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Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis

Bång-Rudenstam, Anna LU orcid ; Cerezo-Magaña, Myriam LU orcid ; Horvath, Marton LU orcid ; Talbot, Hugo LU ; Gustafsson, Emma LU ; Jonathan, Stevanus LU ; Chakraborty, Chaitali ; Nissen, Itzel ; Gonçalves de Oliveira, Kelin LU and Boukredine, Axel LU orcid , et al. (2026) In Nature Cell Biology
Abstract

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging... (More)

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

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Contribution to journal
publication status
epub
subject
in
Nature Cell Biology
publisher
Nature Publishing Group
external identifiers
  • pmid:41673170
ISSN
1465-7392
DOI
10.1038/s41556-026-01879-y
language
English
LU publication?
yes
additional info
© 2026. The Author(s).
id
3e19b355-33b7-4a07-8c46-4ac4945d2597
date added to LUP
2026-02-26 13:58:46
date last changed
2026-02-26 13:58:46
@article{3e19b355-33b7-4a07-8c46-4ac4945d2597,
  abstract     = {{<p>Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.</p>}},
  author       = {{Bång-Rudenstam, Anna and Cerezo-Magaña, Myriam and Horvath, Marton and Talbot, Hugo and Gustafsson, Emma and Jonathan, Stevanus and Chakraborty, Chaitali and Nissen, Itzel and Gonçalves de Oliveira, Kelin and Boukredine, Axel and Beyer, Sarah and Perez, Julio Enriquez and Johansson, Maria C and Kjellén, Lena and Tykesson, Emil and Malmström, Anders and van Kuppevelt, Toin H and Forsberg-Nilsson, Karin and Esko, Jeffrey D and Remeseiro, Silvia and Bengzon, Johan and Governa, Valeria and Belting, Mattias}},
  issn         = {{1465-7392}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cell Biology}},
  title        = {{Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis}},
  url          = {{http://dx.doi.org/10.1038/s41556-026-01879-y}},
  doi          = {{10.1038/s41556-026-01879-y}},
  year         = {{2026}},
}