Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin
IntroductionFerroptosis, an iron-dependent form of regulated cell death, is characterized by the lethal accumulation of lipid peroxides on cellular membranes. It not only inhibits tumor growth but also enhances immunotherapy responses and overcomes drug resistance in cancer therapy. The inhibition o...
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2025-02-01
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| author | Ziwei Yang Ziwei Yang Tixin Han Ruibin Yang Ruibin Yang Yinuo Zhang Yinuo Zhang Yifei Qin Yifei Qin Yifei Qin Jialu Hou Jialu Hou Fei Huo Fei Huo Zhuan Feng Zhuan Feng Yaxin Ding Yaxin Ding Jiali Yang Jiali Yang Gang Zhou Gang Zhou Shijie Wang Shijie Wang Xiaohang Xie Xiaohang Xie Peng Lin Peng Lin Zhi-Nan Chen Zhi-Nan Chen Jiao Wu Jiao Wu |
| author_facet | Ziwei Yang Ziwei Yang Tixin Han Ruibin Yang Ruibin Yang Yinuo Zhang Yinuo Zhang Yifei Qin Yifei Qin Yifei Qin Jialu Hou Jialu Hou Fei Huo Fei Huo Zhuan Feng Zhuan Feng Yaxin Ding Yaxin Ding Jiali Yang Jiali Yang Gang Zhou Gang Zhou Shijie Wang Shijie Wang Xiaohang Xie Xiaohang Xie Peng Lin Peng Lin Zhi-Nan Chen Zhi-Nan Chen Jiao Wu Jiao Wu |
| author_sort | Ziwei Yang |
| collection | DOAJ |
| description | IntroductionFerroptosis, an iron-dependent form of regulated cell death, is characterized by the lethal accumulation of lipid peroxides on cellular membranes. It not only inhibits tumor growth but also enhances immunotherapy responses and overcomes drug resistance in cancer therapy. The inhibition of the cystine-glutamate antiporter, system Xc–, induces ferroptosis. Imidazole ketone erastin (IKE), an inhibitor of the system Xc– functional subunit solute carrier family 7 member 11 (SLC7A11), is an effective and metabolically stable inducer of ferroptosis with potential in vivo applications. However, tumor cells exhibited differential sensitivity to IKE-induced ferroptosis. The intrinsic factors determining sensitivity to IKE-induced ferroptosis remain to be explored to improve its efficacy.MethodsBulk RNA-sequencing data from hepatocellular carcinoma (HCC) and normal liver tissues were collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Differentially expressed genes were identified and intersected with the ferroptosis-related genes (FRGs) listed in the FerrDb database, yielding the identification of 13 distinct FRGs.ResultsA ferroptosis signature index model (Risk Score) was developed to predict HCC prognosis. And SLC7A11 and NAD(P)H quinone dehydrogenase 1 (NQO1) were identified as candidate FRGs indicating poor prognosis of HCC. Dicoumarol (DIC), an inhibitor of NQO1, was subsequently employed to assess its sensitizing effects on IKE in HCC treatment. In HCC cell lines and the subcutaneous xenograft model, the combined suppression of SLC7A11 and NQO1 significantly enhanced the inhibitory effect on tumor growth by inducing ferroptosis.DiscussionIn conclusion, our findings demonstrate that DIC sensitized HCC cells to IKE-induced ferroptosis in HCC. Moreover, the identification of potential drugs that enhance the susceptibility of HCC cells to ferroptosis could provide novel therapeutic strategies for the treatment of HCC. |
| format | Article |
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| institution | Kabale University |
