Rebamipide Induces Hair Regeneration Through EP4-Driven Lipid Metabolism Remodeling

TL;DR

Rebamipide, a drug originally for ulcers, can regrow hair by altering fat cell metabolism and activating hair follicle stem cells.

Contribution

Rebamipide is shown to induce hair regeneration via EP4-driven lipid metabolism remodeling in dermal adipocytes.

Findings

Rebamipide induces autophagy and ATGL-mediated lipolysis in dermal adipocytes.

Lipolysis triggered by rebamipide activates hair follicle stem cells through increased PDGF levels.

Rebamipide binds to EP4, triggering PI3K/ERK-dependent autophagy and lipolysis.

Abstract

Alopecia is a highly prevalent hair loss disorder characterized by an abnormality in 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 originally intended for gastric ulcer treatment—as a promising candidate for hair regeneration by modulating dermal adipocyte metabolism. Topical rebamipide treatment induces autophagy and adipose triglyceride lipase (ATGL)-mediated lipolysis in dermal adipocytes. Using primary culture systems, we demonstrate that rebamipide-driven lipolysis triggers adipocyte dedifferentiation, activating hair follicle stem cells (HFSCs) via elevated platelet-derived growth factor (PDGF) 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 hair loss and position rebamipide as an agent that couples lipid metabolism remodeling with HFSC activation.

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