2. Academic Validation
  3. Downregulation of TDP43 by atovaquone inhibits oxidative phosphorylation and enhances sensitivity of triple-negative breast cancer to EGFR-TKIs

Downregulation of TDP43 by atovaquone inhibits oxidative phosphorylation and enhances sensitivity of triple-negative breast cancer to EGFR-TKIs

  • Free Radic Biol Med. 2026 Jul:250:64-79. doi: 10.1016/j.freeradbiomed.2026.03.047.
Liang Lin 1,  Hao Ke 2,  Mengxin Chen 1,  Yi Zhang 3,  Shiting Fu 4,  Fan Yu 1,  Jianbin Su 1,  Xing Yang 5,  Yingqi Guo 6,  Qianzhe Ding 1,  Yuhan Zhang 1,  Limin Zhao 7
Affiliations

Affiliations

  • 1 Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, 330031, China.
  • 2 Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, 330006, China. Electronic address: [email protected].
  • 3 State Key Laboratory of Vegetation Structure, Function and Construction (VegLab), School of Ecology and Environmental Science, Yunnan University, Kunming, Yunnan, 650504, China; State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
  • 4 Department of Medical Technology, Nanchang Academy of Health Sciences, Nanchang, 330103, China.
  • 5 State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
  • 6 The Institutional Center for Shared Technologies and Facilities of Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
  • 7 Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, 330031, China. Electronic address: [email protected].
PMID: 41862009 DOI: 10.1016/j.freeradbiomed.2026.03.047
Abstract

Epidermal growth factor receptor (EGFR) is overexpressed in most triple-negative breast Cancer (TNBC) patients with poor prognosis; however, the therapeutic benefit of EGFR inhibitors (EGFRi) in breast Cancer remains limited. In this study, we found poor response to EGFRi in TNBC was related to Oxidative Phosphorylation (OXPHOS) and breast Cancer Stem Cells (BCSCs), and demonstrated that TDP43 (TAR DNA-binding protein 43) expression is positively correlated with non-response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). TDP43 knockdown significantly enhances EGFR-TKI sensitivity and decreases EGFR-TKI resistance. Mechanistically, TDP43, a DNA/RNA-binding protein predominantly localized to the nucleus, translocates to mitochondria upon EGFR-TKI stimulation. The increased mitochondrial localization promotes OXPHOS, thereby enriching BCSCs and contributing to EGFR-TKI resistance. Inhibiting TDP43 expression or using our newly identified TDP43 inhibitor, atovaquone, suppresses OXPHOS and reduces EGFR-TKI resistance. Overall, our research identified TDP43 as a key regulator of EGFR-TKI sensitivity and resistance, and offers new therapeutic targets and promising application perspectives in TNBC.

Keywords

Atovaquone; Breast cancer stem cells; EGFR inhibitor resistance; Oxidative phosphorylation; TDP43; Triple-negative breast cancer.

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