Prostaglandin F2α impairs skin regeneration via FP receptor-mediated oxidative stress overriding autophagic protection in fibroblasts

Skin expansion is a widely utilized clinical technique for skin regeneration stimulated by mechanical stretch, yet the inadequate regenerative efficiency of skin remains a significant challenge. While metabolic reprogramming is a known adaptive response to mechanical stress, the specific metabolic alterations in the skin and their functional consequences in skin regeneration are unclear. Using a rat scalp expansion model combined with LC-MS/MS metabolomic analysis, we identified a significant upregulation of prostaglandin F2α (PGF2α) and activation of the arachidonic acid pathway in expanded skin. In addition, mechanical stretch was found to stimulate PGF2α secretion from human dermal fibroblasts, which then potently inhibited fibroblast proliferation and migration. Mechanistically, PGF2α acts through FP receptor activation, triggering mitochondrial damage, oxidative stress, and autophagic flux. Rescue experiments revealed that Reactive Oxygen Species (ROS) served as the primary cytotoxic agent underlying the functional impairment, whereas Autophagy functioned as a compensatory survival pathway. Collectively, these findings identify PGF2α as a key mechanotransduction mediator that signals through the FP receptor to dysregulate fibroblast function, with the net outcome determined by the balance between its induction of damaging ROS and a protective autophagic response. Targeting the PGF2α/FP receptor axis may therefore represent a promising therapeutic strategy to promote skin regeneration during skin expansion.