Rebamipide Induces Hair Regeneration through EP4-Driven Lipid Metabolism Remodeling

Alopecia is a highly prevalent hair loss disorder characterized by abnormality of hair cycling. Induction of autophagy and secretion of growth factors by adipocyte precursors are sufficient to activate quiescent hair follicles. Yet therapies targeting these processes remain limited. Here, we identify rebamipide, a drug initially intended for gastric ulcer treatment, as a promising candidate for hair regeneration by modulating dermal adipocyte metabolism. Topical rebamipide treatment induces autophagy and ATGL-mediated lipolysis in dermal adipocytes. Through primary culture systems, we demonstrate that rebamipide-driven lipolysis triggers adipocyte dedifferentiation, activating HFSCs via elevated PDGFα levels. Mechanistically, computer simulations and target validation experiments confirm that rebamipide directly binds to the prostaglandin E receptor EP4, triggering PI3K/ERK-dependent autophagy and lipolysis. Collectively, our findings highlight EP4 as a novel therapeutic target for alopecia and position rebamipide as an agent that couples lipid metabolism remodeling with HFSC activation. RNA-seq profiling of dorsal skins from C57BL/6 mice treated with vechile or 3% rebamipide at Day 7