Exploring the causal role and mechanism of galanin in glioblastoma: integration of mendelian randomization, network analysis, molecular docking and experimental validation.

BACKGROUND: Glioblastoma (GBM) is a highly malignant central nervous system tumor with an exceptionally poor prognosis. The neuropeptide Galanin is implicated in GBM development, but its specific molecular mechanisms and therapeutic potential remain unclear. In this study, we integrate Mendelian randomization (MR) and network toxicology approaches to systematically characterize the pharmacological activity and mechanistic underpinnings of Galanin in GBM. METHODS: A two-sample MR analysis was employed to investigate the causal relationship between Galanin and GBM risk. Galanin-related targets and differentially expressed genes were screened from public databases. Prognostic genes were identified through protein-protein interaction networks, single-cell sequencing, and the LASSO-COX model, and binding activity was validated by molecular docking. Finally, target genes were silenced using siRNA, and qRT-PCR, CCK-8, and colony formation assays were performed to validate the regulatory roles of CCNA2 and SERPINA1 in GBM cell proliferation. RESULTS: The MR analysis confirmed a causal association between Galanin and GBM risk. Multidimensional bioinformatics identified four core genes: CCNA2, BRCA1, SERPINA1, and LGALS3. Molecular docking confirmed stable binding of Galanin to the proteins encoded by these genes. In vitro experiments demonstrated that silencing CCNA2 or SERPINA1 effectively inhibits GBM cell proliferation and colony formation. CONCLUSION: This study provides a comprehensive analysis of the regulatory mechanisms of Galanin in GBM from both genetic and computational toxicology perspectives. Our findings indicate that Galanin modulates CCNA2, BRCA1, SERPINA1, and LGALS3, likely through mediating the PI3K-Akt and focal adhesion signaling pathways, thereby hindering tumor progression. These results provide a foundational rationale for Galanin-targeted therapeutic strategies in GBM. Furthermore, the in vitro experiments corroborate that CCNA2 and SERPINA1 promote tumor cell proliferation, positioning them as promising therapeutic targets for GBM.