2. Academic Validation
  3. Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis

Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis

  • Nature. 2025 Jun 11. doi: 10.1038/s41586-025-09162-0.
Dylan Calhoon # 1,  Lingjie Sang # 1,  Fubo Ji 1,  Divya Bezwada 1,  Sheng-Chieh Hsu 1,  Feng Cai 1,  Nathaniel Kim 1,  Amrita Basu 2,  Renfei Wu 1,  Anastasia Pimentel 1,  Bailey Brooks 1,  Konnor La 3,  Ana Paulina Serrano 1,  Daniel L Cassidy 1,  Ling Cai 1 4,  Vanina Toffessi-Tcheuyap 5 6,  Maryam E Moussa 7,  Winnie Uritboonthai 8,  Linh Truc Hoang 8,  Meghana Kolli 9,  Brooklyn Jackson 5 6,  Vitaly Margulis 10,  Gary Siuzdak 8,  James Brugarolas 5 6,  Ian Corbin 9,  Derek A Pratt 7,  Ryan J Weiss 2 11,  Ralph J DeBerardinis 1 12,  Kıvanç Birsoy 3,  Javier Garcia-Bermudez 13
Affiliations

Affiliations

  • 1 Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2 Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
  • 3 Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.
  • 4 Quantitative Biomedical Research Center, Peter O'Donnell School of Public Health, University of Texas Southwestern, Dallas, TX, USA.
  • 5 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6 Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 7 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
  • 8 Scripps Center for Metabolomics, The Scripps Research Institute, La Jolla, CA, USA.
  • 9 Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 10 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 11 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA.
  • 12 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 13 Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. Javier.GarciaBermudez@UTSouthwestern.edu.
  • # Contributed equally.
PMID: 40500442 DOI: 10.1038/s41586-025-09162-0
Abstract

Lipids are essential components of Cancer cells due to their structural and signalling roles1. To meet metabolic demands, many cancers take up extracellular lipids2-5; however, how these lipids contribute to Cancer growth and progression remains poorly understood. Here, using functional genetic screens, we identify uptake of lipoproteins-the primary mechanism for lipid transport in circulation-as a key determinant of Ferroptosis sensitivity in Cancer. Lipoprotein supplementation robustly inhibits Ferroptosis across diverse Cancer types, primarily through the delivery of α-tocopherol (α-toc), the most abundant form of vitamin E in human lipoproteins. Mechanistically, Cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Disrupting GAG biosynthesis or acutely degrading surface GAGs reduces lipoprotein uptake, sensitizes Cancer cells to Ferroptosis and impairs tumour growth in mice. Notably, human clear cell renal cell carcinomas-a lipid-rich malignancy-exhibit elevated levels of chondroitin sulfate and increased lipoprotein-derived α-toc compared with normal kidney tissue. Together, our study establishes lipoprotein uptake as a critical anti-ferroptotic mechanism in Cancer and implicates GAG biosynthesis as a therapeutic target.

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