The Myelin-Derived Peptide NSDP1 Promotes Remyelination and Attenuates Neuroinflammation in Cuprizone-Induced Demyelination via Suppression of the cGAS- STING Pathway

Multiple sclerosis (MS) involves demyelination and neuroinflammation. Proteomic analysis identified significant downregulation of the myelin basic protein-derived peptide NSDP1 in the cuprizone (CPZ)-induced demyelination mouse model. In vitro , NSDP1 suppressed LPS-induced microglial activation in BV2 cells, reducing reactive oxygen species (ROS) production, downregulating pro-inflammatory markers (iNOS, TNF-α, IL-1β), and upregulating the expression of anti-inflammatory marker Arg-1. In vivo , NSDP1 administration via intracerebroventricular injection significantly mitigated CPZ-induced weight loss and demyelination in the corpus callosum. NSDP1 promoted functional remyelination, restoring expression of myelin proteins (MAG, MOG), increasing oligodendrocyte precursor cell (OPC) density, improving myelin sheath ultrastructure, and enhancing axonal myelination efficiency. Furthermore, NSDP1 attenuated CPZ-induced reactive gliosis, reducing both microglial activation and astrocytic reactivity in the corpus callosum. RNA sequencing revealed that NSDP1 modulated myelination-related pathways and correlated with improved locomotor recovery. Mechanistically, NSDP1 exerted its anti-inflammatory effects by inhibiting the cGAS-STING signaling pathway, as shown by reduced cGAS and STING expression in LPS-stimulated BV2 cells. The effects of NSDP1 on ROS and pro-inflammatory cytokine release were reversed by the STING activator DMX and mimicked by the STING inhibitor SN-011. Collectively, these findings identify NSDP1 as a downregulated myelin-derived peptide with potent therapeutic potential, which promotes remyelination and suppresses neuroinflammation in demyelinating diseases by inhibiting the cGAS-STING pathway.