SC2-3, a Marine Nutrient Glycopeptide from Nereis succinea: Alleviating Cyclophosphamide-Induced Immunocompromise in Mice via M1-Type Macrophage Polarization

Immunodeficiency is a global health concern, partly due to disrupted rhythms and drugs. Marine glycopeptides, with immunomodulatory and intestinal barrier protective activities, show great potential in dietary supplements and functional foods. Here, a marine glycopeptide, SC2-3, with a molecular weight of 5061 Da, was isolated and purified from <i>Nereis succinea</i>. Monosaccharide composition, NMR data, amino acid composition analysis, and SDS-PAGE analyses identified SC2-3 as a glycopeptide. The N-glycome results of SC2-3 collected by MALDI-TOF-MS revealed that SC2-3 contains fucosylated N-glycans with shorter glycan chains compared to human-derived N-glycans. SC2-3 exerted a significant immune-enhancing effect on macrophages in vitro. In vivo, in cyclophosphamide-induced immunocompromised mice, SC2-3 at different concentrations elevated organ indices, blood cell counts, and serum levels of IL-1β, TNF-α, and IL-6, while repairing cyclophosphamide-damaged/atrophied tissues. Mechanistically, SC2-3 induced the differentiation of RAW264.7 cells toward an M1-like activation profile, significantly promoting the release of NO and ROS, upregulating the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6), and activating the TLR4/NF-κB signaling pathway. Additionally, SC2-3 upregulated intestinal epithelial tight junction proteins and normalized the overexpression of MUC-2, thereby maintaining intestinal barrier integrity. These findings indicated the potential efficacy of the glycopeptide SC2-3 derived from natural marine sources in immunomodulation and protection of intestinal health.