Work

TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia

Year: 2026

Type: article

Abstract: Ferroptosis, an iron-dependent, lipid peroxidation-driven programmed cell death, holds substantial promise for cancer therapy, yet its translational potential is hindered by widespread intrinsic resistance. While glutathione peroxidase 4 (GPX4) is a well-established ferroptosis suppressor, the epigenetic circuitry coordinating GPX4-related mechanisms remains elusive. Here, via genome-wide screening, we identify ten-eleven translocation 1 (TET1)—a key mediator of DNA 5-hydroxymethylation—as a master controller of cancer cell ferroptosis susceptibility. In acute myeloid leukemia (AML), TET1 enhances 5hmC deposition at the glutamate-cysteine ligase catalytic subunit (GCLC) promoter to activate glutathione/γ-glutamyl-peptide metabolism, fortifying GPX4-dependent defense. Concurrently, TET1 activates NFκB signaling to upregulate GTP cyclohydrolase-1 (GCH1), conferring GPX4-independent ferroptosis resistance. Critically, co-targeting TET1/GCLC/GCH1 with low-dose ferroptosis inducers exhibits potent therapeutic effects against both ferroptosis-sensitive and -resistant AML. Our work positions TET1 as a pivotal epigenetic hub governing ferroptosis surveillance, and provides a translatable strategy to overcome ferroptosis resistance in cancer, with AML as a paradigm. DNA demethylation enzyme TET1 is a known oncogene in leukemia. Here, the authors discover that TET1 is involved in GPX4-dependent and -independent ferroptosis in acute myeloid leukemia via the regulation of GSH synthesis enzyme GCLC and BH4 synthesis enzyme GCH1.

Source: Nature Communications

DOI: 10.1038/s41467-026-68509-x