Scutellarein inhibits the malignancy of gliomas by modulating the PI3K/AKT signaling pathway

Glioma is the most common primary intracranial tumor and is characterized by poor prognosis and high invasiveness. Currently, treatment options remain limited. Accumulating evidence has demonstrated the efficacy of diverse natural compounds in cancer treatment. In this study, we evaluated the anticancer effects of scutellarein on gliomas and its underlying mechanisms. Cell proliferation, migration, invasion, and apoptosis were evaluated by CCK-8 assay, colony formation assay, wound healing assay, Transwell assay, and flow cytometry. Network pharmacology, transcriptomics, and western blotting were conducted to investigate the underlying mechanisms. The in vivo effect of scutellarein was evaluated using an intracranial xenograft model. Our results showed that scutellarein significantly inhibited proliferation, invasion, and migration of glioma cells. Furthermore, scutellarein induced glioma cell apoptosis by triggering oxidative stress. This was evidenced by the elevation of reactive oxygen species and malondialdehyde, alongside the suppression of superoxide dismutase and catalase activities. Network pharmacology and transcriptomic analyses suggested that scutellarein may target SRC, EGFR, and AKT1; and exerts its effects through the PI3K/AKT signaling pathway, which was subsequently verified by further experiments. Rescue experiments showed that activation of the PI3K/AKT signaling pathway markedly reversed scutellarein-induced apoptosis and oxidative stress. In an intracranial xenograft model, mice treated with scutellarein survived significantly longer. Moreover, no significant histological differences were observed in the hearts, lungs, spleens, livers, and kidneys of treated mice compared with the controls. In conclusion, our study demonstrates that scutellarein inhibits glioma proliferation, invasion, and migration by modulating the PI3K/AKT signaling pathway and inducing oxidative stress, showing promising therapeutic potential.