Huang Dan, Dong Xin, Li Jianzhe, Chen Yudan, Zhou Ying, Chen Qingjie, Sun Yuewen
Guangxi Vocational University of Agriculture, Nanning, China.
Department of Oncology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China.
Med Oncol. 2023 Mar 28;40(5):132. doi: 10.1007/s12032-023-02000-1.
Hepatocellular carcinoma (HCC) is a common type of solid liver carcinoma. Regulating ferroptosis is important for the treatment of HCC. SSPH I is an anti-HCC steroidal saponin isolated from Schizocapsa plantaginea Hance. In this study, we found that SSPH I exerted significant anti-proliferation and anti-migration effects on HepG2 cell, ferroptosis inhibitor ferrostatin-1 or iron chelator ciclopirox partly attenuated the effect of SSPH I. SSPH I also induced apoptosis and G2/M phase cell cycle arrest. ROS accumulation, glutathione depletion and malondialdehyde accumulation were detected after SSPH I treatment, which leads to lipid peroxidation. Ferrostatin-1 or ciclopirox showed a significant antagonist effect towards SSPH I induced lipid peroxidation. Furthermore, typical morphologic changes of ferroptosis, such as increasing density of mitochondrial membrane and reduction of mitochondrial cristae were observed in HepG2 cells after SSPH I treatment. SSPH I does not regulate the xCT protein. Interestingly, SSPH I elevated the expression levels of SLC7A5, which is the negative regulator of ferroptosis. In contrast, SSPH I upregulated the expression of TFR and Fpn proteins, leading to the accumulation of Fe. Ferrostatin-1 and ciclopirox presented a similar antagonist effect on SSPH I. In conclusion, our research first reveals that SSPH I induced ferroptosis in HepG2 cells. In addition, our results suggest that SSPH I induces ferroptosis by causing iron overload in HepG2 cells.
肝细胞癌（HCC）是一种常见的肝脏实体癌。调节铁死亡对HCC的治疗很重要。SSPH I是从狭叶裂果薯中分离得到的一种抗HCC甾体皂苷。在本研究中，我们发现SSPH I对HepG2细胞具有显著的抗增殖和抗迁移作用，铁死亡抑制剂铁抑素-1或铁螯合剂环吡酮可部分减弱SSPH I的作用。SSPH I还可诱导细胞凋亡和G2/M期细胞周期阻滞。SSPH I处理后检测到活性氧积累、谷胱甘肽耗竭和丙二醛积累，从而导致脂质过氧化。铁抑素-1或环吡酮对SSPH I诱导的脂质过氧化具有显著的拮抗作用。此外，SSPH I处理后的HepG2细胞中观察到了铁死亡的典型形态学变化，如线粒体膜密度增加和线粒体嵴减少。SSPH I不调节xCT蛋白。有趣的是，SSPH I提高了铁死亡负调节因子SLC7A5的表达水平。相反，SSPH I上调了TFR和Fpn蛋白的表达，导致铁的积累。铁抑素-1和环吡酮对SSPH I表现出类似的拮抗作用。总之，我们的研究首次揭示了SSPH I在HepG2细胞中诱导铁死亡。此外，我们的结果表明，SSPH I通过导致HepG2细胞中铁过载来诱导铁死亡。
