First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.
Department of Sports Medicine, Guangzhou Sport University, Guangzhou, People's Republic of China.
Drug Des Devel Ther. 2022 Jul 1;16:2083-2099. doi: 10.2147/DDDT.S364441. eCollection 2022.
Albeit oxidative stress has been implied in the pathogenesis of tubal pregnancy (TP), there are scant data to suggest that ferroptosis occurs in TP. Shikonin plays a pivotal role in redox status, but whether it can regulate ferroptosis to treat TP remains unknown.
We collected and analyzed ferroptosis-related indices from the villous tissue (VT) of women suffering from TP and from women with a normal pregnancy. In vitro, we used shikonin and/or RAS-selective lethal 3 (RSL3) to intervene HTR-8/SVneo cells and further detected ferroptosis indices and cell functions. Finally, the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) is pharmacologically activated to explore the effect of Nrf2 on shikonin regulating ferroptosis.
Increased malondialdehyde content, reduced levels of glutathione and glutathione peroxidase (GPx), and upregulated protein expression which promoted ferroptosis were observed in the VT of TP patients, suggesting that ferroptosis occurred during TP. In vitro, shikonin enhanced ferroptosis sensitivity in HTR-8/SVneo cells induced by RSL3 via amplifying lipid peroxidation, which mainly included increasing cellular reactive oxygen species (ROS), lipid ROS and Fe level. RSL3 and/or shikonin inhibited Nrf2 and downregulated protein expression of SLC7A11 and GPx4 caused by RSL3 + shikonin co-treatment, which could be reversed under activation of Nrf2. Hence, shikonin facilitated lipid peroxidation by inhibiting Nrf2 signaling. Additionally, shikonin and/or RSL3 potently inhibited the invasion and migration of HTR-8/SVneo cells.
This study firstly showed that ferroptosis may be involved in TP pathogenesis and shikonin potentially targeted ferroptosis to treat TP.
尽管氧化应激被认为与输卵管妊娠（TP）的发病机制有关，但目前数据表明铁死亡发生在 TP 中。紫草素在氧化还原状态中起着关键作用，但它是否可以通过调节铁死亡来治疗 TP 尚不清楚。
我们收集并分析了患有 TP 的女性和正常妊娠女性的绒毛组织（VT）中的铁死亡相关指标。在体外，我们使用紫草素和/或 RAS 选择性致死 3（RSL3）干预 HTR-8/SVneo 细胞，并进一步检测铁死亡指标和细胞功能。最后，通过药理学激活核因子红细胞 2 相关因子 2（Nrf2）来探索 Nrf2 对紫草素调节铁死亡的影响。
TP 患者的 VT 中观察到丙二醛含量增加、谷胱甘肽和谷胱甘肽过氧化物酶（GPx）水平降低以及促进铁死亡的蛋白表达上调，表明铁死亡发生在 TP 中。在体外，紫草素通过放大脂质过氧化作用增强了 RSL3 诱导的 HTR-8/SVneo 细胞的铁死亡敏感性，主要包括增加细胞内活性氧（ROS）、脂质 ROS 和 Fe 水平。RSL3 和/或紫草素抑制了 RSL3+紫草素共处理引起的 Nrf2 和 SLC7A11 和 GPx4 蛋白表达下调，在 Nrf2 激活下可以逆转。因此，紫草素通过抑制 Nrf2 信号通路促进脂质过氧化。此外，紫草素和/或 RSL3 强烈抑制 HTR-8/SVneo 细胞的侵袭和迁移。
本研究首次表明铁死亡可能参与 TP 的发病机制，紫草素可能通过靶向铁死亡来治疗 TP。
