ArticleNature cell biology2026
The rise of reducing reagent-resistant TfR1 dimer marks ferroptosis.
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Article in Nature cell biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
34 authors.
Jianping HeDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0009-0001-6177-4179
Mackenzie KelleherDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0009-0007-8559-618X
Geraldine VeeckmansCell Death Signaling Lab, Department of Biomedical Sciences, Inflamed Centre of Excellence, University of Antwerp, Antwerp, Belgium.ORCID http://orcid.org/0000-0002-4597-9692
Yuezhong ZhangDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Luke ReynoldsDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0009-0000-9299-6682
Hannah M TanczosDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0009-0004-2765-7667
Zhengrong HuangDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0000-0001-6406-1011
Brett P McLaughlinDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
Mary Ann Martinez MolinaDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
Ava LightburnDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
Mira ZamarroDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
Wesley HuangDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-0551-8397
Stephenson B OwusuDepartment of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, USA.ORCID http://orcid.org/0000-0002-8557-4606
Magali WalravensCell Death Signaling Lab, Department of Biomedical Sciences, Inflamed Centre of Excellence, University of Antwerp, Antwerp, Belgium.
Cyril WillemartCell Death Signaling Lab, Department of Biomedical Sciences, Inflamed Centre of Excellence, University of Antwerp, Antwerp, Belgium.ORCID http://orcid.org/0009-0004-8425-7707
Behrouz HassanniaCell Death Signaling Lab, Department of Biomedical Sciences, Inflamed Centre of Excellence, University of Antwerp, Antwerp, Belgium.
Lauren E PopeDepartment of Biology, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-0335-9356
Christopher GagerDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
Alec J VaughanDepartment of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Zhe WangDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0009-0001-7092-671X
Simon WeaverDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0000-0003-4354-0309
William BoggessDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
Xin LuDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0000-0002-0284-6478
Thales PapagiannakopoulosDepartment of Pathology, New York University Grossman School of Medicine, New York, NY, USA.ORCID http://orcid.org/0000-0002-2251-1624
Ana Lidia Flores-MirelesDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.ORCID http://orcid.org/0000-0003-4610-4246
Parakkal DeepakInflammatory Bowel Diseases Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.ORCID http://orcid.org/0000-0002-3436-9784
Matthew A CiorbaInflammatory Bowel Diseases Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.ORCID http://orcid.org/0000-0002-7656-0982
Bryan G AllenDepartment of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, USA.ORCID http://orcid.org/0000-0002-4893-7105
John M BuattiDepartment of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, USA.ORCID http://orcid.org/0000-0001-8499-3721
Michael S PetronekDepartment of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, USA.ORCID http://orcid.org/0000-0001-7581-1172
Scott J DixonDepartment of Biology, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0001-6230-8199
Tom Vanden BergheCell Death Signaling Lab, Department of Biomedical Sciences, Inflamed Centre of Excellence, University of Antwerp, Antwerp, Belgium.ORCID http://orcid.org/0000-0002-1633-0974
Yatrik M ShahDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-2487-4816
Zachary T SchaferDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA. zschafe1@nd.edu.ORCID http://orcid.org/0000-0001-9227-3118
Funding
Washington University DDRCC Supplemental Equipment RequestP30DK052574 · NIDDK · WASHINGTON UNIVERSITY · PI Nicholas O. Davidson · 2000 to 2026
$30.8MControl of iron absorption by intestinal HIF2 in iron and hematological disordersR01DK095201 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2012 to 2025
$5.7MThe role of HIF2alpha in colon carcinogenesisR01CA148828 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2010 to 2025
$5.2MCharacterizing the Regulation of FerroptosisR01GM122923 · NIGMS · STANFORD UNIVERSITY · PI Scott Dixon · 2017 to 2026
$3.4MIdentifying metabolic dependencies in genetic subtypes of KRAS-driven lung cancerR37CA222504 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI PAPAGIANNAKOPOULOS, THALES · 2018 to 2024
$3.3MTraining Program in Cell BiologyT32GM136542 · NIGMS · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI SMITH, SUSAN · 2020 to 2024
$3.0MUnderstanding the mechanisms of iron addiction in colon cancerR01CA245546 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2020 to 2024
$2.3MMitophagy-Mediated Cell Death in Mammary TumorigenesisR01CA262439 · NCI · UNIVERSITY OF NOTRE DAME · PI SCHAFER, ZACHARY T. · 2021 to 2025
$2.1MNovel approaches to target KEAP1 mutant tumorsR01CA283049 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI Thales Papagiannakopoulos · 2024 to 2026
$2.0MInvestigating the therapeutic potential of a novel glutamine antagonist in KEAP1 mutant lung cancerR01CA262562 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI Thales Papagiannakopoulos · 2024 to 2026
$2.0MUncovering Genotype Specific Vulnerabilities in KRAS Mutant Lung Cancer?R01CA227649 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI PAPAGIANNAKOPOULOS, THALES · 2018 to 2022
$1.9MUnderstanding the role of catheter-associated protein deposition in the development of CAUTIR01DK128805 · NIDDK · UNIVERSITY OF NOTRE DAME · PI FLORES-MIRELES, ANA LIDIA, HOWELL, CAITLIN L · 2021 to 2025
$1.9MFonds Wetenschappelijk Onderzoek (Research Foundation Flanders) FWO-SB 1SH9524NFonds Wetenschappelijk Onderzoek (Research Foundation Flanders) FWO-SBO S001522NU.S. Department of Health & Human Services | National Institutes of Health (NIH) F30DK131851U.S. Department of Health & Human Services | National Institutes of Health (NIH) P30DK052574U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01DK095201U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01DK128805U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01GM122923U.S. Department of Health & Human Services | National Institutes of Health (NIH) T32GM136542U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA148828U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA227649U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA245546U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA262439U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA262562U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA280097U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA283049U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R37CA222504
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.
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