2. Academic Validation
  3. The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer

The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer

  • Mol Cell. 2026 Apr 2;86(7):1260-1274.e4. doi: 10.1016/j.molcel.2026.03.007.
Maimon E Hubbi 1,  Catherine L Wang 2,  Yasir Suhail 3,  Nadia L Almasri 4,  Jane Xie 5,  Erin E Hollander 6,  Kshitiz 3,  Alexander Muir 7,  Ben Z Stanger 5,  Chi V Dang 8
Affiliations

Affiliations

  • 1 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Ludwig Institute for Cancer Research, New York, NY, USA. Electronic address: [email protected].
  • 2 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Ludwig Institute for Cancer Research, New York, NY, USA; Medical Scientist Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 3 Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT, USA.
  • 4 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5 Department of Medicine and Abramson Cancer Center and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Department of Medicine and Abramson Cancer Center and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Medical Scientist Training Program, University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
  • 8 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Ludwig Institute for Cancer Research, New York, NY, USA; Department of Biochemistry & Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: [email protected].
PMID: 41932308 DOI: 10.1016/j.molcel.2026.03.007
Abstract

Ferroptosis is an iron-dependent form of cell death converging on lipid peroxidation first identified by examining compounds with enhanced lethality to KRAS mutant cells. Despite over 90% of pancreatic ductal adenocarcinoma (PDAC) tumors harboring KRAS mutations, PDAC exhibits relative resistance to Ferroptosis compared with Other tumor types, and the mechanisms behind this resistance remain unclear. Here, we report that exposure to pancreatic tumor interstitial fluid in synergy with hypoxia induced robust protection against Ferroptosis in a manner dependent on the hypoxia-inducible transcription factor 2 (HIF-2). HIF-2 upregulates the expression of both components of the system Xc- cystine transporter and transsulfuration pathway Enzymes CBS and CTH to increase intracellular cysteine levels, enabling anti-ferroptotic glutathione production. HIF-2 also induces the Parkin Mitophagy factor and suppresses mitochondrial function and Reactive Oxygen Species (ROS) generation. Altogether, our findings uncover an unforeseen role of the HIF-2 transcription factor as a coordinator of anti-ferroptotic mechanisms in pancreatic Cancer.

Keywords

HIF-2 transcription factor; ferroptosis; hypoxia; pancreatic ductal adenocarcinoma.

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