Wogonoside Suppresses the Self-renewal Ability of Glioma Stem Cells via Down-regulating AKT/ZEB1 Signaling Pathway.

INTRODUCTION: Glioma is the most prevalent primary central nervous system malignancy. Wogonoside, a flavonoid bioactive derived from Scutellaria baicalensis Georgi, has been reported to induce apoptosis in glioblastoma cells. However, the functional roles and molecular mechanisms in regulating glioma stem cell (GSC)-driven malignant progression remain poorly defined. The authors initially investigated the inhibitory effects of wogonoside on GSCs, as well as the intrinsic mechanisms responsible for these actions. MATERIALS AND METHODS: In vitro functional assays including extreme limiting dilution analysis, tumorsphere formation, tube formation, flow cytometry, immunofluorescence, and Western blotting were performed in primary human GSC lines (GSC#1 and GSC#2). RNA sequencing was applied to identify the key signaling pathways modulated by wogonoside. An orthotopic glioma mouse model was established to verify the in vivo antitumor efficacy of wogonoside. RESULTS: Wogonoside significantly suppressed GSC self-renewal capacity, as evidenced by reduced tumor sphere number and size, decreased tumor-forming frequency, and downregulated the expression of GSC stemness markers SOX2 and CD133. Mechanistically, wogonoside inhibited the PI3K/AKT signaling pathway and enhanced ZEB1-mediated transcriptional repression in GSCs. Notably, ZEB1 rescue substantially reversed the inhibitory effects of wogonoside on GSC sphere formation and stemness marker expression, and restored the expression of ZEB1 target genes. Consistent with the in vitro findings, wogonoside markedly inhibited GSC-derived tumor growth and prolonged the survival of orthotopic glioma-bearing mice. CONCLUSION: This study reveals a novel antitumor mechanism of wogonoside in glioma, whereby it suppresses GSC stemness and malignant progression via PI3K/AKT inactivation and ZEB1-dependent transcriptional regulation. Wogonoside is a promising therapeutic candidate for the treatment of recurrent glioma.