In this study, we designed a small peptide (P5; GLYYF) from the original sequence of endogenous APN to allow transdermal delivery and discovered its role as an effective ligand for activating adiponectin receptor 1 (AdipoR1) in vivo and in vitro, based on the intensive end‐to‐end approach starting from in silico prediction, in vitro biochemical studies, and ex vivo HF organ culture and in vivo genetic mouse model studies, followed by molecular docking simulation. This evidence concerns the gene ADIPOR1 and hydrops fetalis.