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- Title
Inhibition of mTOR enhances sorafenib-induced activated HSC ferroptosis.
- Authors
LI Jia-hao; ZHANG Li-jun; PENG Jin-cheng; XIE Xian-jiao; WANG Guo-kai; FANG Ling
- Abstract
Objective: To investigate the role and mechanism of mTOR in sorafenib-ameliorated liver fibrosis by inducing hepatic stellate cells (HSC) ferroptosis. Methods: The liver fibrosis models of C57BL/6 male mice were induced with carbon tetrachloride (CCl4) and randomly divided into normal group, model group, and sorafenib low (2.5 mg/kg), medium (5 mg/kg), and high (10 mg/kg) dose groups. Except for the normal group, the remaining four groups were treated with intraperitoneal injection of CCl4 for 8 weeks to establish liver fibrosis models. In addition, the corresponding concentrations of sorafenib were administered during the fourth week of modeling. Western blot was used to detect the expression of mTOR and p-mTOR protein in liver tissues. In vitro experiments, HSC-T6 cells were activated by PDGF-BB and then treated with sorafenib (5 μM, 10 μM, 20 μM), an mTOR inhibitor and activator. CCK8 was used to detect HSC-T6 cell viability, Western blot detected the protein expression of α-SMA, COL1α1, GPX4, mTOR and p-mTOR. The levels of serum iron, GSH, and MDA were measured, and the intracellular ROS level was measured by 2',7'-dichlorofluorescein diacetate and dihydroethidium. Results: In vitro results showed that sorafenib significantly decreased the protein expression of α-SMA, COL1α1, GPX4 and p-mTOR, and decreased the level of GSH and increased the content of iron, MDA and ROS in HSC-T6 (P<0.05). Sorafenib (5 μM, 10 μM, 20 μM) significantly inhibited the cell viability of PDGF-BB-enhanced HSCT6 (P<0.05). When mTOR was inhibited, the protein expressions of α-SMA, COL1α1 and GPX4 and the level of GSH were lower (P<0.05), and the contents of iron, MDA and ROS were further increased (P<0.05). When mTOR was activated, the results were reversed. Conclusion: Sorafenib induced ferroptosis to alleviate liver fibrosis, and inhibition of mTOR further enhanced the effect of sorafenib.
- Publication
Journal of Hainan Medical University, 2023, Vol 29, Issue 5, p11
- ISSN
1007-1237
- Publication type
Academic Journal