A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis

Xin Chen (), Jun Huang, Chunhua Yu, Jiao Liu, Wanli Gao, Jingbo Li, Xinxin Song, Zhuan Zhou, Changfeng Li, Yangchun Xie, Guido Kroemer, Jinbao Liu (), Daolin Tang () and Rui Kang ()
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Xin Chen: Guangzhou Medical University
Jun Huang: Central South University
Chunhua Yu: UT Southwestern Medical Center
Jiao Liu: Guangzhou Medical University
Wanli Gao: Guangzhou Medical University
Jingbo Li: UT Southwestern Medical Center
Xinxin Song: UT Southwestern Medical Center
Zhuan Zhou: UT Southwestern Medical Center
Changfeng Li: China-Japan Union Hospital of Jilin University
Yangchun Xie: Central South University
Guido Kroemer: Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Jinbao Liu: Guangzhou Medical University
Daolin Tang: UT Southwestern Medical Center
Rui Kang: UT Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Ferroptosis is a type of lipid peroxidation-dependent cell death that is emerging as a therapeutic target for cancer. However, the mechanisms of ferroptosis during the generation and detoxification of lipid peroxidation products remain rather poorly defined. Here, we report an unexpected role for the eukaryotic translation initiation factor EIF4E as a determinant of ferroptotic sensitivity by controlling lipid peroxidation. A drug screening identified 4EGI-1 and 4E1RCat (previously known as EIF4E-EIF4G1 interaction inhibitors) as powerful inhibitors of ferroptosis. Genetic and functional studies showed that EIF4E (but not EIF4G1) promotes ferroptosis in a translation-independent manner. Using mass spectrometry and subsequent protein-protein interaction analysis, we identified EIF4E as an endogenous repressor of ALDH1B1 in mitochondria. ALDH1B1 belongs to the family of aldehyde dehydrogenases and may metabolize the aldehyde substrate 4-hydroxynonenal (4HNE) at high concentrations. Supraphysiological levels of 4HNE triggered ferroptosis, while low concentrations of 4HNE increased the cell susceptibility to classical ferroptosis inducers by activating the NOX1 pathway. Accordingly, EIF4E-dependent ALDH1B1 inhibition enhanced the anticancer activity of ferroptosis inducers in vitro and in vivo. Our results support a key function of EIF4E in orchestrating lipid peroxidation to ignite ferroptosis.

Date: 2022
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DOI: 10.1038/s41467-022-34096-w

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