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Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit

Acta Pharmacologica Sinica volume 46, pages 1733–1741 (2025) Cite this article

Abstract

Triple negative breast cancer (TNBC) is difficult to treat and novel therapeutic targets remain to be identified. TRIP13, an AAA+ ATPase, is highly expressed in breast cancer and predicts poor prognosis; however, the specific mechanism is not fully understood. In the present study, we found TRIP13 promotes TNBC cell viability and migration. In a mechanistic study, TRIP13 is found to activate STAT3 but not other STAT members. Out of expectation, TRIP13 is found to be upregulated by STAT3 and STAT3 specifically recognizes and binds to the STAT3-recognition element in the regulatory region of TRIP13. Moreover, we found bardoxolone, a recently approved drug for the treatment of chronic kidney disease, displays potent activity by inhibiting STAT3 activation and downregulating TRIP13. Furthermore, bardoxolone inhibits breast cancer cell proliferation and migration, and induces apoptosis. Consistent with this finding, ectopic expression of TRIP13 ablates bardoxolone-induced breast cancer cell apoptosis. Bardoxolone also exerts great activity to suppress TNBC tumor growth in vivo but does not show toxicity. Therefore, we reveal that the TRIP13/STAT3 circuit promotes TNBC cell proliferation and this circuit is a promising target for the treatment of TNBC.

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Fig. 1: TRIP13 promotes breast cancer cell proliferation and migration.
The alternative text for this image may have been generated using AI.
Fig. 2: TRIP13 activates STAT3 but not other STATs in breast cancer.
The alternative text for this image may have been generated using AI.
Fig. 3: TRIP13 is upregulated by STAT3.
The alternative text for this image may have been generated using AI.
Fig. 4: Identification of bardoxolone as an inhibitor of the TRIP13/STAT3 axis.
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Fig. 5: CDDO displays potent activity against breast cancer cells.
The alternative text for this image may have been generated using AI.
Fig. 6: CDDO suppresses TNBC tumor growth in vivo and inhibits the TRIP13/STAT3 signaling axis.
The alternative text for this image may have been generated using AI.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was partly supported by Special Projects in Key Areas for Guangdong Provincial Colleges and Universities (2021ZDZX2009), by Suzhou Municipal Science and Technology Project (#SYS2020165 to YYZ), the National Natural Science Foundation of China (#32100577 to YR), and by Guangzhou Medical University Discipline Construction Funds (Basic Medicine) (#JCXKJS2022A05).

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Author notes

  1. These authors contributed equally: Jun-hao Deng, Hong-yue Li

Authors and Affiliations

  1. The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511436, China

    Jun-hao Deng, Hong-yue Li, Zi-yang Liu, Jing-pei Liang & Xin-liang Mao

  2. Guangdong Provincial Key Laboratory of Protein Modification and Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Jun-hao Deng & Xin-liang Mao

  3. Guangdong Institute for Drug Control, Guangzhou, 510663, China

    Jing-pei Liang

  4. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China

    Ying Ren

  5. Department of Oncology, Suzhou Municipal Hospital, Suzhou, 215100, China

    Yuan-ying Zeng

  6. Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Ya-li Wang

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Contributions

XLM, YLW, and YYZ designed the study; JHD, HYL, ZYL, JPL, and YR conducted experiments. XLM YYZ, and JHD analyzed data; XLM and JHD wrote the manuscript.

Corresponding authors

Correspondence to Yuan-ying Zeng, Ya-li Wang or Xin-liang Mao.

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Deng, Jh., Li, Hy., Liu, Zy. et al. Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit. Acta Pharmacol Sin 46, 1733–1741 (2025). https://doi.org/10.1038/s41401-025-01481-2

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