Discovery of Apigenin as a Multi-Target Therapeutic Drug for Osteoarthritis Complicated With Type 2 Diabetes Mellitus: Based on Network Pharmacology and in Vitro Experimental Validation

Background Osteoarthritis (OA) frequently coexists with type 2 diabetes mellitus (T2DM), and both diseases share common pathological mechanisms, particularly chronic inflammation and metabolic dysregulation. However, the shared molecular networks and potential multi-target therapeutic agents remain poorly understood. Methods Gene expression datasets related to OA and T2DM were obtained from the GEO database. Common differentially expressed genes (DEGs) were identified and analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A protein–protein interaction (PPI) network was constructed to identify hub genes. Molecular docking was subsequently performed to screen potential natural compounds targeting these hub genes. Experimental validation was conducted in an IL-1β plus high-glucose-induced SW1353 chondrocyte comorbidity model using qRT-PCR, Western blotting, CCK-8, TUNEL, and ELISA assays. Results A total of 99 shared DEGs were identified between OA and T2DM, mainly enriched in inflammation- and metabolism-related pathways, including TNF, PI3K–Akt, NF-κB, and AGE–RAGE signaling pathways. Thirteen hub genes were screened, among which CX3CR1, IRF8, and NCF1 were identified as key targets. Molecular docking demonstrated that the natural flavonoid apigenin exhibited strong binding affinity toward these proteins, particularly CX3CR1 (binding energy: −9.3 kcal/mol). In vitro experiments showed that CX3CR1, IRF8, and NCF1 mRNA expression levels were significantly elevated in the OA–T2DM model (P < 0.01). Apigenin treatment dose-dependently inhibited NF-κB activation, improved cell viability, reduced apoptosis, and decreased IL-6 and TNF-α secretion (all P < 0.01). Conclusions This study combined bioinformatics analysis, molecular docking, and experimental validation to elucidate the shared inflammatory molecular mechanisms underlying OA and T2DM. The findings provide the first evidence that apigenin alleviates OA–T2DM-associated cellular injury through a multi-target anti-inflammatory mechanism, supporting its potential as a therapeutic candidate for OA complicated with T2DM.