18ï ¢-Glycyrrhetinic acid suppresses glioblastoma by regulating p38 signaling pathway: an integrative approach combining network analysis, transcriptomics, and experimental assessment.

BACKGROUND: Glioblastoma (GBM) remains a therapeutic challenge with limited treatment options and poor prognosis. 18β-Glycyrrhetinic acid (GA), a natural metabolite from licorice, has shown anti-tumor potential, but its pharmacological effects in GBM and the underlying mechanisms require systematic investigation. METHODS: The anti-GBM activity of GA in vitro was evaluated in GBM cells using CCK-8, colony formation, wound healing, and flow cytometry assays. Intracranial and subcutaneous GBM models in C57BL/6 and nude mice were established to assess the in vivo pharmacological effects of GA. An integrative approach combining network analysis, transcriptomic sequencing, and TCGA data analysis was employed to explore key genes and pathways. Molecular docking predicted GA binding to MAPK11, and Western blotting assessed its impact on p38 signaling pathway. RESULTS: GA significantly inhibited GBM cell proliferation, migration, and induced apoptosis in vitro. In vivo, GA treatment markedly suppressed tumor growth in both intracranial and subcutaneous models, with no observed toxicity. Integrated bioinformatics analysis revealed that high MAPK11 (p38-pathway) expression was significantly associated with poor patient prognosis in TCGA. Molecular docking confirmed a strong binding affinity between GA and MAPK11. Mechanistically, GA downregulated MAPK11 expression, activated p38 signaling pathway, and subsequently suppressed the MEK/ERK signaling pathway. CONCLUSION: This study demonstrats that GA exerted potent anti-GBM effects by regulating p38 signaling pathway, provides novel mechanistic insights, and positions its as a promising therapeutic candidate against GBM.