P53-dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride-induced liver fibrosis and hepatic stellate cell activation
P53-dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride-induced liver fibrosis and hepatic stellate cell activation
复制标题
蒿甲醚需要 P53 依赖性诱导铁死亡来减轻四氯化碳诱导的肝纤维化和肝星状细胞活化
DOI：
10.1002/iub.1895
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发表时间：
2019-01-01
期刊：
影响因子：
4.6
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
--
作者：
Wang, Ling;Zhang, Zili;Zheng, Shizhong
铁凋亡是最近报道的一种新的细胞死亡模式。其基本特征是氧化还原稳态紊乱、铁超载和脂质过氧化作用增加。然而，铁凋亡在肝纤维化中的作用仍然知之甚少。本研究旨在探讨蒿甲醚（ART）对肝纤维化铁凋亡的影响，并进一步阐明其可能的机制。我们的数据显示，ART治疗显著减轻了肝纤维化小鼠模型的肝损伤，减少了纤维化瘢痕形成。此外，体外实验也证实，ART治疗显着降低肝星状细胞（HSC）活化标志物的表达。有趣的是，ART处理的HSC呈现出铁凋亡的形态学特征。此外，ART通过促进铁和脂质过氧化物的积累而显著触发铁凋亡，而特异性抑制剂ferrostatin-1（Fer-1）抑制铁凋亡完全消除ART诱导的抗纤维化作用。更重要的是，我们的发现确定了肿瘤抑制因子P53是ART诱导的HSC铁凋亡的上游分子。相反，通过siRNA敲低P53明显阻断ART诱导的HSC铁凋亡，反过来加重肝纤维化。总的来说，我们的研究结果表明，P53依赖性诱导铁凋亡是必要的ART，以改善四氯化碳诱导的肝纤维化和抑制HSC活化。(c)2018 IUBMB Life，71（1）：45-56，2019
Ferroptosis is recently reported as a new mode of regulated cell death. Its essential characteristics are disturbed redox homeostasis, overloaded iron, and increased lipid peroxidation. However, the role of ferroptosis in liver fibrosis remains poorly understood. In this study, we attempted to investigate the effect of artemether (ART) on ferroptosis in hepatic fibrosis and to further clarify the possible mechanisms. Our data showed that ART treatment markedly attenuated liver injury and reduced fibrotic scar formation in the mouse model of liver fibrosis. Moreover, experiments in vitro also confirmed that ART treatment significantly decreased expression of hepatic stellate cell (HSC) activation markers. Interestingly, HSCs treated by ART presented morphological features of ferroptosis. Furthermore, ART remarkably triggered ferroptosis by promoting the accumulation of iron and lipid peroxides, whereas inhibition of ferroptosis by specific inhibitor ferrostatin-1 (Fer-1) completely abolished ART-induced antifibrosis effect. More importantly, our discovery determined that tumor suppressor P53 was an upstream molecule in the facilitation of ART-induced HSC ferroptosis. Conversely, knockdown of P53 by siRNA evidently blocked ART-induced HSC ferroptosis in turn exacerbated liver fibrosis. Overall, our findings revealed that P53-dependent induction of ferroptosis is necessary for ART to ameliorate CCl4-induced hepatic fibrosis and inhibit HSC activation. (c) 2018 IUBMB Life, 71(1):45-56, 2019