TY - JOUR
T1 - YAP-mediated DDX3X confers resistance to ferroptosis in breast cancer cells by reducing lipid peroxidation
AU - Dai, Jia Zih
AU - Hsu, Wen Jing
AU - Lin, Mei Hsiang
AU - Shueng, Pei Wei
AU - Lee, Chi Ching
AU - Yang, Ching Chieh
AU - Lin, Cheng Wei
N1 - Publisher Copyright:
© 2025
PY - 2025/5
Y1 - 2025/5
N2 - 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.
AB - 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.
KW - Breast cancer
KW - DEAD-box helicase 3 X-linked
KW - Ferroptosis
KW - Glutathione peroxidase 4
KW - Yes-associated protein
UR - http://www.scopus.com/inward/record.url?scp=105000259188&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=105000259188&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2025.03.019
DO - 10.1016/j.freeradbiomed.2025.03.019
M3 - Article
C2 - 40089076
AN - SCOPUS:105000259188
SN - 0891-5849
VL - 232
SP - 330
EP - 339
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -
