Integrated network pharmacology and experimental verification to reveal the role of Shezhi Huangling Decoction against glioma by inactivating PI3K/Akt-HIF1A axis.

Shezhi Huangling Decoction (SHD) has been proven clinically effective in regulating metabolic and immune homeostasis in the treatment of glioma. The investigation aimed to deconstruct the active constituents and mechanisms of SHD. Effects of SHD on malignant characteristics of HS683 and KNS89 cells have been investigated by CCK-8, clone formation, flow cytometry, and Transwell assays. A mouse xenograft model was established to assess the effect of SHD or SHD + temozolomide (TMZ) . A total of 461 constituents were found from SHD in UPLC/Q-TOF-MS/MS analysis. Functional enrichment analysis showed that pathway in cancer, proteoglycans in cancer, regulation of epithelial cell proliferation, inflammation/immune, gliogenesis, brain development, cell adhesion, and autophagy could participate in the treatment of SHD. Additionally, 9 hub genes (AKT1, TP53, CTNNB1, STAT3, EGFR, VEGFA, PIK3CA, ERBB2, and HIF1A) were identified as hub genes. Moreover, we found that SHD may greatly reduce the migration and accelerate apoptosis of HS683 and KNS89 cells. Additionally, SHD coordinates TMZ to restrict tumor growth were found in the mice. Our results suggest that the malignant behaviors of glioma cells are suppressed by SHD and the mechanism may be closing on the inhibition of the PI3K/Akt-HIF1A axis. SHD may serve as a synergistic therapeutic choice for TMZ to suppress glioblastoma growth.