FoxC1 activates Notch3 signaling to promote the inflammatory phenotype of keloid fibroblasts and aggravates keloid

Abstract

Keloids are disfiguring proliferative scars, and their pathological mechanisms are still unclear. We have previously established that FoxC1 plays a significant role in rheumatoid arthritis and osteoarthritis, but its molecular mechanisms in pathological scar formation remain elusive. In this study, we analyzed keloid tissue characteristics using HE staining and immunohistochemistry, revealing abnormal expression of FoxC1 and Notch3 in keloids. Lentiviral modulation of FoxC1 and Notch3 demonstrated that they promote the expression of α-SMA, fibronectin, collagen I, and Hes-1, enhancing the proliferation, migration, invasion, and cytokine production of keloid fibroblasts (KFs) while inhibiting apoptosis. Co-immunoprecipitation (CO-IP), dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) confirmed that FoxC1 can directly bind to the Notch3 promoter and enhance its transcription. Additionally, in vivo, overexpression of FoxC1 and Notch3 promoted keloid formation. In summary, our research highlights the critical regulatory role of FoxC1 in keloid formation through Notch3 activation, potentially offering new therapeutic targets for preventing scar formation.