Department of Dermatology, Gongli Hospital of Shanghai Pudong New Area, Shanghai, China.
Department of Plastic Surgery, Gongli Hospital of Shanghai Pudong New Area, Shanghai, China.
Eur J Pharmacol. 2022 Oct 15;932:175228. doi: 10.1016/j.ejphar.2022.175228. Epub 2022 Aug 22.
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.
增生性瘢痕是一种复杂的纤维化疾病，治疗选择有限。机械应力已被证明对增生性瘢痕（HS）的形成至关重要。在这里，我们表明，类黄酮小分子非瑟酮可以通过抑制成纤维细胞的增殖、激活和胶原产生，显著改善机械拉伸诱导的小鼠模型中的 HS 形成。此外，体外和体内研究表明，非瑟酮通过抑制机械拉伸诱导的黏着斑激酶（FAK）和细胞外信号调节激酶（ERK）的磷酸化，减少 ERK 的核定位，从而抑制伸展诱导的促纤维化作用。从分子对接研究和激酶结合测定来看，这种非瑟酮的生物活性可能是由于其选择性结合到 FAK 的催化区域。综上所述，这些发现表明，非瑟酮是治疗增生性瘢痕和其他过度纤维化疾病的一种有前途的药物。
