Esculin improves wound healing in diabetic rats by modulating extracellular matrix remodeling and molecular pathways

Diabetic wounds, marked by poor regeneration, chronic inflammation, and oxidative stress, pose a major challenge in diabetes. Esculin, a natural coumarin with antioxidant and anti-inflammatory effects, shows promise for wound healing. This study investigated the histopathological, biochemical, and molecular effects of topical esculin on full-thickness wounds in streptozotocin-induced diabetic rats. Excisional wounds were created on 60 Sprague-Dawley rats, assigned to four groups: normal control, diabetic control, esculin ointment 5% and 10%. Tissue samples were collected on days 7, 14, and 21 for histopathological, molecular, and biochemical analysis. Esculin treatment significantly accelerated wound closure and improved re-epithelialization and granulation tissue formation. Histological analysis revealed a decrease in lymphocyte infiltration, increased fibroblast proliferation and neovascularization at the earlier stages, and a higher number of fibrocytes and more organized collagen deposition at later stages of wound healing. Biochemically, esculin significantly elevated antioxidant enzyme activities and reduced oxidative stress markers, indicating restoration of redox balance. Moreover, esculin downregulated the pro-inflammatory cytokine IL-1β and upregulated bFGF, VEG), and TGF-β1, thereby supporting fibroblast activity, angiogenesis, and extracellular matrix remodeling. Collectively, these findings highlight the multifaceted role of esculin in promoting wound healing under diabetic conditions, supporting its potential as a promising adjunct therapy for managing chronic wounds.