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Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway

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Abstract

Multiple myeloma (MM) is a common malignant hematologic neoplasm, and the involvement of epigenetic modifications in its development and drug resistance has received widespread attention. Ferroptosis, a new ferroptosis-dependent programmed death mode, is closely associated with the development of MM. The novel methyltransferase inhibitor DCG066 has higher cell activity, but its mechanism of action in MM has not been clarified. Here, we found that DCG066 (5µM) inhibited the proliferation and induced ferroptosis in MM cells; the intracellular levels of ROS, iron, and MDA were significantly elevated, and the level of GSH was reduced after the treatment of DCG066; The protein expression levels of SLC7A11, GPX4, Nrf2 and HO-1 were significantly reduced, and these phenomena could be reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ). Meanwhile, the protein expression levels of Keap1 was increased, and heat shock proteins (HSP70, HSP90 and HSPB1) were reduced after DCG066 treatment. In conclusion, this study confirmed that DCG066 inhibits MM proliferation and induces ferroptosis via the Nrf2/HO-1 pathway.

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Funding

This work was supported by the Natural Science Foundation of Shandong Province (number ZR2020QC083, ZR2021QH231, and ZR2022MH058) and Development Foundation of Xuzhou Medical University Affiliated Hospital (number XYFM202223).

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Authors and Affiliations

  1. Postgraduate Training Base of Linyi People’s Hospital, Guangzhou University of Chinese Medicine, Linyi, China

    Yu Zhang, Xingfang Xiong & Lanlan Zang

  2. Central Laboratory, Linyi People’s Hospital, Linyi, China

    Yu Zhang, Xiaoqi Li, Xingfang Xiong, Renyu Xue, Lanlan Zang, Zhiqiang Wang & Lijuan Wang

  3. Qingdao Municipal Hospital, Qingdao, China

    Xiaoshun Wang

  4. School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China

    Xiaoqi Li

  5. Key Laboratory of Neurophysiology, Health Commission of Shandong Province, Linyi, China

    Renyu Xue, Lanlan Zang, Zhiqiang Wang & Lijuan Wang

  6. Linyi Key Laboratory of Tumor Biology, Linyi, China

    Renyu Xue, Lanlan Zang, Zhiqiang Wang & Lijuan Wang

  7. Key Laboratory for Translational Oncology, Xuzhou Medical University, Linyi, China

    Renyu Xue, Lanlan Zang, Zhiqiang Wang & Lijuan Wang

  8. Department of Hematology, Linyi People’s Hospital, Linyi, China

    Lijuan Wang

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  1. Yu Zhang
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  2. Xiaoshun Wang
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Contributions

All authors contributed to the study sonception. L.Z. and Y.Z.drafted the manuscript. L.W. and Z.W. designed the strategy. Y.Z. and X.W. and X.X. completed the biological experiments, X.L. and R.X. assisted in part of the in vitro experiments. All authors wrote, read, assisted in the revision, and approved the manuscript.

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Correspondence to Lanlan Zang, Zhiqiang Wang or Lijuan Wang.

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Zhang, Y., Wang, X., Li, X. et al. Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05728-6

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