AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple‐Negative Breast Cancer

Cuproptosis, a recently defined copper-dependent cell death pathway, remains largely unexplored in tumor therapies, particularly in breast cancer. This study demonstrates that triple-negative breast cancer (TNBC) bears a relatively elevated copper levels and exhibits resistance to cuproptosis. Mechanistically, copper activates the AKT signaling pathway, which inhibits ferredoxin-1 (FDX1), a key regulator of cuproptosis. AKT1-mediated FDX1 phosphorylation not only abrogates FDX1-induced cuproptosis and aerobic respiration but also promotes glycolysis. Consequently, the combination of AKT1 inhibitors and the copper ionophores synergistically alleviate TNBC tumorigenesis both in vitro and in vivo. In summary, the findings reveal a crucial mechanism underlying TNBC resistance to cuproptosis and suggest a potential therapeutic approach for TNBC.

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Publication Details

Journal
Advanced Science
Published
2025-02-20
DOI
https://doi.org/10.1002/advs.202408106
Citations
22
Primary Topic
Trace Elements in Health
Type
article
Field-Weighted Citation Impact
24.63

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article

AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple‐Negative Breast Cancer

Xin Liu, Yongcheng Chen, Guanming Lu, Xinya Gao et al.
22 citations
Advanced Science
Trace Elements in Health
24.63
article

AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple‐Negative Breast Cancer

Xin Liu, Yongcheng Chen, Guanming Lu, Xinya Gao, Ciqiu Yang, Hua‐Zhen Xu, Zicheng Sun, Jianping Guo, Jie Li, Kun Wang, Jing Zhang
article en
22 citations

Abstract

Cuproptosis, a recently defined copper-dependent cell death pathway, remains largely unexplored in tumor therapies, particularly in breast cancer. This study demonstrates that triple-negative breast cancer (TNBC) bears a relatively elevated copper levels and exhibits resistance to cuproptosis. Mechanistically, copper activates the AKT signaling pathway, which inhibits ferredoxin-1 (FDX1), a key regulator of cuproptosis. AKT1-mediated FDX1 phosphorylation not only abrogates FDX1-induced cuproptosis and aerobic respiration but also promotes glycolysis. Consequently, the combination of AKT1 inhibitors and the copper ionophores synergistically alleviate TNBC tumorigenesis both in vitro and in vivo. In summary, the findings reveal a crucial mechanism underlying TNBC resistance to cuproptosis and suggest a potential therapeutic approach for TNBC.

Advanced ScienceVol. 12(17)
Sun Yat-sen University (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Affiliated Hospital of Youjiang Medical University for Nationalities (CN), Guangdong Academy of Medical Sciences (CN), Guangdong Provincial People's Hospital (CN), Southern Medical University (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China, Natural Science Foundation of Guangxi Province
Good health and well-being
Openalex Percentile: Top 0%
Trace Elements in Health
24.63
DOIOpen Access PDFOpenAlex
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