The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer
Open accessAbstract
Chemotherapy is still one of the principal treatments for gastric cancer, but the clinical application of 5-FU is limited by drug resistance. Here, we demonstrate that ferroptosis triggered by STAT3 inhibition may provide a novel opportunity to explore a new effective therapeutic strategy for gastric cancer and chemotherapy resistance. We find that ferroptosis negative regulation (FNR) signatures are closely correlated with the progression and chemoresistance of gastric cancer. FNR associated genes (GPX4, SLC7A11, and FTH1) and STAT3 are upregulated in 5-FU resistant cells and xenografts. Further evidence demonstrates that STAT3 binds to consensus DNA response elements in the promoters of the FNR associated genes (GPX4, SLC7A11, and FTH1) and regulates their expression, thereby establishing a negative STAT3-ferroptosis regulatory axis in gastric cancer. Genetic inhibition of STAT3 activity triggers ferroptosis through lipid peroxidation and Fe2+ accumulation in gastric cancer cells. We further develop a potent and selective STAT3 inhibitor, W1131, which demonstrates significant anti-tumor effects in gastric cancer cell xenograft model, organoids model, and patient-derived xenografts (PDX) model partly by inducing ferroptosis, thus providing a new candidate compound for advanced gastric cancer. Moreover, targeting the STAT3-ferroptosis circuit promotes ferroptosis and restores sensitivity to chemotherapy. Our finding reveals that STAT3 acts as a key negative regulator of ferroptosis in gastric cancer through a multi-pronged mechanism and provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance.
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Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Regulation of Ferroptotic Cancer Cell Death by GPX4
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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
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ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
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Ferroptosis: molecular mechanisms and health implications
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Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
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Ferroptosis: process and function
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Cited by
Iron Homeostasis and Ferroptosis in Human Diseases: Mechanisms and Therapeutic Prospects
Ru, Q., Li, Y., Chen, L., Wu, Y., Min, J., & Wang, F. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01969-z · Cited by 724
Li, F.-J., Long, H.-Z., Zhou, Z.-W., Luo, H.-Y., Xu, S.-G., & Gao, L.-C. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.910292 · Cited by 438
Overcoming cancer chemotherapy resistance by the induction of ferroptosis
Wang, Y., Wu, X., Ren, Z., Li, Y., Zou, W., Chen, J., & Wang, H. (2023) · Drug Resistance Updates · doi:10.1016/j.drup.2022.100916 · Cited by 361
Self-citationRelB-activated GPX4 inhibits ferroptosis and confers tamoxifen resistance in breast cancer
Xu, Z., Wang, X., Sun, W., Xu, F., Kou, H., Hu, W., Zhang, Y., Jiang, Q., Tang, J., & Xu, Y. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102952 · Cited by 76
Metadata
- Authors
- Ouyang, S., Li, H., Lou, L., Huang, Q., Zhang, Z., Mo, J., Li, M., Lu, J., Zhu, K., Chu, Y., Ding, W., Zhu, J., Lin, Z., Zhong, L., Wang, J., Yue, P., Turkson, J., Liu, P., Wang, Y., & Zhang, X.
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 52
- Pages
- 102317
- ISSN
- 2213-2317 (ISSN-L)
- OpenAlex
- W4224248664
- Cited by
- 507
- References
- 64
- FWCI
- 59.20
- Type
- journal article
- Language
- en
- Open access
- gold
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- Ouyang, S., Li, H., Lou, L., Huang, Q., Zhang, Z., Mo, J., Li, M., Lu, J., Zhu, K., Chu, Y., Ding, W., Zhu, J., Lin, Z., Zhong, L., Wang, J., Yue, P., Turkson, J., Liu, P., Wang, Y., & Zhang, X. (2022). Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox Biology. https://doi.org/10.1016/j.redox.2022.102317
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