Integrative pan-cancer analysis of UCP family and experimental validation identifies UCP2 as a potential therapeutic target for glioma

Objective To evaluate the prognosis and therapeutic potential of the UCP family, particularly uncoupling protein 2 (UCP2), in 32 types of cancer through integrated analysis of TCGA and CGGA databases. Methods Multi-omics data from TCGA, CGGA, GTEx, cBioPortal, and ROC Plotter were analyzed to assess UCP family expression patterns, prognostic significance, biological functions, immune cell infiltration, and genetic alterations across various cancers. In vitro experiments were carried out to assess UCP2’s impact on glioblastoma (GBM) aggressive traits and apoptosis. Results UCP2 demonstrated significant overexpression in most malignancies, whereas other UCP family members showed reduced expression. High UCP2 expression is a prognostic risk factor for KIRP, LGG, and UVM, while it has protective effects in CESC, OV, SARC, and SKCM. Additional UCP members are associated with enhanced survival in certain cancers, such as BLCA and PAAD. Genetic analysis revealed negative regulation of UCP2 by DNA methylation. Functional enrichment linked the UCP family to epithelial-mesenchymal transition (EMT), G2M checkpoint, UV response, and mitotic processes across cancers. However, in more types of cancer, UCP2 is associated with immune-related pathways. Immune infiltration analysis revealed positive correlations between UCP family expression and stromal/immune scores but negative associations with immunosuppressive cells infiltration. Experimental validation in glioblastoma models confirmed that UCP2 knockdown attenuated EMT, impaired invasion, and improved radiosensitivity. Conclusion This study establishes UCP2 as a prognostic indicator and potential therapeutic target for glioma.