IGK Suppresses Keloid Fibroblast Activation Through Modulation of MDM2 Expression and p53 Signaling

Keloids are intricate fibroproliferative disorders characterized by sustained fibroblast activation, excessive deposition of extracellular matrix, and dysregulated wound-healing responses. This study explored the therapeutic effects and underlying mechanisms of Isoginkgetin (IGK) in keloid fibroblasts (KFbs) and a human keloid xenograft model. Our findings indicated that MDM2 expression was elevated in clinical keloid specimens, and IGK treatment inhibited KFbs proliferation and migration while inducing cell cycle arrest and apoptosis. Mechanistically, IGK downregulated MDM2 expression at the transcriptional level and was associated with the modulation of the MDM2/p53 signaling axis. LiP-MS and molecular docking analyses identified eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) as a potential IGK-associated protein, suggesting that EEF1A1 may play a role in IGK-mediated regulation of MDM2 expression. Moreover, transcriptomic analysis of xenograft tissues combined with serum multicytokine profiling demonstrated that IGK treatment modulated inflammation-associated signatures, including those related to TNF signaling pathways, within the xenograft model. In vivo, administration of IGK resulted in a reduction in volume, collagen deposition, and α-SMA expression in established human keloid xenografts. Taken together, these findings indicate that IGK exerts anti-keloid effects by modulating the MDM2/p53 signaling axis and inflammation-associated pathways, underscoring its potential as a therapeutic candidate for keloid treatment.