Brusatol suppresses meningioma progression via targeting HMGCR to restrict the cholesterol biosynthesis and inhibit PI3K/AKT signaling pathway.

BACKGROUND

3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol metabolism, remains underexplored in meningioma. Additionally, the therapeutic potential of Brusatol (Bru), a triterpene lactone compound with anticancer properties, has yet to be systematically evaluated. This research investigates Bru's efficacy in meningioma treatment and HMGCR-related mechanisms.

METHODS

IC50 was determined using CCK-8 assay. Proliferation, apoptosis, migration, and invasion were assessed through colony formation, EdU, Annexin V/PI staining, Scratch, and Transwell assays, respectively. Cholesterol levels were measured with an assay kit and Filipin III probes. Key pathways and potential meningioma-specific marker were identified via multi-omics with GO/KEGG analyses and bioinformatic analyses. Protein expression was detected via Western blot analysis, and a mouse model of meningioma was employed to evaluate the efficacy of Bru.

RESULTS

Bru inhibited the proliferation, migration, and invasion of meningioma cells, induced apoptosis, and reduced cholesterol accumulation. Proteomic, transcriptomic, and bioinformatic analyses, along with molecular docking, revealed that Bru targeted HMGCR to restrict cholesterol biosynthesis and inhibit the PI3K/AKT signalling pathway. These findings were validated through a series of experiments, including surface plasmon resonance assay, HMGCR knockdown and overexpression, and rescue experiments where HMGCR knockdown or Bru treatment was reversed with an Akt activator SC79. In vivo experiments indicated that Bru effectively suppresses tumour progression, with no significant toxicity observed under the current experimental conditions.

CONCLUSION

These findings demonstrate that Brusatol suppresses meningioma progression by inhibiting of HMGCR and the PI3K/AKT signaling pathway.