Posttranscriptional Regulation of Metabolism in Glioblastoma: A Multipathway Review

Glioblastoma (GBM) is the most aggressive and lethal form of primary brain tumor. A hallmark of GBM metabolism is the Warburg effect, whereby tumor cells preferentially utilize aerobic glycolysis despite oxygen availability, producing ATP inefficiently but supporting anabolic processes. Concurrently, the pentose phosphate pathway (PPP), amino acid metabolism, lipid biosynthesis, and nucleotide synthesis are rewired to meet the energetic and biosynthetic demands of GBM cells. Recent discoveries underscore the role of microRNAs (miRNAs) as master regulators orchestrating these metabolic rewiring events. Acting posttranscriptionally, miRNAs target key transporters, enzymes, and signaling molecules involved in glycolysis, glutaminolysis, lipid biosynthesis, and oxidative metabolism. This review explores how miRNA networks modulate metabolic plasticity in GBM. Specific miRNAs, such as miR-153, miR-451, miR-940, and miR-200b, suppress glutamine metabolism, regulate glucose transporters (e.g., GLUT1/3), inhibit lactate dehydrogenase, and disrupt mitochondrial folate metabolism. Others, such as miR-29 and miR-183, control lipid and nucleotide metabolism via the SREBP1 and IDH2 pathways. Furthermore, regulatory interactions among miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), such as the XIST/miR-126 or circ-CREBBP/miR-375 axes, create complex feedback loops that fine-tune metabolic pathways and enhance tumor survival under stress. We also discuss therapeutic strategies targeting these miRNA-metabolism circuits, including nanoparticle delivery, dietary restriction, and combination therapies that re-sensitize tumors to temozolomide and radiation. Understanding and therapeutically exploiting these networks presents a powerful approach to overcoming GBM's metabolic resilience, thereby opening new avenues for precision oncology.