Clemastine fumarate activates lipophagy to promote oligodendrocyte progenitor cells differentiation and remyelination in a cuprizone-induced demyelination model

Background: Remyelination failure in multiple sclerosis (MS) is associated with impaired oligodendrocyte progenitor cell (OPC) differentiation. Our previous studies showed OPCs phagocytose myelin debris, causing intracellular lipid accumulation that may block differentiation. However, the metabolic consequences of this lipid overload remain unclear. Clemastine fumarate promotes remyelination via muscarinic receptor antagonism, but its role in OPC lipid metabolism is unknown. Objective: To investigate whether clemastine fumarate alleviates lipid droplet (LD) accumulation in OPCs by activating lipophagy, supporting their differentiation and remyelination. Methods: In vitro, primary OPCs and Oli-neu cells were treated with myelin debris; in vivo, a cuprizone-induced demyelination model was used. Outcomes were assessed by immunohistochemistry, fluorescence staining, and RNA sequencing. Results: Clemastine fumarate enhanced OPC differentiation and promoted myelin debris and LD clearance in vitro, upregulating BECN1 and autophagy pathways. In cuprizone mice, it improved myelin integrity, promoted OPC maturation, and reduced LD accumulation and p62 expression. Conclusion: This study reveals a novel mechanism: clemastine fumarate can promote remyelination by activating lipophagy to clear pathological LDs in OPCs.