Targeting LRP1 to Impede Malignant Progression in Glioblastoma: Involving the SP1-Mediated PI3K/AKT Pathway

Background: Lactylation is a new epigenetic modification. Recent research has revealed that it is an indispensable in tumor progression and the immune microenvironment. However, its role in proliferation and invasion within glioblastoma remains unclear. Methods: Using data from TCGA (for GBM) and GTEx (for normal tissues), we screened for genes with potential links to lactylation. Unsupervised consensus cluster analysis was used to classify patients through differentially expressed genes associated with lactylation(LACAGs). analysis. We use the LASSO Cox and multivariate Cox regression, established a robust prognostic model for GBM patients. This model has a well accuracy among K-M curves, AUC curves and nomogram. Subsequently, further integration of single Cell sequencing, pseudo-temporal analysis, and cell communication analysis will be performed to investigate the fundamental biological roles of key genes. Finally, the biological role of LRP1 in GBM cells was validated by in vitro. Results: 144 LACAGs were identified, 28 of which were significantly associated with GBM prognosis. Consensus clustering divided patients into two subtypes with markedly different survival outcomes. We constructed a prognostic model which consists of 4 core genes: LRP1, LOXL1, RARRES2, and APOD. High-risk patients had lower overall survival, higher tumor mutational burden, and stronger immunosuppressive cell infiltration than low ones. Further single-cell analyses showed that LRP1, LOXL1, and APOD were highly expressed in late-differentiated microglia, suggesting their potential involvement in lipid metabolism and tumor immune regulation. In vitro experiments revealed that inhibiting LRP1 impairs GBM cell proliferation and migration, reverses EMT, and inhibits PI3K/AKT pathway activation, with SP1 likely serving as a key mediator. Conclusion: This article first establishes a stable and statistically significant prognostic risk model related to lactate. Further analysis and experimental verification then demonstrate that LRP1 is a key gene that links EMT and the SP1-PI3K/AKT axis to promote GBM migration and progression.These results establish a novel mechanistic framework for lactylation-driven tumor biology and pave the way for developing targeted therapies against GBM.