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Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy
Wenxia Li1,2, Hangjie Fu3, Liuyuan Fang1,2
1The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
Abstract:
Multiple myeloma (MM) is an incurable hematological malignancy that lacks effective therapeutic interventions. Ferroptosis is a newly discovered form of cell death that has shown great potential for MM therapy. As a proteasome inhibitor and necroptosis inducer, shikonin (SHK) performs dual functions in MM cells. However, whether SHK inhibits the development of MM via ferroptosis or any other mechanism remains elusive. Here, we provide evidence that SHK treatment was capable of inducing ferroptosis and immunogenic cell death (ICD) in MM. The results showed that SHK treatment induced lactate dehydrogenase release, triggered cell death, evoked oxidative stress, and enhanced ferrous iron and lipid peroxidation levels. Furthermore, treatment with ferroptosis inhibitors reversed SHK-induced cell death, which indicated that ferroptosis contributed to this phenomenon. Meanwhile, ferroptosis was accompanied by the extracellular release of Adenosine 5'-triphosphate (ATP) and High mobility group protein B1 (HMGB1), which are characteristics of ICD. Further investigation showed that glutamic-oxaloacetic transaminase 1 (GOT1) acted as a critical mediator of SHK-induced ferroptosis by promoting ferritinophagy. In conclusion, our findings suggest that SHK exerts ferroptotic effects on MM by regulating GOT1-mediated ferritinophagy. Thus, SHK is a potential therapeutic agent for MM.
Insights
Shikonin induces ferroptosis and immunogenic cell death in multiple myeloma (MM) by regulating GOT1-mediated ferritinophagy. This suggests shikonin is a promising therapeutic agent for treating this incurable hematological malignancy.
Area of Science:
- Oncology
- Cell Death Mechanisms
- Hematology
Background:
- Multiple myeloma (MM) is an incurable hematological malignancy with limited therapeutic options.
- Ferroptosis, a form of programmed cell death, presents a potential therapeutic strategy for MM.
- Shikonin (SHK), a proteasome inhibitor, has dual functions in MM cells, but its mechanism of action, particularly regarding ferroptosis, is unclear.
Purpose of the Study:
- To investigate whether shikonin (SHK) induces ferroptosis and immunogenic cell death (ICD) in multiple myeloma (MM).
- To elucidate the underlying molecular mechanisms of SHK-induced cell death in MM.
- To evaluate the therapeutic potential of SHK for MM.
Main Methods:
- Treatment of MM cells with shikonin (SHK).
- Assessment of cell death markers, oxidative stress, iron levels, and lipid peroxidation.
- Utilized ferroptosis inhibitors to confirm the role of ferroptosis.
- Measured extracellular release of ATP and HMGB1 to assess ICD.
- Investigated the role of glutamic-oxaloacetic transaminase 1 (GOT1) and ferritinophagy.
Main Results:
- SHK treatment induced significant cell death in MM cells, characterized by increased lactate dehydrogenase release, oxidative stress, ferrous iron, and lipid peroxidation.
- Ferroptosis inhibitors reversed SHK-induced cell death, confirming ferroptosis as a key mechanism.
- SHK-induced ferroptosis was associated with the release of ATP and HMGB1, indicative of immunogenic cell death (ICD).
- Glutamic-oxaloacetic transaminase 1 (GOT1) was identified as a critical mediator, promoting ferritinophagy and ferroptosis.
Conclusions:
- Shikonin (SHK) effectively induces ferroptosis and immunogenic cell death (ICD) in multiple myeloma (MM).
- GOT1-mediated ferritinophagy plays a crucial role in SHK-induced ferroptosis.
- SHK demonstrates potential as a novel therapeutic agent for multiple myeloma (MM).
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