Targeting the elimination of activated hepatic stellate cells (HSCs) and blocking excessive deposition of extracellular matrix are recognized as an effective strategy for the treatment of hepatic fibrosis. As a newly discovered programmed cell death mode, the regulatory mechanism of ferroptosis in the clearance of activated HSCs has not been fully elucidated. In the present study, we reported that the induction of ferroptosis in activated HSCs was required for dihydroartemisinin (DHA) to alleviate hepatic fibrosis. Treatment with DHA could improve the damage of hepatic fibrosis in vivo and inhibit the activation of HSCs in vitro. Interestingly, DHA treatment could trigger ferroptosis to eliminate activated HSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Specific ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 could impair DHA-induced ferroptosis and also damage DHA-mediated the inhibition of activated HSCs. Importantly, autophagy activation may be closely related to DHA-induced ferroptosis. ATG5 siRNA could prevent DHA-mediated autophagy activation and ferroptosis induction, whereas ATG5 plasmid could promote the effect of DHA on autophagy and ferroptosis. Of note, the upregulation of nuclear receptor coactivator 4 (NCOA4) may play a critical role in the molecular mechanism. NCOA4 siRNA could impair DHA-induced ferroptosis, whereas NCOA4 plasmid could enhance the promoting effect of DHA on ferroptosis. Overall, our study revealed the potential mechanism of DHA against hepatic fibrosis and showed that ferroptosis could be a new way to eliminate activated HSCs.

中文翻译：

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双氢青蒿素通过诱导肝星状细胞铁死亡减轻肝纤维化

靶向消除活化的肝星状细胞（HSCs）和阻断细胞外基质的过度沉积被认为是治疗肝纤维化的有效策略。作为一种新发现的程序性细胞死亡模式，铁死亡在清除活化 HSCs 中的调控机制尚未完全阐明。在本研究中，我们报道了双氢青蒿素 (DHA) 需要在活化的 HSC 中诱导铁死亡来缓解肝纤维化。DHA治疗可改善体内肝纤维化损伤，体外抑制HSCs的活化。有趣的是，DHA 治疗可以引发铁死亡，以消除以铁过载、脂质 ROS 积累、谷胱甘肽消耗和脂质过氧化为特征的活化 HSC。特定的铁死亡抑制剂 ferrostatin-1 和 liproxstatin-1 可以削弱 DHA 诱导的铁死亡，也可以损害 DHA 介导的对活化 HSC 的抑制。重要的是，自噬激活可能与 DHA 诱导的铁死亡密切相关。ATG5 siRNA可以阻止DHA介导的自噬激活和铁死亡诱导，而ATG5质粒可以促进DHA对自噬和铁死亡的影响。值得注意的是，核受体共激活因子 4 (NCOA4) 的上调可能在分子机制中起关键作用。NCOA4 siRNA可以抑制DHA诱导的铁死亡，而NCOA4质粒可以增强DHA对铁死亡的促进作用。总体而言，我们的研究揭示了 DHA 对抗肝纤维化的潜在机制，并表明铁死亡可能是消除活化 HSC 的新方法。