Lactate-driven H3K27 lactylation promotes Olig2-dependent remyelination and motor recovery after spinal cord injury.

Demyelination caused by oligodendrocyte death is a key contributor to neurological deficits after spinal cord injury (SCI), highlighting the critical need to promote oligodendrocyte precursor cell (OPC) differentiation and remyelination. The transcription factor Olig2 is a master regulator of this process; however, its activation mechanism remains unclear. Given the marked lactate accumulation in post-SCI ischemic microenvironments, we investigated the role of lactate in SCI as well as its regulation on OPC differentiation. In a rat SCI model, it is found that exogenous lactate administration significantly improves motor recovery, preserves neurons and axons, modulates the glial response. Mechanistically, lactate induces histone H3K27 lactylation (H3K27la), which specifically upregulates Olig2 expression, thereby activating OPC differentiation and remyelination. This study uncovers the lactate-H3K27la-Olig2 metabolic-epigenetic axis as a novel endogenous repair mechanism for SCI, providing a foundation for metabolism-targeted therapeutic strategies.