The brain imaging feature-related gene NRP2 drives the malignant progression of glioblastoma through the FAK pathway: a Mendelian randomization study

• 255 brain imaging features show causal links to glioblastoma risk through MR analysis. • NRP2 is identified as a key driver gene connecting imaging traits to tumor progression via FAK signaling. • NRP2 knockdown inhibits glioblastoma growth in vitro and in vivo , reversible by FAK activation. • Dactinomycin is nominated as a potential therapeutic agent targeting the NRP2-FAK axis. Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. Although brain imaging features are related to biological behaviors of GBM, the causal relationship between them remain unclear. To explore the causal relationship between brain imaging features and GBM, identify key pathogenic genes, and provide a perspective for GBM therapy. Two-sample MR analysis was employed. Causal relationships were evaluated based on brain imaging features, eQTL, and GWAS data. Differentially expressed brain imaging-related genes were screened through gene mapping and differential expression analysis. MR analysis on eQTL data identified key genes, and GSEA was performed. Given its robust genetic association, high expression in GBM, and enrichment association with tumor malignancy, NRP2 was determined as the core gene, with its function verified by in vitro/in vivo experiments. MR analysis identified 255 GBM-associated brain imaging features, with 9 key genes selected. NRP2 was identified as a risk gene. NRP2 knockdown significantly inhibited GBM proliferation, migration, and invasion and promoted apoptosis. The inhibitory effects were reversed by activated FAK-signaling pathway. Mechanistically, NRP2 regulated FAK phosphorylation through direct binding, thereby activating the Focal-adhesion pathway and promoting tumor malignancy. In animal experiments, inhibiting NRP2 slowed tumor growth, which was weakened by FAK agonists. This study establishes the causal relationship between brain imaging features and GBM from a genetic perspective. NRP2 activates Focal-adhesion pathway through FAK signaling to drive GBM progression. NRP2 is a key molecule connecting imaging phenotypes and GBM malignant behaviors, serving as a potential therapeutic target.