Molecular Mechanisms of Ferroptosis Induced by Eleutherococcus senticosus in Glioblastoma

ABSTRACT Introduction Eleutherococcus senticosus , a traditional Chinese medicine, has shown potential in treating glioblastoma (GBM). However, its main active components and mechanisms of action remain unclear. Objective This study aimed to evaluate the inhibitory effects of E. senticosus on GBM cell proliferation and migration using in vitro cellular experiments. Methods Transcriptome sequencing and metabolome analysis were performed on GBM cells treated with E. senticosus . Network pharmacology and correlation analysis identified the main active components and their targets, which were further verified using molecular biology experiments. Electrophoretic mobility shift assays and molecular docking analyses were used to analyze the binding ability and mechanisms of action of transcription factors and promoters. Results E. senticosus significantly inhibited GBM cell proliferation and migration. Treatment with E. senticosus caused significant changes in ferroptosis‐related genes and metabolites in GBM cells, significantly reducing the levels of glutathione, an antagonist of ferroptosis, and its synthetic substrates. GPX4 , FTH1 , and TFR1 were identified as core targets of ferroptosis induction in E. senticosus –induced GBM cells. Quercetin had similar biological effects on GBM cells as E. senticosus and is its main active component. E. senticosus and quercetin changed the binding ability of transcription factors SIX1 and MYBL2 to the promoters of GPX4 , FTH1 , and TFR1 . Conclusion E. senticosus changed the binding ability of SIX1, MYBL2, and promoters of target genes via quercetin, which led to changes in the expression of GPX4 , FTH1 , and TFR1 , finally resulting in ferroptosis induction in GBM cells.