Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis

Dylan Calhoon, Lingjie Sang, Fubo Ji, Divya Bezwada, Sheng-Chieh Hsu, Feng Cai, Nathaniel Kim, Amrita Basu, Renfei Wu, Anastasia Pimentel, Bailey Brooks, Konnor La, Ana Paulina Serrano, Daniel L. Cassidy, Ling Cai, Vanina Toffessi-Tcheuyap, Maryam E. Moussa, Winnie Uritboonthai, Linh Truc Hoang, Meghana Kolli, Brooklyn Jackson, Vitaly Margulis, Gary Siuzdak, James Brugarolas, Ian Corbin, Derek A. Pratt, Ryan J. Weiss, Ralph J. DeBerardinis, Kıvanç Birsoy and Javier Garcia-Bermudez ()
Additional contact information
Dylan Calhoon: University of Texas Southwestern Medical Center
Lingjie Sang: University of Texas Southwestern Medical Center
Fubo Ji: University of Texas Southwestern Medical Center
Divya Bezwada: University of Texas Southwestern Medical Center
Sheng-Chieh Hsu: University of Texas Southwestern Medical Center
Feng Cai: University of Texas Southwestern Medical Center
Nathaniel Kim: University of Texas Southwestern Medical Center
Amrita Basu: University of Georgia
Renfei Wu: University of Texas Southwestern Medical Center
Anastasia Pimentel: University of Texas Southwestern Medical Center
Bailey Brooks: University of Texas Southwestern Medical Center
Konnor La: The Rockefeller University
Ana Paulina Serrano: University of Texas Southwestern Medical Center
Daniel L. Cassidy: University of Texas Southwestern Medical Center
Ling Cai: University of Texas Southwestern Medical Center
Vanina Toffessi-Tcheuyap: University of Texas Southwestern Medical Center
Maryam E. Moussa: University of Ottawa
Winnie Uritboonthai: The Scripps Research Institute
Linh Truc Hoang: The Scripps Research Institute
Meghana Kolli: University of Texas Southwestern Medical Center
Brooklyn Jackson: University of Texas Southwestern Medical Center
Vitaly Margulis: University of Texas Southwestern Medical Center
Gary Siuzdak: The Scripps Research Institute
James Brugarolas: University of Texas Southwestern Medical Center
Ian Corbin: University of Texas Southwestern Medical Center
Derek A. Pratt: University of Ottawa
Ryan J. Weiss: University of Georgia
Ralph J. DeBerardinis: University of Texas Southwestern Medical Center
Kıvanç Birsoy: The Rockefeller University
Javier Garcia-Bermudez: University of Texas Southwestern Medical Center

Nature, 2025, vol. 644, issue 8077, 799-808

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09162-0

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