Glioblastoma (GBM) remains one of the most aggressive human malignancies, and its biological diversity is largely shaped by the isocitrate dehydrogenase (IDH) mutation status. Although apoptosis, autophagy, and ferroptosis have each been implicated in GBM pathophysiology, their coordinated regulation through the immunoproteasome (i-PSM) axis has not been systematically explored. Here, we integrated transcriptomic datasets from The Cancer Genome Atlas and The Chinese Glioma Genome Atlas with immune deconvolution and network analyses to map the IDH-specific crosstalk between i-PSM components and cell death programs. We identified a nine-gene signature (i.e., CD14, HMOX1, CTSB, CTSS, RRAS, BAK1, FTH1, PRKCD, and CYBB) that captures IDH-dependent immune and metabolic divergence. IDH-mutant (IDHmt) astrocytomas exhibited coordinated upregulation of HMOX1 and CD14, suggesting an actively maintained, immunosuppressive niche rather than a merely “immune-cold” state. Receiver operating characteristic analyses demonstrated strong discrimination of IDH status (area under the curve ≥ 0.92 for key genes), whereas structure-guided docking nominated rational, multipathway combinations such as temozolomide + bortezomib, luteolin, or lovastatin. Collectively, this integrative omics approach reframes IDHmt GBM as a redox- and myeloid-driven suppressive ecosystem and provides a systems-level rationale for personalized, IDH-informed therapeutic strategies.
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