Cholesterol Metabolism and Immune Response Modulation

Cholesterol metabolism extends beyond its well-established role in membrane structure and steroidogenesis to become a pivotal regulator of immune function. Endogenous synthesis in the endoplasmic reticulum and uptake via lipoprotein receptors supply cellular cholesterol, while specialised enzymes generate oxidised derivatives, or oxysterols, that serve as signalling mediators. Feedback networks centred on sterol regulatory element-binding proteins (SREBPs), their escort protein SCAP and endoplasmic reticulum retention factors ensure homeostatic control of biosynthesis. Oxysterols such as 25-hydroxycholesterol bridge lipid metabolism and host defence by modulating membrane fluidity, inflammasome assembly, nuclear receptor activation and paracrine antiviral signalling. Cholesterol trafficking pathways, both vesicular and non-vesicular, determine local concentrations of sterols that influence macrophage and microglial activation, T-cell differentiation and cytokine production. Dysregulation of these intersecting networks contributes to chronic inflammation, neurodegeneration, atherosclerosis and viral pathogenesis, while targeted manipulation of oxysterol pathways offers new avenues for therapeutic intervention.

Research from Nature Portfolio

• Aberrant production of cholesterol 25-hydroxylase and its product, 25-hydroxycholesterol, has been identified as a driver of neuroinflammation via activation of the NLRP3 inflammasome. Mechanistic studies reveal that oxysterol-induced potassium efflux, mitochondrial reactive oxygen species generation and liver X receptor signalling converge to promote microglial recruitment, interleukin-1β release and oligodendrocyte death, shedding light on demyelinating processes in X-linked adrenoleukodystrophy. • The antiviral spectrum of oxysterols has been expanded to include non-enveloped pathogens: both 25-hydroxycholesterol and 27-hydroxycholesterol exhibit potent inhibitory activity against human papillomavirus-16, rotavirus and rhinovirus. This work demonstrates that endogenous modulation of oxysterol biosynthesis constitutes a broad-spectrum host defence strategy and informs the development of oxysterol-based antiviral therapeutics.

Cholesterol Metabolism and Immune Response Modulation publication trend

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

Technical terms

Oxysterol: An oxygenated derivative of cholesterol that functions as a lipid signalling molecule, regulating sterol homeostasis and immune pathways.

Cholesterol 25-hydroxylase (CH25H): An enzyme that converts cholesterol to 25-hydroxycholesterol, integrating sterol metabolism with innate immunity.

NLRP3 inflammasome: A multiprotein complex that senses metabolic and pathogen-derived signals, triggering interleukin-1β maturation and inflammatory cell death.

Sterol regulatory element-binding proteins (SREBPs): Membrane-bound transcription factors that control genes involved in cholesterol and fatty acid synthesis.

SCAP: A sterol-sensing escort protein that governs SREBP trafficking from the endoplasmic reticulum to the Golgi for activation.

Ferritinophagy: A selective autophagic process that degrades ferritin complexes to release iron, influencing oxidative cell death pathways.

Ferroptosis: An iron-dependent form of regulated cell death characterised by lipid peroxidation and membrane rupture.

References

1. Nonvesicular cholesterol transport in physiology. Journal of Clinical Investigation (2025).
2. Oxysterol 25-hydroxycholesterol activation of ferritinophagy inhibits the development of squamous intraepithelial lesion of cervix in HPV-positive patients. Cell Death Discovery (2024).
3. 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nature Communications (2016).
4. Oxysterol research: a brief review. Biochemical Society Transactions (2019).
5. The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response. Immunity (2012).
6. Cholesterol and 25-Hydroxycholesterol Inhibit Activation of SREBPs by Different Mechanisms, Both Involving SCAP and Insigs*. Journal of Biological Chemistry (2004).
7. Inhibition of pathogenic non-enveloped viruses by 25-hydroxycholesterol and 27-hydroxycholesterol. Scientific Reports (2014).