Authors
Bingyu Kang, Xuan Wang, Si Li, Shuai Li, Tianjie Zhu, Jing Li, Xiaolu Ma, Jingyuan Zhao
Published in
Epigenomics. Pages 1-13. Nov 06, 2026. Epub Nov 06, 2026.
Abstract
Acute myeloid leukemia (AML) remains a malignancy with a poor prognosis, and therapeutic resistance highlights the need for more effective treatment strategies. This study investigated whether ferroptosis induction enhances the antileukemic effects of the demethylating agent decitabine (DAC) and explored the underlying mechanism.
HL-60 cells were treated with DAC, Erastin, or their combination. Cell viability and ferroptosis were evaluated using CCK-8, malondialdehyde, glutathione, reactive oxygen species, and JC-1 assays. PANX2 expression and function were investigated, and its regulation by methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification was examined using dot blot, MeRIP-qPCR, and RIP-qPCR assays.
DAC and Erastin synergistically reduced cell viability and enhanced ferroptosis in HL-60 cells. PANX2 expression was reduced in AML but increased following DAC treatment, and PANX2 exerted tumor-suppressive effects. Mechanistically, METTL3 inhibition reduced PANX2 m6A modification, decreased PANX2 mRNA stability, and downregulated PANX2 expression. METTL3 promoted PANX2 expression through an m6A-IGF2BP1/2/3-dependent mechanism.
Our study reveals for the first time that ferroptosis can synergize with demethylation drugs, with PANX2 potentially linking m6A regulation to the ferroptosis-associated response. These data provide preclinical evidence for the combined use of DAC and Erastin and offer a new theoretical basis for AML treatment strategies.
PMID:
42992411
Bibliographic data and abstract were imported from PubMed on 06 Nov 2026.
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