2. Academic Validation
  3. AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple-Negative Breast Cancer

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

  • Adv Sci (Weinh). 2025 Feb 20:e2408106. doi: 10.1002/advs.202408106.
Zicheng Sun 1,  Huazhen Xu 1,  Guanming Lu 2,  Ciqiu Yang 3,  Xinya Gao 1,  Jing Zhang 1,  Xin Liu 1,  Yongcheng Chen 2,  Kun Wang 3,  Jianping Guo 4,  Jie Li 1
Affiliations

Affiliations

  • 1 Department of Breast and Thyroid Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510000, China.
  • 2 Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities and Key Laboratory of Molecular Pathology in Tumors of Guangxi, Guangxi, 533000, China.
  • 3 Department of Breast Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510000, China.
  • 4 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510000, China.
PMID: 39976173 DOI: 10.1002/advs.202408106
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.

Keywords

AKT1; FDX1; breast cancer; cuproptosis; metabolic reprogramming.

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