Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells

Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells

Abstract As a novel form of nonapoptotic cell death, ferroptosis is developing into a promising therapeutic target of dedifferentiating and therapy-refractory cancers. However, its application in pancreatic cancer is still unknown. In the preliminary research, we found that F-box and WD repeat domai...

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Main Authors: Zheng Zhang, Huaxiang Xu, Junyi He, Qiangsheng Hu, Yuxin Liu, Zijin Xu, Wenhui Lou, Wenchuan Wu, Lei Zhang, Ning Pu, Chenye Shi, Yaolin Xu, Wenquan Wang, Liang Liu
Format: Article
Language:English
Published: Nature Publishing Group 2025-01-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-025-07330-8
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Summary:Abstract As a novel form of nonapoptotic cell death, ferroptosis is developing into a promising therapeutic target of dedifferentiating and therapy-refractory cancers. However, its application in pancreatic cancer is still unknown. In the preliminary research, we found that F-box and WD repeat domain-containing 7 (FBW7) inhibited the migration and proliferation of pancreatic cancer cells through its substrate c-Myc. We further found that another key substrate of FBW7, KLF5, could inhibit ferroptosis. Inhibiting KLF5 significantly enhances the cytotoxicity of oxaliplatin rather than other chemotherapy drugs. Mechanistically, we found that KLF5 inhibited the expression of heme oxygenase 1 (HMOX1) via repressing zinc finger E-box-binding homeobox 1 (ZEB1). Inhibition of KLF5 facilitated the cytotoxic effect of oxaliplatin via promoting ferroptosis. Oxaliplatin combined with KLF5 inhibitor significantly potentiated cell death in vitro and inhibited tumor growth in vivo compared with either treatment alone. These results reveal a critical role of KLF5 in sensitized chemotherapy of pancreatic cancer, and suggest that ferroptosis combined with platinum-based chemotherapy rather than gemcitabine-based chemotherapy is expected to bring better therapeutic effects.
ISSN:2041-4889

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