Long Noncoding RNA IRAIN Drives Immunometabolic Reprogramming in Glioma via the IGF1R-JAK-STAT-BIRC5 Axis

Glioma is an aggressive malignancy with limited therapeutic options and a poor prognosis. Its progression is closely linked to metabolic reprogramming and immune evasion, underscoring the need to identify molecular regulators that integrate these processes. Here, we established a robust immunometabolic-related gene (IMRG) prognostic signature and elucidated the role of the long noncoding RNA IRAIN in regulating glioma immunometabolism through the IGF1R-JAK-STAT-BIRC5 axis. Transcriptomic and clinical data from TCGA, CGGA (693/325), and GEO (GSE43378) cohorts were analyzed. Differential expression and weighted gene co-expression network analysis (β = 8) ensured scale-free topology, and a leave-one-out cross-validation framework combining ten machine-learning algorithms produced 101 prognostic models. The optimal 17-gene IMRG signature was validated across all cohorts and independently predicted overall survival. Functional assays demonstrated that IRAIN overexpression inhibited IGF1R, suppressed JAK2/STAT3 phosphorylation, and downregulated BIRC5, thereby promoting apoptosis and reducing angiogenesis. Low IRAIN expression correlated with immunosuppressive Tregs and M2 macrophages and with elevated tumor-microenvironment scores, suggesting an immune-evasive phenotype. These findings establish IRAIN as a key regulator of glioma immunometabolic reprogramming and validate the IMRG signature as a reliable prognostic tool, highlighting the IRAIN-IGF1R-JAK-STAT-BIRC5 pathway as a mechanistic bridge linking immune and metabolic dysregulation in glioma and offering potential targets for precision therapy.