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  3. YAP-mediated DDX3X confers resistance to ferroptosis in breast cancer cells by reducing lipid peroxidation

YAP-mediated DDX3X confers resistance to ferroptosis in breast cancer cells by reducing lipid peroxidation

  • Free Radic Biol Med. 2025 Mar 13:232:330-339. doi: 10.1016/j.freeradbiomed.2025.03.019.
Jia-Zih Dai 1,  Wen-Jing Hsu 1,  Mei-Hsiang Lin 2,  Pei-Wei Shueng 3,  Chi-Ching Lee 4,  Ching-Chieh Yang 5,  Cheng-Wei Lin 6
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 Graduate Institute of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 3 Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City, Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  • 4 Istanbul Sabahattin Zaim University, Faculty of Engineering and Natural Sciences, Department of Food Engineering, Istanbul, Turkey; Department of Food Technology and Nutrition, Faculty of Technologies, Klaipėda State University of Applied Sciences, Lithuania.
  • 5 Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan; Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan; School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan. Electronic address: cleanclear0905@gmail.com.
  • 6 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: cwlin@tmu.edu.tw.
PMID: 40089076 DOI: 10.1016/j.freeradbiomed.2025.03.019
Abstract

Metabolic shifts in Cancer cells were found to participate in tumorigenesis, especially driving chemotherapeutic resistance. Ferroptosis is a newly discovered form of cell death induced by excessive accumulations of iron and lipid peroxidation. Susceptibility to Ferroptosis can be intrinsically regulated by various cellular metabolic pathways. Therefore, inducing Ferroptosis might be a promising Anticancer therapeutic strategy. DEAD-box helicase 3 X-linked (DDX3X), a critical modulator of RNA metabolism, was identified as an oncogene in breast Cancer and also participates in Cancer metabolism and chemotherapeutic resistance. However, the molecular regulation of the association between DDX3X and Ferroptosis is largely unknown. Herein, we investigated the correlation between resistance to Ferroptosis and DDX3X expression in breast Cancer cells. We found that elevation of DDX3X was associated with increased resistance to a Ferroptosis inducer in breast Cancer cells, and manipulating DDX3X expression regulated the sensitivity to the Ferroptosis inducer. Importantly, DDX3X upregulated expression of the anti-ferroptotic enzyme Glutathione Peroxidase 4 (GPX4) gene to confer Ferroptosis resistance in breast Cancer cells. Moreover, DDX3X was transcriptionally upregulated by the yes-associated protein (YAP). Knockdown of YAP downregulated DDX3X mRNA expression and facilitated lipid peroxidation, but that were restored in the presence of DDX3X. Clinically, coexpression of DDX3X and YAP was found in a variety of malignancy, and their elevation conferred poor survival prognosis in patients with breast Cancer. Together, our findings reveal the crucial role of DDX3X in sensitivity to Ferroptosis and underscore its potential as a diagnostic marker and therapeutic target. DDX3X renders resistance to Ferroptosis and plays a role in mitigating lipid peroxidation, paving the way for therapeutic vulnerability via targeting Cancer metabolism.

Keywords

Breast cancer; DEAD-box helicase 3 X-linked; Ferroptosis; Glutathione peroxidase 4; Yes-associated protein.

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