Mapping the molecular landscape of glioblastoma: Pathogenesis, therapeutic targets and bioactive interventions

Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors, with limited understanding of its underlying mechanisms. The evolving and heterogeneous nature of GBM makes diagnosis and management particularly challenging. It is a grade IV glioma with a median survival range of 15-18 months after maximal surgical resection, underscoring its potential incurability. First-line therapy includes surgery followed by the primary chemotherapeutic agent temozolomide in combination with radiotherapy. Other drugs, including bevacizumab, carmustine, and the combination of procarbazine, lomustine, and vincristine, offer limited benefits. Despite having optimum efficacy and improved outcomes, these drugs fail to improve the overall survival. Prognosis becomes increasingly difficult as tumors evolve rapidly with the help of neural and glial stem cells, proliferate, infiltrate, and remain heterogeneous, making them resistant to targeted interventions. This review emphasizes the importance of systematic molecular mapping of GBM progression to identify the genetic, metabolic, and regulatory mechanisms that sustain malignancy and therapeutic resistance. Additionally, it also discusses the multimodal mechanism of natural bioactives that align with the overlapping molecular targets and pathways to overcome the limitations of single-target therapies, offering translational combination therapies that provide more effective and precision-based interventions for GBM management.