2. Academic Validation
  3. YAP Expression Confers Therapeutic Vulnerability to Cuproptosis in Breast Cancer Cells by Regulating Copper Homeostasis

YAP Expression Confers Therapeutic Vulnerability to Cuproptosis in Breast Cancer Cells by Regulating Copper Homeostasis

  • Adv Healthc Mater. 2025 Oct 2:e02769. doi: 10.1002/adhm.202502769.
Zei-Wei Liu 1 2,  Cheng-Ying Chu 3,  Yu-Ling Chen 1 2,  Chu-Hung Chung 1 2,  Fwu-Long Mi 1 2,  Ming-Hua Ho 4,  Wen-Jing Hsu 1 2,  Ming-Yi Hsieh 1 2,  Ming-Chen Chiang 1 2,  Cheng-Jui Huang 1,  Pei-Wei Shueng 5 6,  Ching-Chieh Yang 7 8 9,  Chi-Ching Lee 10 11,  Cheng-Wei Lin 1 2 12
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 2 Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 3 CRISPR Gene Targeting Core Lab, Taipei Medical University, Taipei, 11031, Taiwan.
  • 4 Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106335, Taiwan.
  • 5 Division of Radiation Oncology, Far Eastern Memorial Hospital, New Taipei City, 220216, Taiwan.
  • 6 Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 30010, Taiwan.
  • 7 Department of Radiation Oncology, Chi Mei Medical Center, Tainan, 71004, Taiwan.
  • 8 Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, 717, Taiwan.
  • 9 School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
  • 10 Department of Food Engineering, Faculty of Engineering and Natural Sciences, Istanbul Sabahattin Zaim University, Istanbul, 34303, Turkey.
  • 11 Department of Food Technology and Nutrition, Faculty of Technologies, Klaipėda State University of Applied Sciences, Klaipėdos, 91274, Lithuania.
  • 12 Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 807378, Taiwan.
PMID: 41039751 DOI: 10.1002/adhm.202502769
Abstract

Copper metabolism plays a complex role in tumor growth and Cancer progression and thus holds potential as a therapeutic target. However, reliable diagnostic markers and therapeutic tools for successfully predicting personalized treatment outcomes with copper inhibition remain elusive. In this study, it is discovered that Yes-associated protein (YAP) expression conferred susceptibility toward Cuproptosis. Molecular analyses revealed that YAP inhibition significantly abolished cuproptotic characteristics. Interestingly, YAP inhibition does not affect protein lipoylation but disrupts copper homeostasis. Mechanistically, YAP regulates antioxidant-1 (ATOX1), a copper chaperone, and overexpression of ATOX1 restored cuproptotic sensitivity in YAP-silenced cells. To advance copper-targeting therapy, it is identified that melatonin inhibited YAP signaling and attenuated the expression of copper metabolism-related genes. Furthermore, a copper-based functional nanomaterial, EsMP@Fu is developed, which incorporates melatonin and the Cuproptosis Inducer elesclomol complex with copper ions (Cu(II)) (Es:Cu). This formulation facilitates cuproptotic cytotoxicity via fucoidan-decorated nanocarrier to enhance the targeted delivery toward tumor cells. In vivo study demonstrated that EsMP@Fu significantly suppressed tumor growth by 60%, with more pronounced effects on distant metastasis and the induction of antitumor immunity. Collectively, the findings demonstrate that YAP overexpression confers sensitivity and therapeutic vulnerability to Cuproptosis induction, presenting a promising strategy for precision medicine through tailored copper-based therapy.

Keywords

ATOX1; YAP; copper homeostasis; cuproptosis; nanomedicine.

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