ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

Sebastian Doll; Bettina Proneth; Yulia Y. Tyurina; Elena Panzilius; Sho Kobayashi; Irina Ingold; Martin Irmler; Johannes Beckers; Michaela Aichler; Axel Walch; Holger Prokisch; Dietrich Trümbach; Gaowei Mao; Feng Qu; Hulya Bayir; Joachim Füllekrug; Christina H. Scheel; Wolfgang Wurst; Joel A. Schick; Valerian E. Kagan; José Pedro Friedmann Angeli; Marcus Conrad

doi:10.1038/nchembio.2239

ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

Sebastian Doll, Bettina Proneth, Yulia Y. Tyurina, Elena Panzilius, Sho Kobayashi, Irina Ingold, Martin Irmler, Johannes Beckers, Michaela Aichler, Axel Walch, Holger Prokisch, Dietrich Trümbach, Gaowei Mao, Feng Qu, Hulya Bayir, Joachim Füllekrug, Christina H. Scheel, Wolfgang Wurst, Joel A. Schick, Valerian E. KaganJosé Pedro Friedmann Angeli, Marcus Conrad

Research output: Contribution to journal › Article › peer-review

2289 Scopus citations

Abstract

Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

Original language	English
Pages (from-to)	91-98
Number of pages	8
Journal	Nature Chemical Biology
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/nchembio.2239
State	Published - 1 Jan 2017
Externally published	Yes

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Doll, S., Proneth, B., Tyurina, Y. Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., Prokisch, H., Trümbach, D., Mao, G., Qu, F., Bayir, H., Füllekrug, J., Scheel, C. H., Wurst, W., Schick, J. A., ... Conrad, M. (2017). ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nature Chemical Biology, 13(1), 91-98. https://doi.org/10.1038/nchembio.2239

@article{da901722298e43ee987ab4a47896da80,

title = "ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition",

abstract = "Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.",

author = "Sebastian Doll and Bettina Proneth and Tyurina, {Yulia Y.} and Elena Panzilius and Sho Kobayashi and Irina Ingold and Martin Irmler and Johannes Beckers and Michaela Aichler and Axel Walch and Holger Prokisch and Dietrich Tr{\"u}mbach and Gaowei Mao and Feng Qu and Hulya Bayir and Joachim F{\"u}llekrug and Scheel, {Christina H.} and Wolfgang Wurst and Schick, {Joel A.} and Kagan, {Valerian E.} and Angeli, {Jos{\'e} Pedro Friedmann} and Marcus Conrad",

year = "2017",

month = jan,

day = "1",

doi = "10.1038/nchembio.2239",

language = "English",

volume = "13",

pages = "91--98",

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Doll, S, Proneth, B, Tyurina, YY, Panzilius, E, Kobayashi, S, Ingold, I, Irmler, M, Beckers, J, Aichler, M, Walch, A, Prokisch, H, Trümbach, D, Mao, G, Qu, F, Bayir, H, Füllekrug, J, Scheel, CH, Wurst, W, Schick, JA, Kagan, VE, Angeli, JPF & Conrad, M 2017, 'ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition', Nature Chemical Biology, vol. 13, no. 1, pp. 91-98. https://doi.org/10.1038/nchembio.2239

TY - JOUR

T1 - ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

AU - Doll, Sebastian

AU - Proneth, Bettina

AU - Tyurina, Yulia Y.

AU - Panzilius, Elena

AU - Kobayashi, Sho

AU - Ingold, Irina

AU - Irmler, Martin

AU - Beckers, Johannes

AU - Aichler, Michaela

AU - Walch, Axel

AU - Prokisch, Holger

AU - Trümbach, Dietrich

AU - Mao, Gaowei

AU - Qu, Feng

AU - Bayir, Hulya

AU - Füllekrug, Joachim

AU - Scheel, Christina H.

AU - Wurst, Wolfgang

AU - Schick, Joel A.

AU - Kagan, Valerian E.

AU - Angeli, José Pedro Friedmann

AU - Conrad, Marcus

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

AB - Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

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U2 - 10.1038/nchembio.2239

DO - 10.1038/nchembio.2239

M3 - Article

C2 - 27842070

AN - SCOPUS:84995468814

SN - 1552-4450

VL - 13

SP - 91

EP - 98

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 1

ER -

ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

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