Exploring the mechanism of ursodeoxycholic acid in the treatment of osteoarthritis based on network pharmacology, molecular docking, and molecular dynamics simulations

Accumulating evidence suggests that ursodeoxycholic acid (UDCA) has therapeutic potential for osteoarthritis (OA); however, the underlying molecular mechanisms remain poorly understood. The chemical components of UDCA were retrieved from PubChem. Potential UDCA targets were collected from three databases. OA-related targets were obtained from GeneCards, OMIM (Online Mendelian Inheritance in Man), and TTD (Therapeutic Target Database) databases. Venny 2.1.0 was used to identify common targets between OA and UDCA. A protein-protein interaction network was constructed using the STRING database and subsequently analyzed using Cytoscape software to identify core genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using DAVID. Molecular docking validation was conducted using AutoDock software, followed by molecular dynamics simulations using Amber to assess stability of interactions between UDCA and key targets. 194 common targets associated with UDCA and OA were identified. Among these, Albumin ( ALB ), Epidermal growth factor receptor ( EGFR ), Matrix metalloproteinase-9 ( MMP9 ), Proto-oncogene tyrosine-protein kinase Src ( SRC ), Caspase-3 ( CASP3 ), and Estrogen receptor ( ESR1 ) were identified as core targets. UDCA exerts its therapeutic effects on OA primarily through the modulation of protein hydrolysis, negative regulation of apoptosis, and promotion of cell proliferation and differentiation, as well as by influencing the PI3K-Akt, MAPK, and cancer-related signaling pathways. Molecular docking and molecular dynamics simulations demonstrated that UDCA exhibits good binding affinity and forms stable interactions with multiple core targets. By targeting molecules such as ALB, EGFR, MMP9, SRC, CASP3 , and ESR1 , UDCA may interfere with the PI3K-Akt, MAPK, and other signaling pathways, thereby regulating the expression of inflammatory mediators, chondrocyte apoptosis, and cartilage matrix degradation and synthesis, thus contributing to OA treatment.