Umbelliferone preserves skin epidermal barrier integrity in diabetes-induced keratinocytes by regulating actin dynamics and suppressing ROS-mediated apoptosis.

BACKGROUND: The skin serves as a fundamental protective barrier against environmental insults, with the epidermis, particularly the stratum corneum and tight junctions (TJs) connecting keratinocytes, playing a crucial role. Chronic hyperglycemia can impair these TJs, leading to compromised epidermal barrier function and diabetic skin complications. This study aimed to investigate the effects of umbelliferone on epidermal barrier function under type 2 diabetic conditions. METHODS: HaCaT keratinocytes were cultured under hyperglycemic conditions induced by 33 mM glucose with or without 1-20 μM umbelliferone to evaluate cellular protection and barrier-related protein regulation. Type 2 diabetic db/db mice were administered umbelliferone orally at 10 mg/kg per day for 10 weeks. The expression of epidermal barrier-related proteins in HaCaT cells and skin tissues was quantified by Western blot analysis. RESULTS: Umbelliferone enhanced multiple components essential for maintaining the skin barrier. It upregulated filaggrin, increased the expression of the TJ proteins ZO-1 and Occludin, and elevated AQP3 and HAS2 levels to support epidermal hydration, while reducing HYAL1 expression. Under impaired wound healing conditions induced by hyperglycemia, umbelliferone promoted cell migration via modulation of F-actin organization, Rho GTPase signaling, and integrin β1 expression. Additionally, it reduced ROS accumulation and alleviated high glucose-induced apoptosis. CONCLUSIONS: Umbelliferone preserves epidermal barrier integrity by strengthening cell-cell junctions, enhancing hydration, promoting cell migration, and providing protection against oxidative stress and apoptosis. These findings suggest the therapeutic potential of umbelliferone in managing and preventing diabetic skin complications.