Therapeutic Potential of 6‐Gingerol in Glioma: Mechanistic Insights and Experimental Validation

Glioma, a prevalent malignancy globally, presents a serious threat to human health. Recent research has highlighted the significant anti-tumor properties of 6-gingerol (6-G), an active component of the traditional Chinese medicine ginger, though its precise mechanisms in glioma remain to be fully elucidated. This study employed network pharmacology, molecular docking, and dynamic simulation to explore the targets and underlying mechanisms of 6-G's anti-glioma effects, followed by in vitro validation of the key pathways. Drug-related targets were identified via PharmMapper and Swiss target prediction databases, while disease-related targets were sourced from GeneCards, OMIM, and TTD. The intersection of these datasets yielded potential therapeutic targets. Subsequent PPI network analysis using STRING11.5 and core gene screening with Cytoscape 3.9.1 led to the construction of a "drug-target network" and the identification of central genes. GO and KEGG enrichment analyses were conducted on potential therapeutic targets. Molecular docking and dynamic simulations were utilized to analyze the interactions between core genes and 6-G. Ultimately, the primary mechanism underlying 6-G's anti-GC effects was validated through in vitro experiments. A total of 183 potential targets for 6-G treatment of glioma were identified, with PPI analysis and core target screening revealing 10 critical targets. Enrichment analyses underscored the PI3K/AKT pathway as the primary signaling mechanism through which 6-G exerts its therapeutic effects. Molecular docking results showed that AKT1, HSP90AA1, EGFR, and MAPK3 were the key targets of 6-G in the treatment of glioma, and dynamic simulations further verified these findings. In vitro findings demonstrated that 6-G effectively inhibits the proliferation of U87 and U251 glioma cells, induces apoptosis, arrests the G1 phase of the cell cycle, and suppresses migration and invasion. Western blot analysis confirmed a significant downregulation of p-AKT in the PI3K/AKT pathway. In conclusion, 6-G impairs glioma cell proliferation, promotes apoptosis, induces G1 phase arrest, and inhibits migration and invasion, primarily through the suppression of the PI3K-AKT pathway. This finding provides a robust foundation for further research and clinical application.