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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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07330-8 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zheng Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ac144da6226448f2a66961b66f187249 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-ac144da6226448f2a66961b66f1872492025-01-19T12:40:45ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111510.1038/s41419-025-07330-8Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cellsZheng Zhang0Huaxiang Xu1Junyi He2Qiangsheng Hu3Yuxin Liu4Zijin Xu5Wenhui Lou6Wenchuan Wu7Lei Zhang8Ning Pu9Chenye Shi10Yaolin Xu11Wenquan Wang12Liang Liu13Department of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of MedicineInstitute of liver diseases, Shanxi Medical UniversityDepartment of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Pancreatic Surgery, Zhongshan Hospital, Fudan UniversityAbstract 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.https://doi.org/10.1038/s41419-025-07330-8 |
| spellingShingle | 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 Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells Cell Death and Disease |
| title | Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells |
| title_full | Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells |
| title_fullStr | Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells |
| title_full_unstemmed | Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells |
| title_short | Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells |
| title_sort | inhibition of klf5 promotes ferroptosis via the zeb1 hmox1 axis to enhance sensitivity to oxaliplatin in cancer cells |
| url | https://doi.org/10.1038/s41419-025-07330-8 |
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