RAGE signaling pathway in glioblastoma and cognitive decline: Insights into inflammatory mechanisms and therapeutic implications.

Glioblastoma (GBM) remains the most aggressive primary brain tumor, with standard therapies offering only modest survival benefits. A major challenge in its management is radiation therapy (RT), which, while indispensable for tumor control, often damages normal brain tissue and contributes to radiation-induced cognitive decline (RICD). This dual burden of tumor progression and treatment-associated neurotoxicity underscores the need for molecular targets that link oncogenesis and neuroinflammation. The receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor activated by HMGB1, S100 proteins, and advanced glycation end-products (AGEs), all of which are elevated in both GBM and irradiated tissues. RAGE signaling engages NF-κB, JAK/STAT, and MAPK pathways, driving glioma cell migration, angiogenesis, and immune evasion while amplifying oxidative stress and chronic neuroinflammation in the surrounding parenchyma. These effects not only promote tumor progression and resistance to RT but also impair synaptic plasticity and cognitive function, paralleling mechanisms seen in neurodegenerative disease. Therapeutically, targeting RAGE represents a dual opportunity: suppressing GBM aggressiveness while mitigating RICD. Small-molecule inhibitors such as FPS-ZM1 and Azeliragon, biologics including sRAGE and RAGE antagonistic peptides, and phytochemicals such as curcumin, Tanshinone IIA, and berberine demonstrate the feasibility of modulating this pathway in preclinical models. Collectively, the evidence highlights the RAGE signaling as one of the central modulators of GBM progression and RT-induced cognitive decline through NF-κB, JAK/STAT, and MAPK activation. Future strategies that selectively disrupt pathological RAGE signaling, while sparing physiological functions, may provide transformative therapeutic avenues for patients facing the dual burden of glioblastoma and radiation-induced neurotoxicity.