THE DUAL ROLE OF CHOLESTEROL METABOLISM IN MULTIPLE SCLEROSIS: FROM NEUROINFLAMMATION TO REMYELINATION
DOI:
https://doi.org/10.11603/mcch.2410-681X.2026.i3.16577Keywords:
multiple sclerosis; cholesterol; oxysterols; microglia; foam cells; remyelination; oligodendrocytesAbstract
Introduction. Multiple sclerosis (MS) is traditionally conceptualized as a chronic autoimmune disorder. However, the limited efficacy of current disease-modifying therapies in halting disability progression challenges the purely immunocentric view, driving interest toward glial immunometabolism. Given that myelin is a lipid-dense structure, cholesterol dysregulation has emerged as a primary focus in MS pathogenesis. The aim of the study – to systematize and critically evaluate recent scientific data regarding the dual pathophysiological role of cholesterol and its oxysterol derivatives as modulators of neuroinflammation and ratelimiting factors in remyelination. Research Methods. The study employed information retrieval and analytical-comparative methods. Results and Discussion. This review analyzes the dichotomy of cholesterol pathways in MS. Systemic dyslipidemia and intracellular free cholesterol crystallization act as danger signals that trigger the NLRP3 inflammasome in microglia, while oxysterols (27-OHC, 7-KC, 25-OHC) drive autoreactive lymphocyte trafficking across the BBB via EBI2 and promote Th17 differentiation. Conversely, local lipid recycling within the CNS is indispensable for oligodendrocyte survival. Impaired lipid efflux and ABCA1/G1 deficiency result in «foam cell» formation, accumulating cholesterol esters and blocking oligodendrocyte progenitor cell (OPC) maturation. The failure of peripheral lipid-lowering with statins in the phase III MS-STAT2 trial underscores the necessity of targeting intra-CNS pathways. Promising options include LXR/RXR agonists, epigenetic nutraceutical regulators (SCFAs), and CNS-selective thyromimetics (Sob-AM2). Conclusions. Cholesterol homeostasis is a pivotal checkpoint balancing immune-mediated damage and neuroregenerative capacity in MS. Pharmacological targeting of local lipid clearance and the TREM2/ApoE axis offers innovative strategic avenues for managing progressive multiple sclerosis.
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