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

Lingling Yang1,2,3, Jun Lu1,2,3, Weina Yun1,2,3

  • 1Department of Pharmacology, Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, and Zhejiang Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China.

Nature Communications
|January 20, 2026
PubMed

Insights

Ten-eleven translocation 1 (TET1) epigenetically controls ferroptosis susceptibility in cancer. Targeting TET1, GCLC, and GCH1 overcomes ferroptosis resistance, offering a new strategy for acute myeloid leukemia (AML) therapy.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Cell Death Mechanisms

Background:

  • Ferroptosis, a programmed cell death, is promising for cancer therapy but faces resistance.
  • Glutathione peroxidase 4 (GPX4) suppresses ferroptosis, but its regulatory network is unclear.

Purpose of the Study:

  • Identify epigenetic regulators of ferroptosis susceptibility.
  • Investigate the role of ten-eleven translocation 1 (TET1) in ferroptosis.
  • Develop strategies to overcome ferroptosis resistance in cancer, particularly AML.

Main Methods:

  • Genome-wide screening to identify ferroptosis regulators.
  • Analysis of TET1's role in DNA 5-hydroxymethylation (5hmC) and gene expression.
  • Investigating TET1's impact on glutathione/γ-glutamyl-peptide metabolism and NFκB signaling.
  • Evaluating therapeutic strategies targeting TET1, GCLC, and GCH1 in AML models.

Main Results:

  • TET1 was identified as a key regulator of cancer cell ferroptosis susceptibility.
  • TET1 promotes 5hmC deposition at the GCLC promoter, enhancing GPX4-dependent ferroptosis defense.
  • TET1 activates NFκB signaling, upregulating GCH1 for GPX4-independent ferroptosis resistance.
  • Combined targeting of TET1/GCLC/GCH1 with ferroptosis inducers showed potent effects against AML.

Conclusions:

  • TET1 is a critical epigenetic hub controlling ferroptosis surveillance.
  • Targeting TET1 offers a translatable strategy to overcome ferroptosis resistance in AML and potentially other cancers.

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