Curculigoside suppresses glioblastoma progression through the EGFR/MMP2 axis: evidence from network pharmacology and...

Glioblastoma (GBM) is an aggressive primary brain tumor characterized by rapid progression, therapeutic resistance, and poor clinical outcomes. Curculigoside (CUR), a natural compound with anti-inflammatory and antitumor properties, has not been systematically investigated in GBM. This study aimed to investigate the anti-GBM potential of CUR and elucidate its underlying mechanisms through integrated computational analysis and experimental validation. Network pharmacology analysis identified candidate targets of CUR in GBM, followed by functional enrichment, molecular docking, molecular dynamics (MD) simulation, single-cell transcriptomic analysis, and experimental validation. Seventy-four overlapping targets between CUR and GBM were identified, and network analysis highlighted epidermal growth factor receptor (EGFR) and matrix metalloproteinase 2 (MMP2) as potential hub targets. GEPIA2 analysis indicated that EGFR and MMP2 were upregulated in GBM tissues and associated with poor patient prognosis. Molecular docking, MD simulation, and cellular thermal shift assay (CETSA) further supported the stable interaction between CUR and EGFR. In vitro, CUR inhibited GBM cell proliferation and migration while promoting apoptosis, accompanied by significant suppression of the EGFR/MMP2 axis. In xenograft models, CUR inhibited tumor growth and significantly reduced EGFR expression and phosphorylation (Tyr1173), whereas MMP2 protein expression showed a decreasing trend that did not reach statistical significance. CUR also alleviated oxidative stress and inflammatory responses in tumor tissues. Collectively, these findings suggest that CUR exerts anti-GBM effects, at least in part, through modulation of the EGFR/MMP2 signaling axis, accompanied by antioxidant and anti-inflammatory effects. This study provides mechanistic insights into the potential application of CUR as a therapeutic candidate for GBM.