Integrated multi-omics reveals ITGB2 drives the mesenchymal transition in glioblastoma via FAK signaling

Glioblastoma (GBM) is the most lethal primary brain malignancy, characterized by profound heterogeneity and the aggressive mesenchymal (MES) transition, which drives therapeutic resistance and recurrence. Decoding the core molecular drivers governing this phenotypic plasticity is critical for developing effective targeted therapies. In this study, we employed an integrated multi-omics approach combining bulk, single-cell, and spatial transcriptomics with weighted gene co-expression network analysis (WGCNA) and machine learning to identify robust regulators of the MES transition. Bioinformatics predictions were validated through extensive in vitro and in vivo analyses. We identified ITGB2 as a robust core regulator preferentially upregulated in GBM and spatially co-localized with MES niches. Mechanistically, ITGB2 promotes GBM cell proliferation and invasion by activating the FAK–AKT–mTOR signaling axis. Crucially, inhibition of FAK with Y-15 significantly attenuated the ITGB2 -driven malignant phenotype. In vivo, ITGB2 knockdown suppressed GBM xenograft growth and attenuated FAK signaling and MES transition-associated marker changes. Our findings establish ITGB2 as a key regulator of GBM MES transition and malignant progression, suggesting that targeting the ITGB2-FAK axis represents a promising strategy to halt the MES transition in GBM.