirt1并经木犀草素处理的氧化型低密度脂蛋白（ox-LDL）诱导的HUVEC细胞模型。使用定量逆转录聚合酶链反应（qRT-PCR）和蛋白质免疫印迹分析验证Sirt1的沉默效率。分子对接和DARTS实验结果表明，木犀草素能有效结合Sirt1。随后，我们检测了Nrf2和Sirt1的表达、细胞活力、丙二醛（MDA）、谷胱甘肽（GSH）、铁水平、脂质活性氧（ROS）含量、铁死亡相关蛋白谷胱甘肽过氧化物酶4（GPX4）、铁蛋白重链（FTH）、铁蛋白轻链（FTL）的表达以及细胞迁移参数。结果表明，木犀草素可激活Sirt1/Nrf2轴并有效抑制ox-LDL诱导的HUVEC铁死亡。实验结果显示，木犀草素可提高HUVEC细胞活力，降低MDA、铁和ROS水平，增加GSH水平，促进血红素加氧酶-1（HO-1）、GPX4、FTH、FTL的表达，抑制长链脂酰辅酶A合成酶4（ACSL4）和转铁蛋白受体（TFRC）的表达，并增强HUVEC细胞的迁移能力。此外，沉默Sirt1可逆转木犀草素对Sirt1和Nrf2激活的影响，证实这些作用依赖于Sirt1/Nrf2信号通路。总之，本研究表明木犀草素可通过调节Sirt1/Nrf2轴抑制冠心病中HUVEC的铁死亡，为进一步研究冠心病及相关疾病的防治策略提供了依据。
