Xi Chen, Zhou Jie, Zheng Xin, Fu Xiaoyi, Xie Minjuan
Pharmaceutical Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.
School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, Jiangxi, P.R. China.
Sci Rep. 2025 Jan 7;15(1):1141. doi: 10.1038/s41598-024-79723-2.
Sodium aescinate (SA), a natural plant extract with various bioactivities, is widely used to treat oedema and inflammation in clinics. However, adverse events, including liver injury, kidney injury, and phlebitis, have been reported in patients with SA in recent years. In this study, we used BALB/c mice and L02 cells to evaluate the role of ferroptosis in SA-induced liver injury. SA significantly increased AST, ALT, MDA and Fe, decreased GSH levels, and induced pathological changes in the liver in vivo. SA also reduced the viability of L02 cells and induced LDH release, intracellular cysteine reduction, GSH depletion, iron accumulation, ROS production, and lipid peroxidation, indicating that SA causes ferroptosis. In addition, SA inhibited transcriptional activity of activating transcription factor 4 (ATF4) and subsequently reduced the expression of the downstream genes xCT (solute carrier family 7a member 11, SLC7A11) and Cystathionine gamma-lyase (CTH) which play vital roles in GSH biosynthesis. Interestingly, the cytotoxic effects of SA were effectively attenuated by ATF4 overexpression, while they were significantly aggravated by ATF4 silencing. These results revealed that SA triggers hepatocyte ferroptosis by inhibiting the activity of ATF4, which causes an oxidative imbalance.
七叶皂苷钠（SA）是一种具有多种生物活性的天然植物提取物，在临床上广泛用于治疗水肿和炎症。然而，近年来有报道称使用SA的患者出现了包括肝损伤、肾损伤和静脉炎在内的不良事件。在本研究中，我们使用BALB/c小鼠和L02细胞来评估铁死亡在SA诱导的肝损伤中的作用。SA显著升高了体内的天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、丙二醛（MDA）和铁含量，降低了谷胱甘肽（GSH）水平，并诱导了肝脏的病理变化。SA还降低了L02细胞的活力，诱导了乳酸脱氢酶（LDH）释放、细胞内半胱氨酸减少、GSH耗竭、铁积累、活性氧（ROS）产生和脂质过氧化，表明SA导致了铁死亡。此外，SA抑制了激活转录因子4（ATF4）的转录活性，随后降低了下游基因溶质载体家族7成员11（SLC7A11）和胱硫醚γ-裂解酶（CTH）的表达，这两个基因在GSH生物合成中起重要作用。有趣的是，ATF4过表达有效减轻了SA的细胞毒性作用，而ATF4沉默则显著加剧了这种作用。这些结果表明，SA通过抑制ATF4的活性触发肝细胞铁死亡，从而导致氧化失衡。
