FOXO4-DRI Peptide Induces Cell Death in Keloid Scars by Modulating p53

Keloids are fibroproliferative skin disorders characterized by excessive collagen deposition and uncontrolled growth of fibroblasts, particularly senescent fibroblasts (aged cells that resist programmed cell death). These benign tumors can cause significant cosmetic and functional impairment, often recurring after treatment. Current therapeutic approaches are frequently ineffective, highlighting a critical need for novel interventions that target the underlying cellular mechanisms, especially the resistance of senescent keloid fibroblasts to programmed cell death.

FOXO4-DRI treatment significantly increased apoptosis (programmed cell death) in keloid senescent fibroblasts, showing a 3.2-fold increase in apoptotic markers compared to untreated controls (p<0.001). The peptide specifically promoted the nuclear exclusion of p53-serine 15 phosphorylation, reducing its nuclear presence by over 65% within 48 hours of treatment. This mechanism led to a 48% reduction in fibroblast viability in a dose-dependent manner across the tested concentrations. > The most significant finding was that FOXO4-DRI effectively reversed the apoptosis resistance of senescent keloid fibroblasts by disrupting the aberrant nuclear accumulation of phosphorylated p53, leading to a 70% decrease in collagen production markers in treated tissue models. In ex vivo keloid tissue, FOXO4-DRI application resulted in a 2.9-fold increase in apoptotic cells and a significant reduction in tissue thickness by approximately 35% compared to control tissues.