Scutellarein accelerates diabetic wound healing by inhibiting P2RX1 and rescuing mitochondrial dysfunction and oxidative stress in fibroblasts

Methods

A streptozotocin-induced diabetic mouse cutaneous wound model was used to evaluate the effects of topical SCU treatment on wound closure, epithelial repair, and collagen deposition. In vitro, an H₂O₂-induced oxidative injury model in fibroblasts was employed to assess SCU-mediated protection on migration, viability, redox balance, and mitochondrial structure and function. Transcriptomics (RNA-seq) was performed to identify SCU-responsive molecular pathways, and SCU-P2RX1 molecular docking combined with ATP rescue experiments was used to interrogate a P2RX1–calcium axis.

Results: SCU accelerated diabetic wound closure and improved epithelial gap, collagen deposition, fibroblast-like cell proliferation, and angiogenesis in vivo. In vitro, SCU promoted fibroblast migration, suppressed H₂O₂-induced cell death, reduced intracellular ROS, restored mitochondrial morphology and membrane potential, and preserved ATP production. RNA-seq revealed that SCU downregulated P2rx1 and enriched calcium-transport, mitochondrial, and wound-healing pathways.

Molecular docking predicted SCU binding to P2RX1 with a docking score of ΔG = −9.2 kcal/mol, and ATP addition reversed the SCU-mediated suppression of calcium overload, mitochondrial depolarization, and inflammatory gene expression.