FINO(2) initiates ferroptosis through GPX4 inactivation and iron oxidation.
FINO(2) initiates ferroptosis through GPX4 inactivation and iron oxidation.
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DOI：
10.1038/s41589-018-0031-6
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发表时间：
2018-05
影响因子：
14.8
通讯作者：
Stockwell BR
中科院分区：
文献类型：
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作者：
Gaschler MM;Andia AA;Liu H;Csuka JM;Hurlocker B;Vaiana CA;Heindel DW;Zuckerman DS;Bos PH;Reznik E;Ye LF;Tyurina YY;Lin AJ;Shchepinov MS;Chan AY;Peguero-Pereira E;Fomich MA;Daniels JD;Bekish AV;Shmanai VV;Kagan VE;Mahal LK;Woerpel KA;Stockwell BR
铁下垂是一种由谷胱甘肽依赖的过氧化脂质清除网络失效引起的非凋亡性细胞死亡。FINO2是一种内含过氧化氢的1，2-二氧杂环戊烷，可以在工程癌细胞中选择性地引发铁下垂。我们研究了FINO2启动铁性下垂所必需的机制和结构特征。我们发现，FINO2既需要内过氧化部分，也需要附近的羟基头基来启动铁性下垂。与先前描述的铁下垂诱导剂不同，FINO2不像erastin和RSL3那样抑制系统Xc−或直接靶向Gpx4，也不像FIN56那样耗尽Gpx4蛋白。相反，FINO2既导致Gpx4酶功能的间接丧失，又直接氧化铁，最终导致广泛的脂质过氧化。这些发现表明，FINO2等内源性过氧化物质可以启动铁性下垂的多管齐下机制。
Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc− or directly target GPX4, as do erastin and RSL3, respectively, or deplete GPX4 protein, as does FIN56. Instead, FINO2 causes both indirect loss of GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multi-pronged mechanism of ferroptosis.
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影响因子：
56.9
作者：
HWANG, C;SINSKEY, AJ;LODISH, HF
通讯作者：
LODISH, HF
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
11.1
作者：
Krishna, Sanjeev;Ganapathi, Senthil;Ster, Irina Chis;Saeed, Mohamed E. M.;Cowan, Matt;Finlayson, Caroline;Kovacsevics, Hajnalka;Jansen, Herwig;Kremsner, Peter G.;Efferth, Thomas;Kumar, Devinder
通讯作者：
Kumar, Devinder
影响因子：
--
作者：
Crespo-Ortiz MP;Wei MQ
通讯作者：
Wei MQ