Introduction: Glioblastoma (GBM) is a high-grade primary brain tumor with a high proliferation rate, metabolic reprogramming, and unresponsiveness to existing therapeutic interventions. One of the most important glycolytic enzymes is pyruvate kinase M2 (PKM2), which plays two roles in GBM: controlling tumor metabolism and nuclear gene expression. The complexity of PKM2 functions is important in the formulation of effective targeted treatments against GBM. Methods: A comprehensive search of electronic databases such as PubMed, Scopus, Web of Science, and Google Scholar was conducted from inception until 2025. The keywords used were PKM2, glioblastoma, cancer metabolism, and therapeutic targeting. The screening and selection of studies were based on their relevance to the molecular biology of PKM2, its metabolic and nuclear functions, and GBM therapeutic approaches. Results: The outcomes show that PKM2 enhances the Warburg effect in GBM, maintaining glycolytic flux and biosynthetic pathways that support tumor growth under hypoxic conditions. Moreover, PKM2 is associated with proliferation-, stemness-, and immune-evasion-related gene expression. Small-molecule activators and inhibitors, RNA-based therapies, and advanced drug-delivery systems that bypass the blood-brain barrier are therapeutic approaches for targeting PKM2. Medicinal chemistry initiatives have optimized PKM2 modulators, but challenges remain regarding isoform selectivity and effective brain penetration. Discussion: The discussion of PKM2 reveals that it has both metabolic and nuclear functions, making it a promising therapeutic target. However, the difficulties in specific targeting and delivery require combined solutions using molecular, pharmacological, and nanotechnological methods. Conclusion: In general, the bifunctional metabolic and nuclear characteristics of PKM2 indicate its relevance as a therapeutic target in glioblastoma, suggesting that combined approaches are needed to support clinical translation.
Kumar et al. (Fri,) studied this question.