The Myelin-Derived Peptide NSDP1 Suppresses Neuroinflammation and Attenuates Demyelination in Chronic Cuprizone-Fed Mice via Modulation of cGAS-STING Signaling

Multiple sclerosis (MS) is characterized by demyelination and neuroinflammation. In a cuprizone (CPZ)-induced demyelination mouse model, proteomic analysis revealed the significant downregulation of a myelin basic protein-derived peptide (sequence: DTGILDSIGRFFS), which we have designated as NSDP1 (nervous system-derived peptide 1). 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 attenuated CPZ-induced demyelination, 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 attenuates demyelination and suppresses neuroinflammation in demyelinating diseases by inhibiting the cGAS-STING pathway.