Nonapeptide AOP-P1 ameliorates UVB-induced hyperpigmentation by suppressing melanogenesis via targeting natriuretic peptide receptor 2

Hyperpigmentation disorders remain challenging to treat because most available agents mainly act on downstream melanogenic Enzymes rather than upstream regulatory mechanisms. In this study, we identified AOP-P1, an amphibian skin-derived nonapeptide, as a potent anti-melanogenic peptide with nanomolar activity and no detectable cytotoxicity. By integrating in vitro and in vivo functional assays with transcriptomic profiling, receptor-binding studies, genetic perturbation, and pathway validation, the natriuretic peptide receptor 2 (NPR2) was identified as a unrecognized upstream regulator of melanogenesis in previous and also a mechanistically relevant target of AOP-P1. We further showed that AOP-P1 suppresses melanin production by inhibiting the NPR2/cGMP/MITF signaling axis, thereby attenuating UVB-induced hyperpigmentation. Collectively, our findings define AOP-P1 as a naturally derived bioactive peptide with receptor-linked anti-melanogenic activity and establish an NPR2-centered molecular basis for peptide-mediated regulation of pigmentation. These results expand current understanding of melanogenesis control and support the value of natural peptides as bioactive molecular scaffolds for pigmentation-related research.