Table 2.

Overview of oxysterol sources and role in the CNS.

Oxysterol	Primary source/production	Enzymes	Key receptors	Protective/homeostatic roles	Toxic/pathological effects in the CNS	References
Cholesterol	Produced locally by glia Transported to neurons via ApoE Internalised via LDLR/LRP1.	Oxysterol precursor	LDLR, LRP1	Essential for myelin, membranes, synaptic function.	Excess levels can undergo oxidation to toxic oxysterols.	Dietschy and Turley (2004), Pfrieger and Ungerer (2011)
24S-hydroxycholesterol (24S-OHC)	Produced in the brain by neurons and glial cells Exported across BBB.	CYP46A1	LXRα/β; NMDA receptors	Maintains cholesterol turnover and homeostasis Regulates gene expression and synaptic plasticity.	Elevated CSF levels reflect active neurodegeneration (AD, HD, MS) Reduced levels linked to neuronal loss in late-stage disease.	Lund et al. (1999), Björkhem et al. (2009), Testa et al. (2016)
7α-hydroxycholesterol (7α-OHC)	Produced in brain and periphery Intermediate in cholesterol metabolism Increases during oxidative stress.	CYP7B1	LXRα/β	Contributes to cholesterol homeostasis.	High levels promote inflammation and cytotoxicity Accumulates in AD and MS.	Russell (2003), Björkhem and Meaney (2004)
27-hydroxycholesterol (27-OHC)	Produced peripherally Crosses BBB into brain.	CYP27A1	LXRα/β; ERα	Maintains cholesterol turnover and signaling.	Neurotoxic at high levels Associated with AD, cognitive decline, neurovascular dysfunction.	Heverin et al. (2005), Björkhem et al. (2009), Hughes et al. (2013)
25-hydroxycholesterol (25-OHC)	Mainly induced by interferons and inflammatory stimuli.	CH25H	LXRα/β	Immunomodulatory oxysterol Broad-spectrum antiviral molecule (neurotropic viruses).	Promotes oxidative stress, apoptosis, and neuronal/oligodendrocyte injury Implicated in demyelination (MS).	Bauman et al. (2009), Cyster et al. (2014)
7β-hydroxycholesterol (7β-OHC)	Formed via oxidative stress.	Non-enzymatic	Interacts with a variety of cellular receptors and pathways to exert its effects	Potential antiviral properties, but these effects are often overshadowed by its cytotoxicity, especially in severe infections like COVID-19.	Strong pro-oxidant and pro-inflammatory actions Cytotoxic to neurons and glia; impairs myelination Accumulates in AD, PD, MS.	Poli et al. (2013), Testa et al. (2016)
7-ketocholesterol (7-KC)	Formed via oxidative stress.	Non-enzymatic	Interacts with several established nuclear receptors and other protein targets, particularly microglia	Primarily a toxic oxysterol with no known beneficial physiological function Weak antiviral activity in specific contexts, these potential benefits are generally counterbalanced by its potent cytotoxicity.	Potent pro-oxidant/pro-inflammatory oxysterol Alters membrane signaling and lipid raft composition Drives neuronal injury, demyelination, synaptic dysfunction Accumulates in AD, PD, MS.	Véjux and Lizard (2009), Anderson et al. (2020), Testa et al. (2016)

Conceptual takeaway: Oxysterols act as context-dependent lipid signals in the CNS, integrating cholesterol metabolism with receptor-mediated transcriptional, synaptic, and immune pathways. Enzymatically produced oxysterols primarily support cholesterol homeostasis and neuronal function, whereas oxysterols generated during inflammation or oxidative stress accumulate to drive neurotoxicity, neuroinflammation, and myelin dysfunction, thereby linking metabolic imbalance to neurodegenerative disease.