Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis

• 成果类型: Article
• 署名作者: Calhoon, Dylan; Sang, Lingjie; Ji, Fubo; Bezwada, Divya; Hsu, Sheng-Chieh; Cai, Feng; Kim, Nathaniel; Basu, Amrita; Wu, Renfei; Pimentel, Anastasia; Brooks, Bailey; La, Konnor; Paulina Serrano, Ana; Cassidy, Daniel L.; Cai, Ling; Toffessi-Tcheuyap, Vanina; Moussa, Maryam E.; Uritboonthai, Winnie; Hoang, Linh Truc; Kolli, Meghana; Jackson, Brooklyn; Margulis, Vitaly; Siuzdak, Gary; Brugarolas, James; Corbin, Ian; Pratt, Derek A.; Weiss, Ryan J.; DeBerardinis, Ralph J.; Birsoy, Kivanc; Garcia-Bermudez, Javier
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University System of Georgia; University of Georgia; Rockefeller University; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Ottawa; Scripps Research Institute; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University System of Georgia; University of Georgia; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1678
• DOI: 10.1038/s41586-025-09162-0
• 发表日期: 2025-08-21
• 关键词: low-density-lipoprotein; vitamin-e; chondroitin sulfate; heparan-sulfate; cell-death; serum-lipoproteins; lipid-peroxidation; cancer; receptor; plasma

摘要

Lipids are essential components of cancer cells due to their structural and signalling roles1. To meet metabolic demands, many cancers take up extracellular lipids2, 3, 4-5; 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 alpha-tocopherol (alpha-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 alpha-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.