2. Academic Validation
  3. Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit

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

  • Acta Pharmacol Sin. 2025 Feb 12. doi: 10.1038/s41401-025-01481-2.
Jun-Hao Deng # 1 2,  Hong-Yue Li # 1,  Zi-Yang Liu 1,  Jing-Pei Liang 1 3,  Ying Ren 4,  Yuan-Ying Zeng 5,  Ya-Li Wang 6,  Xin-Liang Mao 7 8
Affiliations

Affiliations

  • 1 The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511436, China.
  • 2 Guangdong Provincial Key Laboratory of Protein Modification and Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • 3 Guangdong Institute for Drug Control, Guangzhou, 510663, China.
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China.
  • 5 Department of Oncology, Suzhou Municipal Hospital, Suzhou, 215100, China. zengyuanying@163.com.
  • 6 Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. yaliwang@gzhmu.edu.cn.
  • 7 The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511436, China. xinliangmao@gzhmu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Protein Modification and Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. xinliangmao@gzhmu.edu.cn.
  • # Contributed equally.
PMID: 39939802 DOI: 10.1038/s41401-025-01481-2
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.

Keywords

STAT3; TRIP13; bardoxolone; triple negative breast cancer.

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