铁死亡是一种铁依赖性细胞死亡方式，以脂质过氧化积累为特征，与肿瘤、神经退行性疾病及代谢性疾病密切相关。青蒿素衍生物通过多靶点调控诱导铁死亡：其活性基团可螯合游离铁离子，通过芬顿反应产生活性氧；选择性抑制谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）活性；并调控酰基辅酶A合成酶长链家族成员4介导的脂质代谢重编程。构效关系研究表明，C-10位化学修饰能显著增强铁死亡诱导效能。双氢青蒿素通过激活p53/GPX4轴抑制肝癌生长；青蒿琥酯靶向胱氨酸/谷氨酸反向转运系统（cystine/glutamate reverse transport system，System Xc-）/谷胱甘肽通路治疗食管鳞癌；蒿甲醚则通过调节铁调节蛋白2​铁代谢网络缓解肝纤维化。分子机制上，青蒿素特有的“双氧桥”结构是铁依赖性活性氧生成的关键，同时通过干预血红素氧合酶-1介导的铁释放和核因子E2相关因子2/Kelch样ECH关联蛋白1抗氧化通路动态平衡，在动脉粥样硬化等疾病中拓展了铁死亡调控的应用场景。该研究为重大疾病干预提供了新型先导化合物，并构建了天然活性成分与现代细胞死亡机制交叉研究的范式，对推动靶向药物研发和中医药现代化具有重要科学价值。

Ferroptosis is an iron-dependent form of cell death characterized by the accumulation of lipid peroxides, which is closely associated with tumors, neurodegenerative diseases, and metabolic disorders. Artemisinin derivatives induce ferroptosis through multi-target regulation: their active groups chelate free iron ions to generate reactive oxygen species via the Fenton reaction; selectively inhibit glutathione peroxidase 4 (GPX4) activity; and reprogram lipid metabolism mediated by acyl-CoA synthetase long-chain family member 4. Structure-activity relationship studies indicate that chemical modifications at the C-10 position significantly enhance ferroptosis-inducing efficacy. Dihydroartemisinin suppresses hepatocellular carcinoma growth by activating p53/GPX4 axis. Artesunate treats esophageal squamous carcinoma by targeting the cystine/glutamate reverse transport system (System Xc-)/glutathione pathway. Artemether alleviates liver fibrosis by modulating the iron regulatory protein 2-mediated iron metabolism network. Mechanistically, the unique “hydrogen peroxide bridge” in artemisinins is crucial for iron-dependent reactive oxygen species generation. Additionally, artemisinins modulate heme oxygenase-1-mediated iron release and the dynamic balance of the nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1 antioxidant pathway, broadening application scenarios of ferroptosis regulation in diseases like atherosclerosis. This research provides novel lead compounds for major disease interventions and establishes a paradigm for interdisciplinary studies between natural active components and modern cell death mechanisms, offering significant scientific value for advancing targeted drug development and the modernization of traditional Chinese medicine.

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中国农业科学院创新工程（CAAS-ASTIP-2014-LIHPS）；国家肉牛牦牛产业技术体系（CARS-37）