Therapeutic Targeting of the LXR Pathway for Improving Myelin Integrity in Neurodegeneration

Neurodegenerative and demyelinating diseases are often associated with impaired cholesterol homeostasis, glial dysfunction, neuroinflammation, and impaired myelin maintenance. Because myelin is highly enriched in cholesterol and other lipids, efficient lipid transport, recycling, and availability are essential for oligodendrocyte function and remyelination. Liver X receptors (LXRα and LXRβ) are lipid-sensitive nuclear receptors that connect cholesterol metabolism with glial responses and myelin regulation. In the CNS, the 24S-hydroxycholesterol (24S-OHC)-LXR-ABCA1/ABCG1-ApoE axis serves as an important regulatory pathway for cholesterol efflux, ApoE-mediated lipid redistribution, microglial handling of myelin-derived lipids, and maintenance of cholesterol availability required for oligodendrocyte maturation and myelin formation. The 24S-OHC generated from cholesterol by CYP46A1 acts as an endogenous LXR ligand and promotes transcription of cholesterol efflux genes such as ABCA1 and ABCG1, along with ApoE-mediated lipid transport. Although previous studies with LXR agonists have focused on oligodendrocyte health and remyelination via inflammatory regulation, translation of LXR agonists remains limited by poor CNS exposure, lack of isoform selectivity, and LXRα-mediated hepatic lipogenesis and metabolic toxicity. These limitations have shifted therapeutic development toward LXRβ-biased agonists, CNS-restricted delivery, partial agonism, and modulation of the CYP46A1/24S-OHC pathway. Overall, LXR signaling represents a mechanistic link among brain cholesterol homeostasis, glial lipid handling, and myelin integrity; therefore, the development of next-generation selective LXR agonists offers substantial potential to restore lipid homeostasis and enhance neuroprotection across neurodegenerative diseases.