Mechanism of Gujian Tiaosui Decoction in the treatment of osteoarthritis: Based on network pharmacological analysis and Mendelian randomization.

Osteoarthritis (OA) is widely recognized as a common degenerative joint disease that imposes a significant burden on patients and society. Gujian Tiaosui Decoction (GTD), an empirical formula from Zhejiang Provincial Hospital of Traditional Chinese Medicine, has demonstrated clinical efficacy in treating OA. However, the therapeutic mechanisms underlying GTD's effects on OA remain unclear. Potential targets of GTD and OA-related targets were identified using the TCMSP, OMIM, and GeneCards databases. A visual network of "GTD-compounds-key targets-pathways-OA" was constructed. Gene ontology and Kyoto encyclopedia of genes and genomes analyses were performed to explore biological processes and pathways. Key targets were further screened using Mendelian randomization and expression analyses. Molecular docking was conducted between key bioactive compounds and targets to identify signaling pathways and proteins associated with GTD's therapeutic effects on OA. A total of 160 compounds with 575 unique targets related to GTD were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and 185 overlapping targets between GTD and OA were identified. Protein-protein interaction network analysis revealed core targets including AKT serine/threonine kinase 1, hypoxia-inducible factor-1α (HIF1A), estrogen receptor 1, SRC proto-oncogene, non-receptor tyrosine kinase, epidermal growth factor receptor, mitogen-activated protein kinase 3, matrix metalloproteinase 9, and signal transducer and activator of transcription 3. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses indicated that relevant biological processes involved in GTD's anti-OA effects may include inflammatory response, positive regulation of protein kinase B signaling, protein phosphorylation, integral component of membrane, and protein serine/threonine/tyrosine kinase activity. Mendelian randomization analysis suggested a positive causal relationship between OA and 2 genes: HIF1A and IMPDH2. Molecular docking of 5 active ingredients with HIF1A and inosine-5'-monophosphate dehydrogenase 2 showed strong binding affinity. This study reveals the multicomponent, multi-target, and multi-pathway mechanism of GTD in the treatment of OA, providing a foundation for further experimental validation and suggesting new research directions.