ACSL4 Dictates Ferroptosis Sensitivity by Shaping Cellular Lipid Composition

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2016 Nov 15

PMID 27842070

Citations 1539

Authors

Sebastian Doll

Bettina Proneth

Yulia Y Tyurina

Elena Panzilius

Sho Kobayashi

Irina Ingold

Martin Irmler

Johannes Beckers

Michaela Aichler

Axel Walch

Holger Prokisch

Dietrich Trumbach

Gaowei Mao

Feng Qu

Hulya Bayir

Joachim Fullekrug

Christina H Scheel

Wolfgang Wurst

Joel A Schick

Valerian E Kagan

Jose Pedro Friedmann Angeli

Marcus Conrad

Affiliations

Soon will be listed here.

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.

Citing Articles

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