Drug Design, Development and Therapy (Jul 2022)

Shikonin Could Be Used to Treat Tubal Pregnancy via Enhancing Ferroptosis Sensitivity

  • Lai Y,
  • Zeng F,
  • Chen Z,
  • Feng M,
  • Huang Y,
  • Qiu P,
  • Zeng L,
  • Ke Y,
  • Deng G,
  • Gao J

Journal volume & issue
Vol. Volume 16
pp. 2083 – 2099

Abstract

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Yuling Lai,1,2 Fuling Zeng,1 Zhenyue Chen,1 Min Feng,1 Yanxi Huang,3 Pin Qiu,3 Lihua Zeng,1 Yan Ke,4 Gaopi Deng,3,* Jie Gao3,* 1First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Sports Medicine, Guangzhou Sport University, Guangzhou, People’s Republic of China; 3Department of Gynaecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4Department of Gynaecology, Shenzhen Chinese and Western Medicine Hospital, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Gao; Gaopi Deng, Email [email protected]; [email protected]: 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.Methods: 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.Results: 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 Fe2+ 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.Conclusion: This study firstly showed that ferroptosis may be involved in TP pathogenesis and shikonin potentially targeted ferroptosis to treat TP.Keywords: ectopic pregnancy, shikonin, lipid peroxidation, iron dependent

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