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

Area of Science:

• Cell Biology
• Biochemistry
• Oncology

Background:

• Ferroptosis, a lipid peroxidation-dependent cell death, is a promising cancer therapeutic target.
• The precise mechanisms governing ferroptosis, particularly lipid peroxidation generation and detoxification, require further elucidation.

Purpose of the Study:

• To investigate the role of eukaryotic translation initiation factor EIF4E in ferroptosis.
• To identify novel regulators of ferroptosis and potential therapeutic targets for cancer treatment.

Main Methods:

• Drug screening to identify ferroptosis inhibitors.
• Genetic and functional studies to determine EIF4E's role.
• Mass spectrometry and protein-protein interaction analysis.
• In vitro and in vivo experiments to assess therapeutic efficacy.

Main Results:

• Eukaryotic translation initiation factor EIF4E (EIF4E) was identified as a key regulator of ferroptosis, independent of its translation function.
• EIF4E was found to inhibit ALDH1B1 in mitochondria, an enzyme that metabolizes 4-hydroxynonenal (4HNE).
• Both supraphysiological 4HNE levels and EIF4E-mediated ALDH1B1 inhibition promoted ferroptosis, while low 4HNE concentrations sensitized cells to ferroptosis inducers via the NOX1 pathway.
• Inhibition of EIF4E enhanced the anticancer effects of ferroptosis inducers in vitro and in vivo.

Conclusions:

• EIF4E plays a critical role in controlling lipid peroxidation and thus ferroptosis sensitivity.
• Targeting the EIF4E-ALDH1B1 axis presents a novel therapeutic strategy to enhance ferroptosis-based cancer treatments.