Background: Naringin, a natural flavonoid prevalent in citrus fruits, is known for its antioxidant, anti-inflammatory, and antitumor properties. Recent studies suggest its potential influence on bone metabolism, proposing it as an anti-osteoporotic agent. However, specific mechanisms of action remain unclear.
Objective: This study aimed to validate the anti-osteoporotic effects of naringin by combining network pharmacology analysis and molecular docking validation.

Methods: Employing network pharmacology and molecular docking, we constructed an analysis framework for "Naringin-Targets-GO and KEGG-Osteoporosis" using Cytoscape software and R software. This framework integrated various online public databases, Protein-Protein Interaction (PPI) analysis, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and molecular docking using AutoDock Vina software.

Results: We identified 272 target genes associated with naringin and 5,785 target genes related to osteoporosis, with 197 overlapping genes. Further analysis led to the selection of eight core targets: TP53, TNF, JUN, STAT3, AKT1, ESR1, BCL2, and IL6. GO functional enrichment analysis and KEGG pathway enrichment analysis revealed that naringin might influence osteoporosis progression by regulating biological processes, such as apoptosis, cell proliferation, and inflammatory responses, as well as signaling pathways, such as TNF, FoxO, and PI3K-Akt. Molecular docking validation confirmed the high binding affinity of naringin to the eight core targets, with binding energies below 7.2 kcal/mol.

Conclusion: The therapeutic mechanism of naringin against osteoporosis may involve the regulation of gene expression, including TP53, IL6, TNF, JUN, STAT3, AKT1, ESR1, and BCL2, and mediating signaling pathways such as TNF, FoxO, IL-17, PI3K-Akt, AMPK, and VEGF, thereby affecting multiple biological processes, such as bidirectional regulation of osteoblast proliferation and apoptosis, angiogenesis, and downregulation of inflammatory responses.