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Arvanil induces ferroptosis of hepatocellular carcinoma by binding to MICU1

Cancer Gene Therapy volume 31, pages 148–157 (2024)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate that requires research and improved treatment strategies. Chemotherapy is still one of the main methods of HCC treatment, but it may lead to drug resistance and damage to normal organs. Capsaicin, a naturally occurring active ingredient in chili peppers, has demonstrated anticancer properties in a variety of malignant tumor cell lines. However, the anti-cancer mechanism of capsaicin needs to be further explored in HCC. In this study, we utilized Arvanil, a non-stimulating synthetic capsaicin analog, in place of capsaicin. We found that Arvanil induced high mitochondrial calcium flow, which contributed to a decrease in mitochondrial membrane permeability transition pore (mPTP) opening and oxidative phosphorylation levels, ultimately triggering cellular ferroptosis by live cells in real time with a high content screening (HCS) platform and confocal microscopy. It was further confirmed by vina molecular docking and point mutation experiments that Arvanil directly binds to two amino acid sites of mitochondrial calcium uptake protein 1 (MICU1), namely Ser47 and Phe128, to trigger this process, which in turn inhibits the growth of HCC cells. In addition, it was confirmed that Arvanil enhances cisplatin chemosensitivity by inducing HCC cellular ferroptosis in vivo. In conclusion, our study suggests that Arvanil induces ferroptosis in HCC cells and is a candidate drug for the treatment of HCC.

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Fig. 1: Arvanil induces high mitochondrial calcium flow and reduces mitochondrial membrane potential.
Fig. 2: Arvanil modulates mitochondrial function in HCC cells.
Fig. 3: Arvanil induces ferroptosis in HCC cells by regulating mitochondrial function.
Fig. 4: Arvanil exerts biological effects by binding to MICU1.
Fig. 5: Arvanil induces ferroptosis in HCC cells by binding to MICU1.
Fig. 6: Arvanil-induced ferroptosis increases cisplatin chemosensitivity in vivo.

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Data availability

This study includes no data deposited in external repositories. Structure of MICU1 (PDB: 4xsj) from PDB database: https://www.rcsb.org/structure/4XSJ.Tertiary structure of Arvanil (Compound CID: 6449767) obtained from PubChem: https://pubchem.ncbi.nlmnihgov/# uery=Avanil.

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Funding

Funding

This study was funded by the National Natural Science Foundation of China (No.82103653), the China Postdoctoral Science Foundation (No.2021M693553), the Natural Science Foundation of Hunan Province (No.2022JJ40659 and No.2022JJ40686).

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Authors and Affiliations

  1. Department of Pathology, Xiangya Hospital, Central South University, Changsha, China

    Xiangying Deng & Liling Li

  2. Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

    Xiangying Deng

  3. Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China

    Yajun Gui, Lin Zhao & Namei Li

  4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

    Liling Li

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  1. Xiangying Deng
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Contributions

Supervision: LL and XD; study concept and design: LZ and LL; drafting of the manuscript: LZ, XD, NL and YG; collection, analysis, or interpretation of data: LZ, YG, NL and XD; technical or material support: LZ and XD.

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Correspondence to Liling Li.

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Deng, X., Gui, Y., Zhao, L. et al. Arvanil induces ferroptosis of hepatocellular carcinoma by binding to MICU1. Cancer Gene Ther 31, 148–157 (2024). https://doi.org/10.1038/s41417-023-00690-3

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