Shuo Tang, Qiang Fu, Can Zheng, Minliang Chen
Successful re-epithelialization requires keratinocytes to undergo partial epithelial-mesenchymal transition (pEMT), yet endogenous mechanisms maintaining homeostatic quiescence remain poorly understood. Here, we identified family with sequence similarity 19 member A5 (FAM19A5) as a novel negative regulator of cutaneous wound healing. FAM19A5 was predominantly expressed in keratinocytes and significantly downregulated during wound repair. Exogenous FAM19A5 administration dose-dependently delayed wound closure and impaired re-epithelialization by suppressing pEMT, as evidenced by increased E-cadherin and decreased vimentin expression. In vitro, FAM19A5 inhibited keratinocyte migration without affecting proliferation. Mechanistically, FAM19A5 knockdown enhanced peroxisome proliferator-activated receptor delta (PPARD) nuclear translocation by 2.3-fold and upregulated downstream targets matrix metallopeptidase 1, angiopoietin-like 4, and Snail. PPARD antagonist GSK3787 substantially attenuated FAM19A5 knockdown-induced migration, whereas PPARD agonist GW501516 recapitulated key features of FAM19A5 deficiency. These findings suggest the FAM19A5-PPARD-Snail axis as a proposed regulatory mechanism that suppresses keratinocyte migration and maintains the epithelial phenotype, offering potential therapeutic targets for managing impaired wound healing.