Panax quinquefolius saponins promote remyelination via orchestrating HMGCS1-NPC1-MAL-mediated lipid metabolism and rebalancing JAK-STAT signaling in a cuprizone-induced demyelination model.

Panax quinquefolius L. is traditionally used as a "Qi-tonifying and Yin-nourishing" herb for weakness and limb flaccidity, symptoms described as "Feng fei" or flaccidity syndrome. These manifestations partially resemble motor dysfunction in multiple sclerosis (MS). Panax quinquefolius Saponins (PQS), are major bioactive constituents, but their effects on demyelination and related molecular changes remains unclear. To investigate the effects of PQS on demyelination and explore associated changes in inflammatory signaling and lipid metabolism. PQS was qualitatively profiled by UPLC-QTOF-MS and quantitatively standardized by HPLC-DAD. Male C57BL/6N mice were randomly divided into six groups (n = 12-16/group): Control, Model (daily intragastric administration of 330 mg/kg of cuprizone (CPZ) for 6 weeks), Positive control (10 mg/kg of Clemastine), and low-, medium-, and high-dose PQS groups (25, 50, or 100 mg/kg). During week 2-6, mice received drugs by daily intragastric administration. Behavioral assessments including pole test, rotarod, and open field test were performed. Myelin integrity and related molecular changes were evaluated by histological staining, immunofluorescence (IF), transcriptomics, Western blotting, and molecular docking. PQS ameliorated CPZ-induced motor dysfunction in behavioral assessments (P < 0.05). PQS also attenuated myelin loss in the corpus callosum (CC), with the high-dose group increasing myelinated areas to approximately 74% of control levels (P < 0.01). Transcriptomic and protein analyses showed that PQS downregulated JAK1/STAT3/NLRP3 inflammatory pathway. In parallel, the HMGCS1-NPC1-MAL axis was upregulated, accompanied by increased mevalonate (MVA) and total cholesterol (TC) levels (P < 0.05) and reduced PLIN2 expression (P < 0.001), suggesting decreased lipid droplet accumulation and altered cholesterol metabolism.Molecular docking predicted ginsenosides Rb3, Rk3, Re, Rc, Ro, and Rf may interact with targets related to inflammatory and lipid metabolism. PQS supported myelin restoration, which is correlated with a modulation of the JAK-STAT signaling pathway and HMGCS1/NPC1-associated lipid homeostasis. PQS may represent a potential therapeutic lead for demyelinating diseases, although mechanisms require further validation.