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| spelling | doaj-art-2893da42353b4a61b7afe2bdcabe21762025-02-11T15:04:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15318741531874Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastinZiwei Yang0Ziwei Yang1Tixin Han2Ruibin Yang3Ruibin Yang4Yinuo Zhang5Yinuo Zhang6Yifei Qin7Yifei Qin8Yifei Qin9Jialu Hou10Jialu Hou11Fei Huo12Fei Huo13Zhuan Feng14Zhuan Feng15Yaxin Ding16Yaxin Ding17Jiali Yang18Jiali Yang19Gang Zhou20Gang Zhou21Shijie Wang22Shijie Wang23Xiaohang Xie24Xiaohang Xie25Peng Lin26Peng Lin27Zhi-Nan Chen28Zhi-Nan Chen29Jiao Wu30Jiao Wu31Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaShaanxi Key Laboratory of Bio-electromagnetic Detection and Intelligent Sensing, Military Biomedical Engineering School, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaInstitutes of Biomedicine and Department of Cell Biology, Jinan University, Guangzhou, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaDepartment of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, ChinaState Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Department of Cell Biology, Fourth Military Medical University, Xi'an, ChinaIntroductionFerroptosis, an iron-dependent form of regulated cell death, is characterized by the lethal accumulation of lipid peroxides on cellular membranes. It not only inhibits tumor growth but also enhances immunotherapy responses and overcomes drug resistance in cancer therapy. The inhibition of the cystine-glutamate antiporter, system Xc–, induces ferroptosis. Imidazole ketone erastin (IKE), an inhibitor of the system Xc– functional subunit solute carrier family 7 member 11 (SLC7A11), is an effective and metabolically stable inducer of ferroptosis with potential in vivo applications. However, tumor cells exhibited differential sensitivity to IKE-induced ferroptosis. The intrinsic factors determining sensitivity to IKE-induced ferroptosis remain to be explored to improve its efficacy.MethodsBulk RNA-sequencing data from hepatocellular carcinoma (HCC) and normal liver tissues were collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Differentially expressed genes were identified and intersected with the ferroptosis-related genes (FRGs) listed in the FerrDb database, yielding the identification of 13 distinct FRGs.ResultsA ferroptosis signature index model (Risk Score) was developed to predict HCC prognosis. And SLC7A11 and NAD(P)H quinone dehydrogenase 1 (NQO1) were identified as candidate FRGs indicating poor prognosis of HCC. Dicoumarol (DIC), an inhibitor of NQO1, was subsequently employed to assess its sensitizing effects on IKE in HCC treatment. In HCC cell lines and the subcutaneous xenograft model, the combined suppression of SLC7A11 and NQO1 significantly enhanced the inhibitory effect on tumor growth by inducing ferroptosis.DiscussionIn conclusion, our findings demonstrate that DIC sensitized HCC cells to IKE-induced ferroptosis in HCC. Moreover, the identification of potential drugs that enhance the susceptibility of HCC cells to ferroptosis could provide novel therapeutic strategies for the treatment of HCC.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1531874/fullhepatocellular carcinomaferroptosisNRF2NQO1SLC7A11prognostic model |
| spellingShingle | Ziwei Yang Ziwei Yang Tixin Han Ruibin Yang Ruibin Yang Yinuo Zhang Yinuo Zhang Yifei Qin Yifei Qin Yifei Qin Jialu Hou Jialu Hou Fei Huo Fei Huo Zhuan Feng Zhuan Feng Yaxin Ding Yaxin Ding Jiali Yang Jiali Yang Gang Zhou Gang Zhou Shijie Wang Shijie Wang Xiaohang Xie Xiaohang Xie Peng Lin Peng Lin Zhi-Nan Chen Zhi-Nan Chen Jiao Wu Jiao Wu Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin Frontiers in Immunology hepatocellular carcinoma ferroptosis NRF2 NQO1 SLC7A11 prognostic model |
| title | Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin |
| title_full | Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin |
| title_fullStr | Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin |
| title_full_unstemmed | Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin |
| title_short | Dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin |
| title_sort | dicoumarol sensitizes hepatocellular carcinoma cells to ferroptosis induced by imidazole ketone erastin |
| topic | hepatocellular carcinoma ferroptosis NRF2 NQO1 SLC7A11 prognostic model |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1531874/full |
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