Chinese giant salamander (Andrias davidianus) skin-derived collagen peptides counteract UVB-induced skin photoaging through the miR-4521/EGFR/MAPK signaling axis.

Dietary collagen peptides have been shown to alleviate UVB-induced skin photoaging. However, the upstream regulatory mechanisms and the bioactive peptide sequences underlying these effects remain unclear. In this study, using UVB-induced photoaging models in HaCaT cells and nude mice, we demonstrated that Chinese giant salamander-derived skin collagen peptides (CPs) ameliorate photoaging through the miR-4521/EGFR/MAPK axis and identified GPY (Gly-Pro-Try) as a representative anti-photoaging tripeptide. In HaCaT cells, UVB irradiation downregulated miR-4521. Bioinformatics and transfection analyses suggested that EGFR is regulated by miR-4521 and functions as an upstream regulator of the MAPK pathway. CPs treatment increased miR-4521, inhibited EGFR and MAPK activation, and consequently ameliorated photoaging-related phenotypes. Compared with UVB irradiation alone, GPY increased the expression of type I collagen and elastin in HaCaT cells by 61.9 and 10.0%, respectively, while suppressing MAPK activation. In nude mice exposed to UVB for 10 weeks, dermal collagen fibers became disorganized, and the collagen area and type I collagen level decreased to approximately 20 and 10% of the corresponding control values, respectively. Dietary CPs intervention restored collagen fiber organization and increased the collagen area and type I collagen to 66.7 and 76.0% of the control levels, respectively. CPs supplementation also suppressed MAPK signaling, as evidenced by reductions of 22.3, 81.3, and 44.7% in p-JNK, p-ERK, and p-p38 levels, respectively, relative to the UVB-only group. Overall, these findings reveal the miR-4521/EGFR/MAPK axis and GPY as key bases for the anti-photoaging effects of CPs.