Acsl4 Dictates Ferroptosis Sensitivity by Shaping Cellular Lipid Composition

By S. Doll, B. Proneth, Y. Tyurina, Elena Panzilius, Sho Kobayashi, Irina Ingold, M. Irmler, J. Beckers, M. Aichler, A. Walch and 12 more. Nature Chemical Biology, 2016

3,603 citations recorded by the source corpus.

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 this form of cell death 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 presented an unprecedented resistance to ferroptosis. Mechanistically, Acsl4 enriches cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, Acsl4 is preferentially expressed in a panel of basal-like breast cancer cell lines and predicts their sensitivity to ferroptosis. We further demonstrate that pharmacological targeting of Acsl4 with the antidiabetic compound class, thiazolidinediones, ameliorates tissue demise in a murine model of ferroptosis, suggesting that Acsl4 inhibition is a viable therapeutic approach to prevent ferroptosis-related diseases.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/38c0bca96ec681735f2c9c3517423d77c7154d8c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

In Pulmonary and Respiratory Medicine

Citations in the corpus

The Development of the Concept of Ferroptosis (2018, positive): “ACSL4 and LPCAT3, involved in the insertion of PUFAs into membrane phospholipids, contribute to ferroptosis induction [146,147]”
Role of Mitochondria in Ferroptosis (2018, background): “Supporting this possibility, ferroptosis is associated with dramatic morphological changes of mitochondria, including mitochondrial fragmentation and cristae enlargement (Dixon et al., 2012; Doll et al., 2017); and some potent ferroptosis inhibitors appear to be exquisitely targeted to mitochondria ”
Iron Metabolism in Ferroptosis (2020, background): “AcylCoA synthetase long-chain family member 4 (ACSL4) is a crucial pro-ferroptotic regulator by catalyzing the synthesis of long-chain polyunsaturated CoAs, especially arachidonic acid, thus enriching cellular membranes with PUFA (Yuan et al., 2016b; Doll et al., 2017; Kagan et al., 2017).”
Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “The activation of the GPX4, AIFM2, or ESCRT-III pathways can limit or repair the oxidation of PUFAs that result from the activation of the ACSL4-LPCAT3-ALOX pathway.”
NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis (2019, background): “NADPH and the enzyme acyl-CoA synthetase long chain family member 4 (ACSL4), which metabolizes lipid peroxides, are both biomarkers correlated with an enhanced sensitivity to ferroptosis [16,17].”
Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. (2017, positive): “Additionally, as neurons contain a high content of polyunsaturated fatty acids (PUFAs), necessary for migration and synapse formation, they are exquisitely sensitive to ferroptosis as recently shown for other cells (Doll et al., 2017).”
The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. (2017, positive): “In particular, acetyl coenzyme A (acyl-CoA) synthetase long-chain family member 4 (ACSL4) is critical for lipid peroxidation in ferroptotic cell death due to catalyzing esterification of arachidonoyl or adrenoyl into phosphatidylethanolamines (Doll et al., 2017; Kagan et al., 2017; Yuan et al., 2016”