Cholesterol Metabolism in Cancer Progression and Biology

Cancer cells rewire cholesterol metabolism to support rapid proliferation, survival under stress and dissemination. Endogenous cholesterol synthesis via the mevalonate pathway and exogenous uptake through lipoprotein receptors converge to maintain membrane fluidity, lipid raft formation and production of bioactive metabolites known as oxysterols. These oxysterols act as signalling molecules in the tumour microenvironment, modulating nuclear receptors and immune cell function. Dysregulated cholesterol homeostasis also confers resistance to ferroptotic cell death, a form of iron-dependent lipid peroxidation, by up-regulating protective enzymes. In many carcinomas, key biosynthetic enzymes and transporters are overexpressed or hyperactivated, creating vulnerabilities to targeted inhibitors. At the same time, cholesterol accumulation in mitochondria impairs apoptosis, contributing to the metabolic shift towards aerobic glycolysis. Collectively, these alterations underpin tumour growth, metastasis and therapy resistance, and they offer opportunities for intervention through statins, enzyme-specific blockers and dietary modulation.

Research from Nature Portfolio

Recent studies have revealed a mechanism by which colorectal cancer cells co-opt a vacuolar ATPase subunit to enhance exogenous cholesterol import, leading to accumulation of 24-hydroxycholesterol in the endoplasmic reticulum. This oxysterol activates liver X receptor signalling, up-regulates TGF-β1 release and suppresses memory CD8+ T-cell activity, pointing to a novel immunosuppressive axis and a potential repurposing of an antiviral agent as an inhibitor. Additionally, work on cholesterol-driven ferroptosis resistance has shown that chronic exposure to the oxysterol 27-hydroxycholesterol selects for cells with increased uptake and lipid biosynthesis. These cells depend on GPX4, a ferroptosis suppressor, to survive lipid peroxidation, thereby promoting tumourigenicity and metastasis. Interrupting GPX4 function restores ferroptotic sensitivity and attenuates metastatic potential.

Cholesterol Metabolism in Cancer Progression and Biology publication trend

The graph below shows the total number of articles in cholesterol metabolism in cancer progression and biology across all publications each year (not limited to Nature Index journals).

Technical terms

Mevalonate pathway: A metabolic cascade converting acetyl-CoA to cholesterol and isoprenoids, regulated by HMG-CoA reductase.

Oxysterol: An oxygenated derivative of cholesterol that modulates nuclear receptors and immune signalling.

Liver X receptor (LXR): A nuclear receptor activated by oxysterols that controls genes involved in lipid homeostasis and inflammation.

Ferroptosis: Iron-dependent cell death caused by lipid peroxidation, counteracted by glutathione peroxidase 4.

Tumour microenvironment: The complex milieu of stromal cells, immune cells, extracellular matrix and signalling molecules surrounding a tumour.

References

1. ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells. Nature Communications (2024).
2. Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer. Nature Communications (2021).
3. Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. Nature Communications (2015).
4. Cholesterol and Its Metabolites in Tumor Growth: Therapeutic Potential of Statins in Cancer Treatment. Frontiers in Endocrinology (2019).
5. Mitochondria, cholesterol and cancer cell metabolism. Clinical and Translational Medicine (2016).