Honokiol attenuates neuroinflammation and enhances remyelination in mouse models of multiple sclerosis through PPARγ-mediated ERK/AKT signalling.

Multiple sclerosis is characterized by inflammatory demyelination and insufficient myelin repair, which together drive progressive neurological impairment. While existing immunomodulatory treatments have demonstrated efficacy in reducing acute relapse frequency, they fail to address the critical deficits in oligodendrocyte precursor cell (OPC) differentiation and subsequent remyelination, leaving patients with irreversible neurological disability. This highlights the pressing necessity for pharmacological interventions that can simultaneously mitigate neuroinflammation and stimulate endogenous myelin regeneration. In the present work, we evaluated the therapeutic potential of honokiol, a naturally occurring bioactive polyphenol derived from Magnolia officinalis, using both experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination paradigm. Our results demonstrate that honokiol improved myelin restoration and exerted potent anti-inflammatory effects by suppressing glial activation, modulating inflammatory cytokine profiles, and restoring lipid homeostasis. Transcriptomic analysis indicated a global downregulation of immune-related pathways, and significant upregulation of signalling cascades critically involved in myelination and oligodendrocyte maturation. Molecular dynamics simulations revealed that honokiol stably bound to cannabinoid receptors and peroxisome proliferator-activated receptor gamma (PPARγ) receptor via energetically favourable interactions. In primary OPC cultures, honokiol directly facilitated the differentiation of OPC into mature oligodendrocytes. Pharmacological blockade of PPARγ eliminated both honokiol-induced OPC maturation and subsequent activation of the extracellular signal-regulated kinase/protein kinase B (ERK/AKT) signalling axis. Taken together, these findings indicate that honokiol attenuates neuroinflammation and may facilitate myelin repair through both immunomodulatory actions and direct effects on oligodendrocyte lineage cells, supporting its potential as a disease-modifying strategy for demyelinating disorders.