Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis
Abstract 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 use...
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-79723-2 |
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| author | Chen Xi Jie Zhou Xin Zheng Xiaoyi Fu Minjuan Xie |
| author_facet | Chen Xi Jie Zhou Xin Zheng Xiaoyi Fu Minjuan Xie |
| author_sort | Chen Xi |
| collection | DOAJ |
| description | Abstract 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 Fe2+, 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. |
| format | Article |
| id | doaj-art-b8a9416b0af945aeaaf8b707e3d679f7 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-b8a9416b0af945aeaaf8b707e3d679f72025-01-12T12:23:42ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-024-79723-2Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosisChen Xi0Jie Zhou1Xin Zheng2Xiaoyi Fu3Minjuan Xie4Pharmaceutical Department, The First Affiliated Hospital of Zhengzhou UniversitySchool of Medicine, Yichun UniversitySchool of Medicine, Yichun UniversitySchool of Medicine, Yichun UniversitySchool of Medicine, Yichun UniversityAbstract 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 Fe2+, 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.https://doi.org/10.1038/s41598-024-79723-2Sodium aescinateATF4GSHFerroptosisHepatotoxicity |
| spellingShingle | Chen Xi Jie Zhou Xin Zheng Xiaoyi Fu Minjuan Xie Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis Scientific Reports Sodium aescinate ATF4 GSH Ferroptosis Hepatotoxicity |
| title | Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis |
| title_full | Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis |
| title_fullStr | Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis |
| title_full_unstemmed | Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis |
| title_short | Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis |
| title_sort | sodium aescinate induced hepatotoxicity via atf4 gsh gpx4 axis mediated ferroptosis |
| topic | Sodium aescinate ATF4 GSH Ferroptosis Hepatotoxicity |
| url | https://doi.org/10.1038/s41598-024-79723-2 |
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