Dietary Isoflavonoids and Brain Tumors: Unlocking Neuroprotective Potential, Molecular Mechanisms, and Novel Therapeutic Avenues in Neuro-Oncology

Brain tumours, particularly Glioblastoma (GBM), remain among the most aggressive malignancies because of profound molecular heterogeneity, Blood-Brain Barrier (BBB)-restricted drug delivery, therapeutic resistance, and an immunosuppressive tumour microenvironment. Naturally occurring dietary isoflavonoids, including genistein, daidzein, biochanin A, formononetin, glycitein, and the metabolite equol, have emerged as promising multitarget phytochemicals with potential applications in neuro-oncology. This review comprehensively summarises current evidence regarding the molecular mechanisms, pharmacokinetic characteristics, preclinical efficacy, translational advances, and emerging therapeutic applications of dietary isoflavonoids in brain tumour prevention and treatment, with particular emphasis on glioblastoma. A narrative literature review was conducted using PubMed, Scopus, Embase, and Web of Science to identify English-language studies published between 2000 and 2025. Experimental investigations, clinical studies, systematic reviews, and relevant regulatory reports were critically evaluated. Evidence was synthesised to examine BBB transport, epigenetic regulation, oxidative stress modulation, apoptosis, angiogenesis, immune remodeling, anti-invasive mechanisms, nanotechnology-based drug delivery, and combination therapeutic strategies. Accumulating evidence demonstrates that dietary isoflavonoids regulate multiple oncogenic pathways by inhibiting DNA methyltransferases, suppressing PI3K/Akt, NF-κB, STAT3, and VEGF signalling, promoting mitochondrial apoptosis, reversing epithelial-mesenchymal transition, reducing matrix metalloproteinase activity, and enhancing antitumor immune responses through macrophage polarisation and PD-L1 modulation. Nanocarrier formulations substantially improve BBB penetration, bioavailability, and therapeutic efficacy while enhancing sensitivity to temozolomide and radiotherapy. Nevertheless, clinical translation remains constrained by metabolic variability, limited oral bioavailability, gut microbiota-dependent equol production, and sex-related pharmacokinetic differences. Dietary isoflavonoids represent promising multitarget adjunctive agents for precision neuro-oncology by simultaneously targeting tumour cells, the BBB, and the tumour microenvironment. Future well-designed clinical trials integrating biomarker-guided patient selection, nanomedicine platforms, microbiome-based interventions, and personalized pharmacokinetic optimisation are essential to establish their clinical value in brain tumour management.