Recent research has delved into the molecular underpinnings of glioblastoma (GBM), particularly focusing on the roles of GPR56 and TG2 in mesenchymal transition. A study conducted a comprehensive multi-omics analysis, employing transcriptomics, proteomics, and phospho-proteomics to investigate the effects of GPR56 downregulation in the GBM cell line U373. The findings indicated that GPR56 knockdown led to significant alterations in gene expression profiles, highlighting pathways associated with mesenchymal transition. Notably, the study observed an increase in cell invasion and migration behaviors in GPR56-deficient cells, suggesting that GPR56 plays a critical role in maintaining the epithelial characteristics of GBM cells (ref: Ganesh doi.org/10.3389/fonc.2022.841890/). Furthermore, the inverse expression patterns of GPR56 and TG2 were confirmed through spatial gene expression analysis in GBM tissues, indicating a potential regulatory relationship between these two proteins in the tumor microenvironment. This relationship underscores the complexity of molecular interactions in GBM and suggests that targeting these pathways may offer new therapeutic avenues for treatment. Overall, the integration of multi-omics approaches provides a robust framework for understanding the dynamic molecular landscape of glioblastoma and its implications for tumor behavior.