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Brusatol induces ferroptosis to inhibit hepatocellular carcinoma progression by targeting ATF3
Yuanyuan Wan1, Jingsong Cheng1,2, Debiao Gan3
1Laboratory of Stem Cells and Tissue Engineering, Department of Histology and Embryology, College of Basic Medicine, Chongqing Medical University, Chongqing, China.
Abstract:
Ferroptosis is a novel form of programmed cell death that is triggered by iron-dependent lipid peroxidation. Brusatol (BRU), a natural nuclear factor erythroid 2-related factor 2 inhibitor, exhibits potent anticancer effects in various types of cancer. However, the exact mechanism of BRU in the treatment of hepatocellular carcinoma (HCC) remains unknown. The anticancer effects of BRU in HCC were detected using cell counting kit-8 and colony formation assays and a xenograft model. RNA sequencing (RNA-seq) and bioinformatics analyses of HCC cells were utilized to elucidate the mechanism underlying the effects of BRU in HCC. The levels of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe2+ were measured using assay kits. The expression of activating transcription factor 3 (ATF3) was tested using RT-qPCR, western blotting, and immunofluorescence staining. The role of ATF3 in BRU-induced ferroptosis was examined using siATF3. BRU significantly inhibited HCC cell proliferation, both in vitro and in vivo. BRU activated the ferroptosis signaling pathway and increased ATF3 expression. Furthermore, ATF3 knockdown impeded BRU-induced ferroptosis. BRU suppressed HCC growth through ATF3-mediated ferroptosis, supporting BRU as a promising therapeutic agent for HCC.
Insights
Brusatol effectively inhibits hepatocellular carcinoma (HCC) growth by inducing iron-dependent cell death, known as ferroptosis. This occurs through increased activating transcription factor 3 (ATF3) expression, highlighting Brusatol as a potential HCC therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ferroptosis is an iron-dependent form of programmed cell death involving lipid peroxidation.
- Brusatol (BRU), a natural nuclear factor erythroid 2-related factor 2 inhibitor, shows anticancer potential.
- The precise mechanism of Brusatol in hepatocellular carcinoma (HCC) treatment is not fully understood.
Purpose of the Study:
- To investigate the anticancer effects and underlying mechanism of Brusatol in hepatocellular carcinoma (HCC).
- To determine if Brusatol induces ferroptosis in HCC cells and its role in this process.
Main Methods:
- In vitro and in vivo assays (cell counting kit-8, colony formation, xenograft model) assessed BRU's anticancer effects.
- RNA sequencing and bioinformatics analyses elucidated BRU's mechanism.
- Measurements of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe2+ levels were performed.
- Activating transcription factor 3 (ATF3) expression was analyzed via RT-qPCR, western blotting, and immunofluorescence.
- siATF3 was used to examine ATF3's role in BRU-induced ferroptosis.
Main Results:
- Brusatol significantly inhibited HCC cell proliferation both in vitro and in vivo.
- BRU treatment activated the ferroptosis signaling pathway and upregulated ATF3 expression.
- Knockdown of ATF3 diminished BRU-induced ferroptosis, indicating ATF3's crucial role.
Conclusions:
- Brusatol suppresses HCC growth by inducing ATF3-mediated ferroptosis.
- Brusatol demonstrates potential as a therapeutic agent for hepatocellular carcinoma.
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