FINO 2 initiates ferroptosis through GPX4 inactivation and iron oxidation
Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and s...
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Published in | Nature chemical biology Vol. 14; no. 5; p. 507 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.05.2018
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Abstract | Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO
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 FINO
. We found that FINO
requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO
does not inhibit system x
or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO
both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO
can initiate a multipronged mechanism of ferroptosis. |
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AbstractList | Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO
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 FINO
. We found that FINO
requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO
does not inhibit system x
or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO
both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO
can initiate a multipronged mechanism of ferroptosis. |
Author | Shchepinov, Mikhail S Stockwell, Brent R Andia, Alexander A Daniels, Jacob D Shmanai, Vadim V Bos, Pieter H Peguero-Pereira, Eveliz Tyurina, Yulia Y Lin, Annie J Mahal, Lara K Bekish, Andrei V Kagan, Valerian E Reznik, Eduard Gaschler, Michael M Vaiana, Christopher A Fomich, Maksim A Ye, Ling F Chan, Amy Y Heindel, Daniel W Liu, Hengrui Csuka, Joleen M Hurlocker, Brisa Woerpel, K A Zuckerman, Dylan S |
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Snippet | Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO
is an... |
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Title | FINO 2 initiates ferroptosis through GPX4 inactivation and iron oxidation |
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