A novel tyrosinase inhibitory peptide derived from Sipunculus nudus suppresses melanogenesis in B16F10 cells by down-regulating TRP-1/TRP-2 expression

Tyrosinase inhibitory peptides (TIPs), naturally abundant in mammals as well as agricultural and aquatic products, have emerged as promising alternatives to synthetic skin whitening agents due to their exceptional biosafety. Building upon our previous identification of the novel TIP (IIAPPERKY) from Sipunculus nudus through integrated bioinformatics screening and molecular dynamics simulations, this study aim to elucidate its anti-melanogenic mechanism using B16F10 cells. Biochemical assays revealed that IIAPPERKY significantly reduced melanin synthesis and tyrosinase activity while enhancing antioxidant capacity. Molecular docking confirmed direct binding between IIAPPERKY and tyrosinase (−7.80 kcal/mol), suggesting allosteric interference. Gene and protein expression analyses demonstrated marked downregulation of tyrosinase-related protein-1 (TRP-1) and tyrosinase-related protein-2 (TRP-2) at transcriptional and translational levels. These findings indicated that IIAPPERKY suppresses melanogenesis through dual mechanisms: antioxidant-driven inhibition of TRP-1/TRP-2 and binding to tyrosinase. Its biosafety and efficacy highlight potential applications in functional cosmetics and food industries, expanding the utilization of agricultural resources. • IIAPPERKY significantly reduced the expression levels of tyrosinase and melanin. • IIAPPERKY bound to the tyrosinase active site by multiple binding forces engagement strategy and reduced intracellular tyrosinase activity. • IIAPPERKY's antioxidant capacity effectively inhibited the auto-oxidation reaction of tyrosinase. • IIAPPERKY down-regulated the protein expression of TRP-1/TRP-2, and ultimately inhibited melanogenesis