Unraveling the Therapeutic Potential of Taohong Siwu Decoction for Fracture Healing Through Network Pharmacology and Computational Validation

This study aimed to explore the potential mechanisms of Taohong Siwu Decoction (THSWD) in promoting fracture healing using network pharmacology, molecular docking, and molecular dynamics (MD) simulations. Active compounds and corresponding targets of THSWD were screened from the TCMSP database. Fracture-related targets were collected from the GeneCards, NCBI Gene, and OMIM databases using the keywords "bone fracture," "fracture healing," and "femoral fracture." Drug-disease intersecting targets were identified to construct compound-target and protein-protein interaction (PPI) networks, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and MD simulations were subsequently performed to evaluate interactions between selected compounds and target proteins. A total of 53 active compounds and 233 potential targets of THSWD were identified. Network analysis revealed HIF-1α, MMP-9, RUNX2, and KDR as key targets. GO and KEGG enrichment analyses indicated that the intersecting targets were mainly involved in biological processes related to hypoxic response, transcriptional regulation, and apoptosis, and were significantly enriched in angiogenesis-associated pathways, particularly the HIF-1 and VEGF signaling pathways. Molecular docking predicted favorable binding between the selected compounds and the target proteins HIF-1α and VHL. MD simulations further showed that the VHL-luteolin and HIF-1α-quercetin complexes reached equilibrium after approximately 50 ns, with RMSD values of approximately 4.1 Å and 2.0 Å, respectively, while maintaining hydrogen-bond interactions. These findings suggest that THSWD may promote fracture healing by regulating targets such as HIF-1α, VHL, VEGF, MMP-9, and RUNX2, thereby participating in hypoxic response, angiogenesis, osteogenic differentiation, and apoptosis. The HIF-1/VEGF signaling pathway may represent a critical mechanism underlying the therapeutic effects of THSWD on fracture healing.