Integrative Multiomics and Network Pharmacology Exploration of Active Components and Mechanisms of Action of Qufu Shengxin Ointment in Treating Chronic Nonhealing Wounds

BACKGROUND: Chronic nonhealing wounds (CNHWs) are characterized by persistent inflammation and impaired autophagy, which hinder normal wound repair. Qufu Shengxin Ointment (QFSO) has shown clinical benefits in treating chronic wounds, but its active components and molecular mechanisms remain largely unclear. This study aimed to investigate the pharmacological mechanisms of QFSO in the treatment of CNHWs. METHODS: Differentially expressed genes (DEGs) were identified from Gene Expression Omnibus (GEO) transcriptomic datasets, and weighted gene co-expression network analysis (WGCNA) was performed to screen genes associated with CNHWs. Active compounds and potential targets of QFSO were retrieved from the TCMSP database, and a compound-target network was constructed. Mendelian randomization (MR) analysis was applied to evaluate the potential causal effects of key targets on CNHW risk. Gene set enrichment analysis (GSEA) and immune infiltration analysis were conducted to explore biological functions and immune mechanisms. Molecular docking and in vivo animal experiments were performed to validate the predicted interactions and therapeutic effects. RESULTS: About 1274 DEGs were identified between CNHW and normal wound tissues. Enrichment analyses indicated that the PI3K/Akt/mTOR pathway was significantly involved in CNHW pathogenesis. MR analysis identified AKR1B1 and VCAM1 as potential causal risk factors for CNHWs. Functional enrichment and single-cell RNA sequencing analyses revealed that these genes participate in immune-inflammatory regulation and autophagy-related processes. Molecular docking showed stable binding between key QFSO compounds and the targets AKR1B1 and VCAM1. In vivo experiments demonstrated that QFSO treatment significantly accelerated wound healing. The therapeutic effects were associated with reduced inflammation, enhanced angiogenesis, and activation of autophagy through regulation of the PI3K/Akt/mTOR pathway. CONCLUSIONS: QFSO promotes the repair of CNHWs by regulating the PI3K/Akt/mTOR pathway, enhancing autophagy, alleviating inflammation, and promoting angiogenesis. These findings identify AKR1B1 and VCAM1 as potential molecular targets for the treatment of chronic wounds.