Cholesterol Homeostasis as a Vulnerability: Investigating the IDOL-LDLR Axis in Glioblastoma Progression
Srushti Shukla, Mansi Vekariya, Mittal Bhadiyadra, Vatsal Shah, Ekta PatelIntroduction:
Glioblastoma remains difficult to treat, partly because tumor cells can adjust their metabolism to support growth and survival. Cholesterol handling is one part of this adaptation, as glioblastoma cells need lipids for membrane formation, signaling, and stress tolerance.
Methods:
This review discusses published work on cholesterol homeostasis in glioblastoma, with emphasis on low-density lipoprotein receptor-mediated cholesterol uptake, liver X receptor signaling, and the inducible degrader of the low-density lipoprotein receptor.
Results:
Several studies indicate that glioblastoma cells increase low-density lipoprotein receptordependent cholesterol uptake to meet their lipid requirements. The inducible degrader of the lowdensity lipoprotein receptor is an E3 ubiquitin ligase that promotes lysine 63-linked ubiquitination and lysosomal degradation of the low-density lipoprotein receptor. Increasing its activity might reduce receptor availability at the cell surface and limit cholesterol entry into tumor cells.
Discussion:
This pathway is relevant because reduced cholesterol uptake may affect lipid raft organization, protein kinase B-related survival signaling, and lipid droplet use. At the same time, glioblastoma cells may compensate by increasing internal cholesterol synthesis, and normal brain cholesterol regulation must be considered.
Conclusion:
The inducible degrader of the low-density lipoprotein receptor–low-density lipoprotein receptor axis is a useful framework for studying cholesterol dependence in glioblastoma and may support future preclinical work on lipid-targeted therapeutic strategies.