Uridine Metabolism–associated Signature Defines Immune Landscape and Predicts Therapeutic Vulnerability in Glioblastoma

Glioblastoma multiforme (GBM) is a highly aggressive malignancy, characterized by poor prognosis and limited therapeutic options. This study aimed to develop a uridine metabolism–related gene signature for prognostic stratification and explore the potential biological mechanisms underlying GBM progression. Differential expression analysis was performed using The Cancer Genome Atlas (TCGA) dataset to identify genes dysregulated in GBM. Uridine-related differentially expressed genes (UR-DEGs) were obtained by intersecting GBM-associated DEGs with a curated uridine metabolism gene set. A prognostic signature was constructed through univariate Cox regression, random forest, and least absolute shrinkage and selection operator (LASSO) analyses. The prognostic value of the signature was evaluated in an independent Chinese Glioma Genome Atlas (CGGA) cohort. Immune infiltration characteristics, functional enrichment patterns, somatic mutation landscape, and drug sensitivity profiles were compared between high- and low-risk groups. The expression patterns of key genes were further validated in clinical GBM samples using quantitative real-time PCR (RT-qPCR). A total of 72 UR-DEGs were identified and a three-gene prognostic signature comprising UPP1, GALNT11, and PLOD3 were established. This signature effectively stratified patients into high- and low-risk groups with distinct survival outcomes in both both the TCGA training cohort and the CGGA validation cohort. Immune profiling revealed significant different infiltration in macrophages M0, monocytes, and activated natural killer (NK) cells between the two risk groups. Functional enrichment analysis indicated that the signature-related genes were primarily involved in cytokine–receptor interaction and immune-related pathways. Somatic mutation analysis showed that TP53, PTEN, EGFR, and TTN were the most frequently altered genes. Notably, patients in the high-risk group exhibited higher estimated IC50 values for Vorinostat and Daporinad, indicating potential differences in therapeutic sensitivity. RT-qPCR validation confirmed increased expression of UPP1 and PLOD3 and decreased expression of GALNT11 in GBM tissues. We developed and independently validated a uridine metabolism–related prognostic signature based on UPP1, GALNT11, and PLOD3 for GBM. This signature highlights the potential involvement of uridine metabolism in GBM progression and provides a promising framework for prognostic evaluation and further investigation of individualized therapeutic strategies.