Language
English
Publication Date
8-1-2026
Journal
Nature Cell Biology
DOI
10.1038/s41556-026-02016-5
PMID
42576015
PMCID
PMC13457094
PubMedCentral® Posted Date
8-7-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for therapy-resistant cancers. Glutathione peroxidase 4 and the selenoprotein biosynthesis pathway essential for its translation are key regulators of ferroptosis but lack effective therapeutic targeting. In a drug screening using a selenoprotein translation reporter, here we identify FMS-like tyrosine kinase 3 (FLT3) inhibitors as suppressors of selenoprotein translation that induce ferroptosis in FLT3-mutant acute myeloid leukaemia. Mechanistically, FLT3 inhibition disrupts selenocysteine recoding, in which a UGA stop codon is recoded as selenocysteine via the SECIS element and associated binding proteins. Notably, the antileukemic efficacy of the FLT3 inhibitor gilteritinib was markedly reduced by dietary vitamin E, which attenuated ferroptosis. This study highlights ferroptosis as a vulnerability in FLT3-mutant acute myeloid leukaemia and suggests that high vitamin E intake may compromise tyrosine kinase inhibitor efficacy partly by suppressing ferroptosis.
Keywords
Ferroptosis, fms-Like Tyrosine Kinase 3, Leukemia, Myeloid, Acute, Animals, Humans, Protein Kinase Inhibitors, Selenocysteine, Aniline Compounds, Pyrazines, Mutation, Cell Line, Tumor, Vitamin E, Mice, Selenoproteins, Xenograft Model Antitumor Assays
Published Open-Access
yes
Recommended Citation
Li, Minhua; Zhu, Yudan; Kageyama, Yuki; et al., "Targeting Oncogenic FLT3 Uncovers a Ferroptosis Vulnerability Through Selenocysteine Recoding in Acute Myeloid Leukaemia" (2026). Faculty, Staff and Students Publications. 8183.
https://digitalcommons.library.tmc.edu/baylor_docs/8183