Diosmetin Inhibits Bladder Cancer through Suppression of the PI3K-AKT Signaling Pathway and Activation of the p53 Signal Pathway Revealed by Network Pharmacology and In Vitro Experimental Verification.
INTRODUCTION: Diosmetin, a naturally occurring flavonoid abundant in plants such as chrysanthemums, lemons, and oranges, has been reported to exhibit diverse antitumor properties. However, its potential efficacy against bladder cancer remains unexplored. This study aims to investigate the anti-bladder cancer effects of Diosmetin and elucidate the underlying mechanisms using network pharmacology combined with in vitro experiments. METHODS: Public databases were employed to identify shared targets between Diosmetin and bladder cancer. A Protein-Protein Interaction (PPI) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to predict core targets and signaling pathways. The predicted mechanisms were subsequently validated through in vitro assays. RESULTS: A total of 48 common targets were identified. PPI network analysis revealed 22 hub genes, including AKT1 and MDM2. GO analysis indicated enrichment in 208 biological processes, 23 cellular components, and 38 molecular functions. KEGG analysis suggested that Diosmetin exerts anti-bladder cancer effects primarily through pathways such as Pathways in cancer, PI3K-AKT signaling, and Proteoglycans in cancer. Notably, the PI3K-AKT pathway showed the highest gene enrichment, indicating its potential prominence. In vitro experiments demonstrated that Diosmetin suppresses bladder cancer cell proliferation and induces apoptosis. Additionally, Diosmetin reduced the expression of p-PI3K, p-AKT, and MDM2, while upregulating p53 expression, suggesting involvement of both the PI3K-AKT and p53 pathways. DISCUSSION: These findings align with network pharmacology predictions and highlight the potential of Diosmetin as a multi-target agent against bladder cancer, warranting further in vivo investigation. CONCLUSION: Diosmetin inhibits bladder cancer cell proliferation and promotes apoptosis by suppressing the PI3K-AKT pathway and activating the p53 pathway.