Peptide GCSTVLC derived from Sipunculus nudus alleviates diabetic nephropathy partialy through NF-κB pathway regulation

Marine-derived peptides are increasingly recognized as valuable bioactive food compounds due to their structural diversity and high bioactivity. In this study, protein hydrolysates from Sipunculus nudus (SNH), an edible marine organism traditionally consumed as food and medicine, were fractionated and evaluated for their dietary renoprotective potential. The administration of the peptide fraction SNH-A significantly ameliorated renal dysfunction in a diabetic nephropathy (DN) mouse model, as indicated by reduced levels of serum creatinine, blood urea nitrogen, and urinary protein, along with improved histopathological outcomes. Additionally, SNH-A treatment improved insulin sensitivity (as reflected by decreased HOMA-IR), regulated lipid metabolism, and downregulated key inflammatory cytokines. Through bioassay-guided purification, we identified a novel hexapeptide, GCSTVLC, which markedly suppressed the production of pro-inflammatory cytokines (TNF-α, IL-1β, and MCP-1) in high glucose-induced renal tubular cells. Mechanistic investigations revealed that GCSTVLC inhibited phosphorylation of both IκBα and NF-κB p65, thereby blocking NF-κB activation and subsequent inflammatory responses. Collectively, these findings support S. nudus -derived peptides, particularly GCSTVLC, as functional food-derived bioactives with potential to mitigate inflammation-associated renal injury in diabetic nephropathy. • SNH-A improved renal function and reduced pathology in DN mice. • Bioactive peptides from SNH-A were isolated and identified by LC–MS/MS. • Six novel peptide sequences were discovered, with GCSTVLC showing the strongest anti-inflammatory effect. • GCSTVLC suppressed NF-κB activation in glucose-stimulated HK-2 cells.