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The TET3/GATA6 Axis Drives Lipid Metabolism and Therapeutic Vulnerabilities in Pancreatic Ductal Adenocarcinoma

Shuai Liu1, Shaobo Kang1, Na Lin1

  • 1Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 26, 2025
PubMed

Insights

The DNA demethylase TET3 regulates lipid metabolism in pancreatic cancer. Inhibiting TET3 and targeting lipid metabolism with epigenetic drugs may improve pancreatic cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Metabolic reprogramming, particularly lipid metabolism, is crucial for cancer progression and treatment resistance.
  • Pancreatic ductal adenocarcinoma (PDAC) exhibits significant metabolic alterations.
  • Identifying key regulators of lipid metabolism in PDAC is essential for developing novel therapeutic strategies.

Purpose of the Study:

  • To identify regulators of lipogenic metabolism in pancreatic ductal adenocarcinoma (PDAC).
  • To elucidate the role of the DNA demethylase TET3 in PDAC lipid metabolism and its therapeutic implications.

Main Methods:

  • Analysis of TET3 expression in PDAC subtypes and correlation with patient prognosis.
  • Genetic ablation of TET3 to assess its impact on lipid homeostasis and cell proliferation.
  • Investigation of the molecular mechanism involving TET3, GATA6, histone deacetylases (HDACs), and lipogenic enzymes.
  • Evaluation of combined therapeutic strategies including HDAC inhibitors, ferroptosis inducers, and chemotherapy.

Main Results:

  • TET3 expression is elevated in lipogenic PDAC and linked to poor prognosis.
  • TET3 ablation disrupts lipid homeostasis, alters fatty acid profiles, and reduces proliferation.
  • TET3 non-catalytically represses GATA6 via HDAC recruitment and H3K27 deacetylation.
  • Loss of TET3 derepresses GATA6, suppressing lipogenic enzymes and sensitizing cells to ferroptosis.
  • Combined HDAC inhibition (SAHA) and ferroptosis induction (Erastin) potentiates gemcitabine efficacy in lipogenic PDAC.

Conclusions:

  • TET3 plays a critical, non-catalytic role in sustaining lipid metabolic reprogramming in PDAC.
  • The TET3/GATA6 axis is a key regulator of lipogenesis and ferroptosis sensitivity in PDAC.
  • Targeting the TET3/GATA6 pathway, combined with ferroptosis and epigenetic modulators, presents a promising therapeutic avenue for overcoming resistance in pancreatic cancer.
Keywords:
GATA6TET3epigenetic regulationlipid metabolic reprogrammingpancreatic ductal adenocarcinoma

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