鐵死亡是一種鐵依賴性細胞死亡方式，以脂質(zhì)過氧化積累為特征，與腫瘤、神經(jīng)退行性疾病及代謝性疾病密切相關(guān)。青蒿素衍生物通過多靶點調(diào)控誘導(dǎo)鐵死亡：其活性基團可螯合游離鐵離子，通過芬頓反應(yīng)產(chǎn)生活性氧；選擇性抑制谷胱甘肽過氧化物酶4（glutathione peroxidase 4，GPX4）活性；并調(diào)控?；o酶A合成酶長鏈家族成員4介導(dǎo)的脂質(zhì)代謝重編程。構(gòu)效關(guān)系研究表明，C-10位化學(xué)修飾能顯著增強鐵死亡誘導(dǎo)效能。雙氫青蒿素通過激活p53/GPX4軸抑制肝癌生長；青蒿琥酯靶向胱氨酸/谷氨酸反向轉(zhuǎn)運系統(tǒng)（cystine/glutamate reverse transport system，System Xc-）/谷胱甘肽通路治療食管鱗癌；蒿甲醚則通過調(diào)節(jié)鐵調(diào)節(jié)蛋白2​鐵代謝網(wǎng)絡(luò)緩解肝纖維化。分子機制上，青蒿素特有的“雙氧橋”結(jié)構(gòu)是鐵依賴性活性氧生成的關(guān)鍵，同時通過干預(yù)血紅素氧合酶-1介導(dǎo)的鐵釋放和核因子E2相關(guān)因子2/Kelch樣ECH關(guān)聯(lián)蛋白1抗氧化通路動態(tài)平衡，在動脈粥樣硬化等疾病中拓展了鐵死亡調(diào)控的應(yīng)用場景。該研究為重大疾病干預(yù)提供了新型先導(dǎo)化合物，并構(gòu)建了天然活性成分與現(xiàn)代細胞死亡機制交叉研究的范式，對推動靶向藥物研發(fā)和中醫(yī)藥現(xiàn)代化具有重要科學(xué)價值。

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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中國農(nóng)業(yè)科學(xué)院創(chuàng)新工程（CAAS-ASTIP-2014-LIHPS）；國家肉牛牦牛產(chǎn)業(yè)技術(shù)體系（CARS-37）