Morroniside maintains mitochondrial homeostasis in microglia and mitigates neuroinflammation in experimental autoimmune encephalomyelitis

Microglia-mediated neuroinflammation in the central nervous system is a hallmark of both multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE). Current immunosuppressive therapies for MS have limited efficacy and notable side effects. This study aimed to investigate mechanisms underlying anti-neuroinflammatory effects of morroniside, an iridoid glycoside derived from Cornus officinalis, which is used in Chinese herbal medicine. Morroniside treatment significantly attenuated lipopolysaccharide-induced alterations and mitochondrial dysfunction in BV2 microglia cells. In vivo, morroniside treatment improved clinical scores and ameliorated pathological findings and neurological deficits in a mouse EAE model. Mechanistic investigations revealed that morroniside activated the Nrf2/HO-1 signaling axis, promoted Nrf2 nuclear translocation and elevated HO-1 expression. This activation also upregulated p62, thereby enhancing LC3-II/PINK1/Parkin-mediated mitophagosome formation. The resultant mitophagy suppressed p65 phosphorylation leading to anti-inflammatory effects. Collectively, our findings suggest that morroniside ameliorates EAE by increasing anti-inflammatory microglial activation through upregulating the Nrf2/HO-1/p62 axis to mitigate mitochondrial oxidative stress and enhance mitophagy. These results identify morroniside as a promising therapeutic candidate for MS and emphasize the importance of the Nrf2-p62-mitophagy axis in resolving neuroinflammation and maintaining mitochondrial homeostasis.