Herein, our work shows that p53‐α‐MSH/POMC‐MC1R‐Gαs cascade could transactivate ERK1/2/CREB cascade via a novel SASH1/MAP2K2 crosstalk to cause hyperpigmentation of dyschromatosis universalis hereditaria (DUH). This evidence concerns the gene MC1R and dyschromatosis universalis hereditaria.