Peptides derived from sea cucumber accelerate cells proliferation and migration for wound healing by promoting energy metabolism and upregulating the ERK/AKT pathway

Numerous bioactive peptides have high potential in accelerating skin repair. This study aimed to explore wound healing capacity of sea cucumber-derived tetrapeptides with amino acid sequence of Val-Thr-Pro-Tyr (VTPY) and Val-Leu-Leu-Tyr (VLLY) by human skin fibroblast (HSF) and human umbilical vein endothelial cells (HUVEC) in vitro. The results showed that VTPY and VLLY possessed excellent capacity to induce the proliferation and migration of HSF cells and HUVEC cells. Among them, VTPY possessed a higher cell migration-promotion capacity than VLLY. Meanwhile, VTPY and VLLY increased mitochondrial respiratory capacity of cells, leading to the significant increase in adenosine triphosphate (ATP) production. Additionally, VTPY and VLLY significantly increased the percentage of S phase in cell cycle of HUVEC via upregulation of extracellular regulated protein kinases (ERK) and protein kinase B (AKT) signaling pathway. Molecular docking further indicated the interaction of peptides with mitogen-activated protein kinase phosphatase (MKP) and PH domain leucine-rich repeat protein phosphatase (PHLPP) binding site in the ERK2 and AKT, respectively, leading to subsequent increased phosphorylation of ERK1/2 and AKT. Overall, peptides of VTPY and VLLY possessed outstanding capacity to induce the proliferation and migration of HSF cells and HUVEC cells in vitro and the mechanism was mainly related to improving mitochondrial respiratory capacity to produce more ATP for biological energy, blocking the binding of MKP to ERK2 and PHLPP to AKT and thus upregulating the ERK/AKT pathway.