Therapeutic targeting of mechanical stretch-induced FAK/ERK signaling by fisetin in hypertrophic scars

Abstract

Hypertrophic scarring is a complex fibrotic disease with few treatment options. Mechanical stress has been proven to be crucial for hypertrophic scar (HS) formation. Here, we showed that the flavonoid small molecule fisetin, could dramatically ameliorate HS formation in a mechanical stretch-induced mouse model. In addition, in vitro and in vivo studies demonstrated that fisetin inhibited the stretch-induced profibrotic effects by suppressing the proliferation, activation, and collagen production of fibroblasts. Mechanistically, we revealed that fisetin obviously downregulated mechanical stretch-induced the phosphorylation of FAK and ERK, and reduced nuclear localization of ERK. This bioactivity of fisetin may result from its selective binding to the catalytic region of FAK, which was suggested by the molecular docking study and kinase binding assay. Taken together, these findings suggest that fisetin is a promising agent for the treatment of hypertrophic scars and other excessive fibrotic diseases.

Keywords: FAK/ERK; Fibroblasts; Fisetin; Hypertrophic scar; Mechanical force.