Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging. [Display omitted] •An epigenetic barrier impedes myelin production in multiple sclerosis lesions•Small-molecule inhibitor ESI1 promotes CNS myelin production and regeneration•ESI1 enhances (re)myelination in aged mice while reversing cognitive decline•ESI1-induced active chromatin landscape and SREBP condensation boost myelinogenesis Oligodendrocytes in multiple sclerosis lesions exhibit epigenetic silencing that precludes myelin restoration. This study identifies a small-molecule inhibitor that counteracts epigenetic silencing, effectively enhancing myelin production and thereby promoting (re)myelination in animal models and human organoids while reversing age-related cognitive decline.