FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

Michael M. Gaschler, Alexander A. Andia, Hengrui Liu, Joleen M. Csuka, Brisa Hurlocker, Christopher A. Vaiana, Daniel W. Heindel, Dylan S. Zuckerman, Pieter H. Bos, Eduard Reznik, Ling F. Ye, Yulia Y. Tyurina, Annie J. Lin, Mikhail S. Shchepinov, Amy Y. Chan, Eveliz Peguero-Pereira, Maksim A. Fomich, Jacob D. Daniels, Andrei V. Bekish, Vadim V. ShmanaiValerian E. Kagan, Lara Mahal, Keith Woerpel, Brent R. Stockwell

Research output: Contribution to journalArticle

Abstract

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 the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.

Original languageEnglish (US)
Pages (from-to)507-515
Number of pages9
JournalNature Chemical Biology
Volume14
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Lipid Peroxides
Hydroxyl Radical
Lipid Peroxidation
Glutathione
Cell Death
Iron
Enzymes
Neoplasms
Proteins
formal glycol
erastin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Gaschler, M. M., Andia, A. A., Liu, H., Csuka, J. M., Hurlocker, B., Vaiana, C. A., ... Stockwell, B. R. (2018). FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nature Chemical Biology, 14(5), 507-515. https://doi.org/10.1038/s41589-018-0031-6

FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. / Gaschler, Michael M.; Andia, Alexander A.; Liu, Hengrui; Csuka, Joleen M.; Hurlocker, Brisa; Vaiana, Christopher A.; Heindel, Daniel W.; Zuckerman, Dylan S.; Bos, Pieter H.; Reznik, Eduard; Ye, Ling F.; Tyurina, Yulia Y.; Lin, Annie J.; Shchepinov, Mikhail S.; Chan, Amy Y.; Peguero-Pereira, Eveliz; Fomich, Maksim A.; Daniels, Jacob D.; Bekish, Andrei V.; Shmanai, Vadim V.; Kagan, Valerian E.; Mahal, Lara; Woerpel, Keith; Stockwell, Brent R.

In: Nature Chemical Biology, Vol. 14, No. 5, 01.05.2018, p. 507-515.

Research output: Contribution to journalArticle

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, L, Woerpel, K & Stockwell, BR 2018, 'FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation', Nature Chemical Biology, vol. 14, no. 5, pp. 507-515. https://doi.org/10.1038/s41589-018-0031-6
Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nature Chemical Biology. 2018 May 1;14(5):507-515. https://doi.org/10.1038/s41589-018-0031-6
Gaschler, Michael M. ; Andia, Alexander A. ; Liu, Hengrui ; Csuka, Joleen M. ; Hurlocker, Brisa ; Vaiana, Christopher A. ; Heindel, Daniel W. ; Zuckerman, Dylan S. ; Bos, Pieter H. ; Reznik, Eduard ; Ye, Ling F. ; Tyurina, Yulia Y. ; Lin, Annie J. ; Shchepinov, Mikhail S. ; Chan, Amy Y. ; Peguero-Pereira, Eveliz ; Fomich, Maksim A. ; Daniels, Jacob D. ; Bekish, Andrei V. ; Shmanai, Vadim V. ; Kagan, Valerian E. ; Mahal, Lara ; Woerpel, Keith ; Stockwell, Brent R. / FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. In: Nature Chemical Biology. 2018 ; Vol. 14, No. 5. pp. 507-515.
@article{c5d6249e433b4dca86cc8089603aabec,
title = "FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation",
abstract = "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 the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.",
author = "Gaschler, {Michael M.} and Andia, {Alexander A.} and Hengrui Liu and Csuka, {Joleen M.} and Brisa Hurlocker and Vaiana, {Christopher A.} and Heindel, {Daniel W.} and Zuckerman, {Dylan S.} and Bos, {Pieter H.} and Eduard Reznik and Ye, {Ling F.} and Tyurina, {Yulia Y.} and Lin, {Annie J.} and Shchepinov, {Mikhail S.} and Chan, {Amy Y.} and Eveliz Peguero-Pereira and Fomich, {Maksim A.} and Daniels, {Jacob D.} and Bekish, {Andrei V.} and Shmanai, {Vadim V.} and Kagan, {Valerian E.} and Lara Mahal and Keith Woerpel and Stockwell, {Brent R.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1038/s41589-018-0031-6",
language = "English (US)",
volume = "14",
pages = "507--515",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

AU - Gaschler, Michael M.

AU - Andia, Alexander A.

AU - Liu, Hengrui

AU - Csuka, Joleen M.

AU - Hurlocker, Brisa

AU - Vaiana, Christopher A.

AU - Heindel, Daniel W.

AU - Zuckerman, Dylan S.

AU - Bos, Pieter H.

AU - Reznik, Eduard

AU - Ye, Ling F.

AU - Tyurina, Yulia Y.

AU - Lin, Annie J.

AU - Shchepinov, Mikhail S.

AU - Chan, Amy Y.

AU - Peguero-Pereira, Eveliz

AU - Fomich, Maksim A.

AU - Daniels, Jacob D.

AU - Bekish, Andrei V.

AU - Shmanai, Vadim V.

AU - Kagan, Valerian E.

AU - Mahal, Lara

AU - Woerpel, Keith

AU - Stockwell, Brent R.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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 the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.

AB - 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 the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.

UR - http://www.scopus.com/inward/record.url?scp=85044753310&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044753310&partnerID=8YFLogxK

U2 - 10.1038/s41589-018-0031-6

DO - 10.1038/s41589-018-0031-6

M3 - Article

VL - 14

SP - 507

EP - 515

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 5

ER -