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). The gene discussed is POMC; the disease is dyschromatosis universalis hereditaria.