2. Academic Validation
  3. TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia

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

  • Nat Commun. 2026 Jan 20;17(1):1800. doi: 10.1038/s41467-026-68509-x.
Lingling Yang # 1 2 3,  Jun Lu # 1 2 3,  Weina Yun # 1 2 3,  Xinquan Yang 4,  Jie Sun 5,  Chaodong Ge 6,  Fei Han 1 2 3,  Xiang Li 1 2 3,  Junxia Min 4,  He Huang 5,  Fudi Wang 7 8,  Xi Jiang 9 10 11
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China.
  • 3 Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China.
  • 4 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5 Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 6 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 8 Global Innovation Institute of Element Science (GIIES-JLU), The First Hospital of Jilin University, Changchun, China. [email protected].
  • 9 Department 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. [email protected].
  • 10 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. [email protected].
  • 11 Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 41559050 DOI: 10.1038/s41467-026-68509-x
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.

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