Metabolic Pathway Alterations in Glioblastoma Stem Cells Under Hypoxia: Computational Analysis of Hypoxia-Activated Pathways

Author(s): Shivi Kumar, Teryn Mitchell, Katheryn Campos, Ray Song, Deirdre Richardson, Eric Jaiswal

Therapy resistance in glioblastoma stem cells (GSCs) often arises in hypoxic microenvironments, yet most computational studies analyze single pathways in isolation. Here, we introduce HypoPINN-lite, a graph-based framework that integrates differential expression, enrichment analysis, and pathway interaction modeling to capture multi-pathway crosstalk under hypoxia. Applying this approach to transcriptomic profiles from GSE77307, we identified a tightly coupled metabolism–inflammation module linking glycolysis (LDHA, GLUT1), fatty acid synthesis (FASN), oxidative phosphorylation, and COX-2 signaling (PTGS2). Unlike standard enrichment, which highlights pathways independently, our framework reveals that hypoxia drives these pathways to function as a single adaptive collapse network. This convergence suggests therapeutic leverage points: disrupting both metabolic and inflammatory edges may destabilize the module and prevent adaptation. Beyond glioblastoma, HypoPINN-lite is generalizable to other cancers and stress conditions, offering a systems-level strategy to identify multi-pathway vulnerabilities invisible to traditional analyses.