Integrated experimental and computational evaluation of the wound-healing potential of Fraxinus xanthoxyloides bark extract

Abstract Wound healing remains a significant clinical challenge, driving the need for innovative natural therapeutics. This study investigated F. xanthoxyloides bark methanolic extract (FXBM) using integrated in vitro, in vivo, and in silico approaches. LC-ESI-MS/MS identified eight bioactive compounds: gallic acid, cinnamaldehyde, coumaric acid, sinapic acid, vanillic acid, caffeic acid, hydroxybenzoic acid, and quercetin. FXBM demonstrated high cell viability (122.35 ± 2.72% and 126.02 ± 0.9%) at 20 µg/mL in HaCaT keratinocytes and NIH3T3 fibroblasts, respectively. Scratch assays showed dose-dependent wound closure, with 20 µg/mL FXBM achieving near-complete closure in both cell lines after 48 h. It also protected HaCaT cells from apoptosis, reducing total apoptotic cells by 75% at 20 µg/mL. In BALB/c mice, 10% FXBM gel achieved 99.79 ± 0.083% wound closure by day 21, comparable to 1% silver sulfadiazine. Histology confirmed enhanced collagen deposition, re-epithelialization, and hair follicle regeneration. FXBM activated antioxidant defenses by reducing malondialdehyde and enhancing superoxide dismutase and catalase activities. It dually regulated inflammation by decreasing TNF-α, IL-6, and IL-1β while upregulating VEGF, and activated the Nrf2/HO-1 pathway and MMP-1-mediated tissue remodeling. In silico analysis confirmed Lipinski compliance; network pharmacology identified EGFR, STAT3, MMP9, TLR4, and RELA as key targets, with GO/KEGG implicating oxidative stress, NF-κB, and MAPK signaling. Molecular docking showed strong binding affinities, with sinapic acid exhibiting highest affinity for MMP-1 (− 6.8 kcal/mol). These findings establish F. xanthoxyloides as a promising wound-healing candidate for clinical translation.