An AAQPR peptide from Aspergillus oryzae-fermented wheat peptone promotes the regenerative potential of dermal and epidermal layers of the skin in in vitro assays and clinical trials†

Because of the activity and stability of existing traditional proteins, promoting the regenerative potential of skin defects caused by various environmental stresses is challenging. Small peptides with relatively high activity and stability show potential for skin tissue regeneration. We previously demonstrated that Aspergillus oryzae-fermented wheat peptone enhanced the proliferation and hydration of human epidermal keratinocytes. In this study, the AAQPR peptide (INCI ID: 37800, PEP5) was selected from Aspergillus oryzae-fermented wheat peptone, and its regenerative potential was examined in both human primary dermal fibroblasts and epidermal keratinocytes. Moreover, the translational properties of PEP5 have been investigated in humans. Cell proliferation, collagen production, oxidative stress, and pro-inflammatory cytokines in fibroblasts and keratinocytes are important factors that affect skin regeneration. We observed that PEP5 induced collagen production through the Smad2/3 signaling pathway in human dermal fibroblasts. Autodock analysis showed the possibility that PEP5 physically interacts with the transforming growth factor-β receptor, leading to collagen production. PEP5 attenuated ultraviolet A (UVA)-induced dysregulation of metalloproteinase activity, collagen integrity, and inflammatory signaling in human fibroblasts. A comparable protective effect was observed in the human epidermal keratinocyte cell line, HaCaT cells, where PEP5 suppressed UVA-induced oxidative stress and cytokine production. Furthermore, PEP5 upregulated the expression of hydration-related genes in HaCaT cells, leading to skin hydration. In clinical studies, PEP5 treatment resulted in increased skin hydration and a reduction in fine wrinkles compared to the placebo group. These data suggest that PEP5 could be introduced as a potential therapeutic agent to help improve external stress on the skin.