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浙江大学学报（医学版）
浙江大学学报（医学版）  2021, Vol. 50 Issue (5): 601-606    DOI: 10.3724/zdxbyxb-2021-0198
专题报道     
天然药物成分干预铁死亡抑制肿瘤的作用研究进展
宣自学,张轶雯,潘宗富,郑小卫,黄萍
浙江省人民医院 杭州医学院附属人民医院临床药学研究中心药学部，浙江 杭州 310014
Natural medicinal ingredients induce tumor ferroptosis and related mechanisms
XUAN Zixue,ZHANG Yiwen,PAN Zongfu,ZHENG Xiaowei,HUANG Ping
Department of Pharmacy, Clinical Pharmacy Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
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摘要：

铁死亡是一种铁依赖的程序性死亡，不同于传统的细胞死亡方式（如凋亡、焦亡、坏死、自噬），其特征是活性氧诱导脂质过氧化物堆积。铁死亡在肿瘤发生发展中发挥着重要的调控作用。最新研究表明，天然药物成分可通过谷胱甘肽/谷胱甘肽过氧化物酶4途径、铁代谢、脂质代谢等调控机制诱导肿瘤细胞铁死亡。研究发现了30多种天然药物成分具有诱导肿瘤细胞铁死亡的作用，且有多通路、多靶点的特点。本文综述了天然药物成分通过干预铁死亡抑制肿瘤的作用研究进展。
关键词： 铁死亡;  肿瘤;  天然药物;  中药;  调控机制;  综述    
Abstract:

Ferroptosis is an iron-dependent programmed cell death characterized by reactive oxygen species-induced lipid peroxide accumulation, which is different from cell apoptosis, pyroptosis, necrosis or autophagy. Ferroptosis plays an important role in the regulation of tumorigenesis and tumor development. Recent studies have shown that natural medicinal ingredients can induce ferroptosis in tumor cells through glutathione (GSH)/glutathione peroxidase 4 (GPx4) pathway, iron metabolism, lipid metabolism or other mechanisms. It has been reported that more than 30 natural medicinal ingredients can induce ferroptosis in tumor cells with multiple pathways and multiple targets. This article reviews the current research progress on the antitumor effects of natural medicinal ingredients through inducing cell ferroptosis.
Key words: Ferroptosis    Tumor    Natural medicine    Traditional Chinese medicine    Regulatory mechanism    Review
收稿日期: 2021-07-13 出版日期: 2021-12-29
:  R932  
基金资助: 浙江省中医药科技计划（2018ZZ006，2021ZA006）
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宣自学
张轶雯
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郑小卫
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引用本文:

宣自学,张轶雯,潘宗富,郑小卫,黄萍. 天然药物成分干预铁死亡抑制肿瘤的作用研究进展[J]. 浙江大学学报（医学版）, 2021, 50(5): 601-606.

XUAN Zixue,ZHANG Yiwen,PAN Zongfu,ZHENG Xiaowei,HUANG Ping. Natural medicinal ingredients induce tumor ferroptosis and related mechanisms. J Zhejiang Univ (Med Sci), 2021, 50(5): 601-606.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0198    或    https://www.zjujournals.com/med/CN/Y2021/V50/I5/601

图 1  铁死亡的调控机制①SLC7A11、SLC3A2可在向细胞内转运胱氨酸的同时外排等量的谷氨酸. 胱氨酸通过还原反应可生成GSH生物合成的限速底物半胱氨酸，GSH是GPx4的辅酶因子以及其降解脂质过氧化物的必需反应底物. GPx4作为调控铁死亡的关键酶，可通过催化脂质过氧化物的还原反应，抑制铁死亡的发生. 硫转移途径、甲羟戊酸途径、谷氨酰胺途径、p53调控轴等也参与铁死亡的GSH/GPx4途径. ②血液循环中的三价铁离子与转铁蛋白结合并运输，通过细胞膜上的转铁蛋白受体1进入细胞内被还原为二价铁离子后，再被转运并释放到细胞质铁池中，导致铁过量，产生活性氧，引发铁死亡. 铁蛋白代谢相关的ATG5-ATG7-NCOA4通路和p62-Keap1-NRF2通路也可参与铁死亡过程. ③ACSL4通过在内质网相关的氧合作用中心产生氧化的PE来促进铁死亡，而ACSL4催化花生四烯酸或肾上腺素的附着以产生酰基辅酶A衍生物，随后通过LPCAT3将其酯化为PE，进而被脂氧合酶氧化以产生脂质氢过氧化物，最终导致铁死亡. SLC7A11：溶质载体家族7成员11；SLC3A2：溶质载体家族3成员2；GSH：谷胱甘肽；GPx：谷胱甘肽过氧化物酶；ATG：自噬相关基因；NCOA：核受体辅激活因子；Keap：Kelch样环氧氯丙烷相关蛋白；NRF：核因子E2相关因子；ACSL：长链脂酰辅酶A合成酶；PE：磷脂酰乙醇胺；LPCAT：溶血卵磷脂酰基转移酶；PUFA：多不饱和脂肪酸.
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