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Publications

Journal Article Ahead of print

PubMed: 42907496 DOI: 10.1038/s41556-026-02107-3

The rise of reducing reagent-resistant TfR1 dimer marks ferroptosis.

Nat Cell Biol

Authors: Jianping He, Mackenzie Kelleher, Geraldine Veeckmans, Yuezhong Zhang, Luke Reynolds, Hannah M Tanczos, Zhengrong Huang, Brett P McLaughlin, Mary Ann Martinez Molina, Ava Lightburn, Mira Zamarro, Wesley Huang, Stephenson B Owusu, Magali Walravens, Cyril Willemart, Behrouz Hassannia, Lauren E Pope, Christopher Gager, Alec J Vaughan, Zhe Wang, Simon Weaver, William Boggess, Xin Lu, Thales Papagiannakopoulos, Ana Lidia Flores-Mireles, Parakkal Deepak, Matthew A Ciorba, Bryan G Allen, John M Buatti, Michael S Petronek, Scott J Dixon, Tom Vanden Berghe, Yatrik M Shah, Zachary T Schafer

Affiliations

  • Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
  • Cell Death Signaling Lab, Department of Biomedical Sciences, Inflamed Centre of Excellence, University of Antwerp, Antwerp, Belgium.
  • Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, USA.
  • Department of Biology, Stanford University, Stanford, CA, USA.
  • Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
  • Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York, NY, USA.
  • Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
  • Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
  • Inflammatory Bowel Diseases Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • VIB-UGent Center for Inflammation Research, Ghent, Belgium.
  • Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.

Abstract

Ferroptosis is an iron-dependent type of cell death caused by excessive membrane lipid peroxidation. It remains a challenge to detect ferroptotic cells, especially in in vivo settings, hindering translational studies. Here we discover that a reducing reagent-resistant (3R) dimer of the transferrin receptor 1 (TfR1) is a highly specific indicator for lipid peroxidation. The 3R dimer is elevated in cells when ferroptosis is induced, either by pharmacological agents or by genetic perturbations. Furthermore, the 3R dimer can be used to detect disease-associated ferroptosis in tissue and in extracellular vesicles isolated from mouse or patient plasma. Given the near-ubiquitous expression of TfR1, we posit that the 3R dimer may function as a ferroptosis marker with widespread potential utility for basic and translational studies.

MeSH

Cells, Ferroptosis, Cell Biology