Betulinic Acid Inhibits Glioma Progression by Inducing Ferroptosis Through the PI3K/Akt and NRF2/HO-1 Pathways

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine Pub Date : 2025-02-18 DOI:10.1002/jgm.70011

Jinxiang Huang, Qixuan Li, Hongxiang Wang, Shuai Zhang, Xiaorong Zhou, Fang Huang, Juxiang Chen, Luning Xu, Dezhi Kang

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引用次数: 0

Abstract

Background

Gliomas currently have a poor prognosis and limited therapy options. Betulinic acid (BA) has demonstrated antitumor activity in various cancers. This study is aimed at clarifying the underlying mechanisms by which BA inhibits gliomas.

Methods

We assessed how BA affected the migration, apoptosis, invasion, proliferation, and viability of U251 glioma cells. The genes that were differentially expressed after BA treatment were identified via RNA sequencing. Utilizing Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes, research was done to determine the affected pathways. Molecular docking was applied to explore the interaction of BA with key pathway molecules. Experimental assays were conducted to confirm the impact of BA on these pathways and targets.

Results

In U251 cells, BA reduced viability; inhibited colony formation, migration, and invasion; and triggered apoptosis. Through RNA sequencing, 923 up- and 1469 downregulated genes were found, with notable enrichment in the TNF, PI3K-Akt, and ferroptosis pathways. BA can stably bind to TNF and PI3K-Akt pathway molecules, especially AKT1 (binding energy = −10.2 kcal/mol). BA administration decreased the levels of phosphorylated PI3K and AKT. Moreover, BA-induced ferroptosis and HO-1 and NRF2 levels were increased. Ferrostatin-1 and zinc protoporphyrin pretreatment decreased intracellular iron and lipid peroxidation and decreased the decrease in cell viability caused by BA.

Conclusions

BA controls the PI3K/Akt and NRF2/HO-1 pathways, which results in glioma ferroptosis. Understanding BA's multipathway mechanism may inform its therapeutic potential in glioma treatment.

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.