From Natural Compound Screening to Myelin-Associated Effects: Identification of Morusin as a Potent Promoter of Oligodendrocyte Differentiation

Myelination is essential for rapid axonal conduction and neuronal integrity, and its loss in demyelinating diseases such as multiple sclerosis (MS) leads to progressive neurological impairment. Despite advances in immunomodulatory therapies, effective strategies that promote remyelination remain limited. Here, we identify Morusin, a prenylated flavonoid natural compound, as a potent enhancer of oligodendrocyte (OL) differentiation and myelination-associated outcomes. Using a fluorescence-based screen of diverse flavonoids in primary rat oligodendrocyte progenitor cells (OPCs), it was found that Morusin markedly increased myelin basic protein (MBP) expression. To enable cross-species validation, we established a SOX10-inducible human OPC differentiation system, which shortened differentiation time and allowed functional screening in human cells. In this platform, Morusin enhanced OL maturation and induced a transcriptional profile enriched for myelination- and axon ensheathment-related genes, including MBP, PLP1, MAG, and SIRT2. Furthermore, in myelin oligodendrocyte glycoprotein (MOG)35–55-induced experimental autoimmune encephalomyelitis (EAE) mice, Morusin improved myelination-associated histological features and functional recovery, comparable to the benchmark compound Benztropine. Collectively, these findings identify Morusin as a promising natural compound with pro-myelinating activity across multiple experimental systems and highlight the potential of rationally guided natural compound screening for regenerative therapy in demyelinating diseases.