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.