Natural Polyphenols in Glioblastoma: A Multifaceted Approach to Targeting Tumor Progression.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a median survival of less than two years despite surgery, radiotherapy, and temozolomide. Its poor outcome reflects diffuse invasion, cellular heterogeneity, and the activation of overlapping pathways (PI3K/AKT/mTOR, Wnt/β-catenin, Notch, and NF-κβ) that sustain growth, therapy resistance, and recurrence. This article reviews evidence that natural polyphenols, especially curcumin, resveratrol, quercetin, and Epigallocatechin Gallate (EGCG), can act as multitarget agents against GBM. Polyphenols promote apoptosis by disrupting mitochondrial potential and regulating caspases; restoring the autophagic balance via AMPK/ULK1 activation and mTOR inhibition; and dampening angiogenesis by reducing HIF-1α and VEGF. They moderate oxidative stress, inhibit NF-κB/STAT3, and remodel the tumor microenvironment by lowering IL-6/TNF-α and Matrix Metalloproteinases (MMP-2/MMP-9), thereby curbing invasion. Epigenetically, they inhibit DNMTs and HDACs and modulate noncoding RNAs, re-expressing tumor-suppressor programs. Importantly, several polyphenols impair glioblastoma stem-like cells by reducing self-renewal, downregulating the expression of stemness markers, and sensitizing cells to temozolomide and radiation. These pleiotropic actions suggest value as adjuncts to current care and in rational combinations with precision approaches. Although these beneficial effects are promising, the efficacy of natural polyphenolic compounds in GBM is limited by their bioavailability and blood‒brain barrier permeability.