GK improves behavioral dysfunction and demyelination in cuprizone(CPZ) model, followed by the migration and enrichment of astrocytes in the corpus callosum. Both in vitroand in vivo experiments demonstrates that GK triggers the upregulation of Nrf2/HO-1 in astrocytes and inhibitionof p-NF-kB/p65, which is associated with the outcome of anti-inflammation and anti-oxidation bysuppressing the production of IL-6 and TNFα as well as nitric oxide and iNOS in astrocytes. Further findingssuggest that IGF/PI3K, but not BDNF, was induced in the corpus callosum after GK treatment, revealing that Nrf2activation inhibited caspase-3 and apoptosis in O4+ oligodendrocytes possibly through IGF/PI3K signalingmolecules. Since the current immunomodulatory therapies for MS have failed to prevent patients from enteringthe progressive phase of the disease, thus targeting Nrf2 in astrocytes with GK would be an ideal strategy formyelin protection and regeneration.