Phytochemical-mediated targeting of signaling pathways in glioblastoma: preclinical evidence, translational potential, and emerging nano-based therapeutic approaches.
OBJECTIVES Glioblastoma (GBM) is a highly aggressive brain cancer characterized by rapid growth, extensive infiltration, significant molecular diversity, and notable resistance to standard treatments, resulting in a poor prognosis for patients. This emphasizes the necessity for innovative therapeutic strategies based on novel mechanisms. KEY FINDINGS GBM tumorigenesis, glioma stem cell maintenance, immunological evasion, and treatment resistance are significantly influenced by the abnormal activation of various oncogenic signaling pathways, such as PI3K/Akt/mTOR, JAK/STAT, NF-κB, MAPK, Wnt/β-catenin, and receptor tyrosine kinases like EGFR and Axl. Phytochemicals such as quercetin, curcumin, resveratrol, and epigallocatechin gallate influence crucial signaling pathways in GBM by inhibiting specific pathways, inducing apoptosis and autophagy, suppressing glioma stemness, and modifying the tumor microenvironment. Furthermore, nano-based delivery systems such as dendrimers, lipid-based nanocarriers, polymeric nanoparticles, and biomimetic exosome-inspired systems enhance stability, bioavailability, and targeted delivery, thereby improving therapeutic efficacy. SUMMARY This review i) explores the potential of phytochemicals in targeting these pathways, ii) summarizes current evidence on phytochemicalmediated modulation of dysregulated signaling pathways in GBM, and iii) highlights emerging nanobased delivery strategies to improve therapeutic efficacy. Overall, phytochemical modulation of signaling pathways paired with nano-based drug delivery shows potential for enhancing treatment efficacy in GBM.