Abstract
Cutaneous wound healing is an orderly and intricate process that restores the barrier function and integrity of injured skin. Re-epithelialization, which involves the proliferation and migration of keratinocytes to cover the denuded surface, is essential for successful wound closure. There are many members of the FGF family, of which the paracrine-acting FGF1 and FGF7 subfamily members have been identified as positive regulators of wound repair. However, the role and underlying mechanisms of some other paracrine FGFs in wound repair still remain obscure. In this report, we found that paracrine FGF4 localized predominantly to the epidermal keratinocytes and was markedly upregulated at the wound edges in response to re-epithelialization in human and mouse wound models. Blockade of FGF4 resulted in delayed re-epithelialization of human ex vivo skin wounds, whereas recombinant FGF4 treatment promoted re-epithelialization and wound repair. Mechanistically, recombinant FGF4 promotes p38 MAPK‒GSK3β‒mediated stabilization of Slug by reducing its ubiquitination, which triggers epithelial-to-mesenchymal transition and promotes the migration and proliferation of keratinocytes and thus wound re-epithelialization. Our findings uncover FGF4 as an important regulator of wound healing, highlighting a promising therapeutic avenue for skin injury.