Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2
Abstract Diffuse large B-cell lymphoma (DLBCL), the most prevalent non-Hodgkin lymphoma (NHL), is characterized by rapid growth and an unfavorable prognosis. Artesunate (ART), a derivative of Artemisinin, is a widely recognized antimalarial drug that displays notable antitumor properties across dive...
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| Format: | Article |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07822-7 |
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| author | Xiaohui Liu Liyi Zeng Jing Liu Yulun Huang Hua Yao Jinman Zhong Jiewen Tan Xuenjuan Gao Dan Xiong Langxia Liu |
| author_facet | Xiaohui Liu Liyi Zeng Jing Liu Yulun Huang Hua Yao Jinman Zhong Jiewen Tan Xuenjuan Gao Dan Xiong Langxia Liu |
| author_sort | Xiaohui Liu |
| collection | DOAJ |
| description | Abstract Diffuse large B-cell lymphoma (DLBCL), the most prevalent non-Hodgkin lymphoma (NHL), is characterized by rapid growth and an unfavorable prognosis. Artesunate (ART), a derivative of Artemisinin, is a widely recognized antimalarial drug that displays notable antitumor properties across diverse cancers. Our previous studies have demonstrated ART’s capacity to inhibit DLBCL progression via the induction of ferroptosis. However, its direct target molecules mediating this effect remained elusive. In this study, using small molecule (SM) pull-down combined with mass spectrometry analysis (LC–MS/MS), we have identified two peroxidases, PRDX1 and PRDX2, which play key roles in cellular antioxidant processes, as potential target proteins for ART in the treatment of DLBCL cells. Subsequently, we utilized cellular thermal shift assay (CETSA), fluorescence titration, circular dichroism (CD) spectroscopy, molecular docking, and pull-down assays to confirm that ART directly binds to PRDX1 and PRDX2. The Gly4 residue on PRDX1 and the Arg7 and Thr120 residues on PRDX2 are respectively responsible for ART binding. Knockdown of either PRDX1 or PRDX2 not only reproduced the ferroptosis-inducing effect of ART but also significantly attenuated the sensitivity of cells to ART. Furthermore, PRDX2 overexpression attenuated the reactive oxygen species (ROS) production and cytotoxicity in cells treated with ART. Consistently, ART selectively killed DLBCL cells, sparing normal cells thanks to their lower PRDX1 expression. In nude mice bearing U2932 xenografts, ART treatment inhibited significantly tumor growth and improved liver function without causing cardiac or hepatic toxicity, which was associated with an elevated level of ferroptosis and a significantly decreased peroxidase activity. Collectively, our findings elucidate the molecular mechanism by which ART induces ferroptosis through direct interaction with PRDX1 or PRDX2 and highlight these PRDXs as potential therapeutic targets for DLBCL. |
| format | Article |
| id | doaj-art-2197e4d452ab448cb83288e3030ee727 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-2197e4d452ab448cb83288e3030ee7272025-08-20T03:43:34ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111210.1038/s41419-025-07822-7Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2Xiaohui Liu0Liyi Zeng1Jing Liu2Yulun Huang3Hua Yao4Jinman Zhong5Jiewen Tan6Xuenjuan Gao7Dan Xiong8Langxia Liu9MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan UniversityDepartment of Hematology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)Department of Hematology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan UniversityDepartment of Hematology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan UniversityAbstract Diffuse large B-cell lymphoma (DLBCL), the most prevalent non-Hodgkin lymphoma (NHL), is characterized by rapid growth and an unfavorable prognosis. Artesunate (ART), a derivative of Artemisinin, is a widely recognized antimalarial drug that displays notable antitumor properties across diverse cancers. Our previous studies have demonstrated ART’s capacity to inhibit DLBCL progression via the induction of ferroptosis. However, its direct target molecules mediating this effect remained elusive. In this study, using small molecule (SM) pull-down combined with mass spectrometry analysis (LC–MS/MS), we have identified two peroxidases, PRDX1 and PRDX2, which play key roles in cellular antioxidant processes, as potential target proteins for ART in the treatment of DLBCL cells. Subsequently, we utilized cellular thermal shift assay (CETSA), fluorescence titration, circular dichroism (CD) spectroscopy, molecular docking, and pull-down assays to confirm that ART directly binds to PRDX1 and PRDX2. The Gly4 residue on PRDX1 and the Arg7 and Thr120 residues on PRDX2 are respectively responsible for ART binding. Knockdown of either PRDX1 or PRDX2 not only reproduced the ferroptosis-inducing effect of ART but also significantly attenuated the sensitivity of cells to ART. Furthermore, PRDX2 overexpression attenuated the reactive oxygen species (ROS) production and cytotoxicity in cells treated with ART. Consistently, ART selectively killed DLBCL cells, sparing normal cells thanks to their lower PRDX1 expression. In nude mice bearing U2932 xenografts, ART treatment inhibited significantly tumor growth and improved liver function without causing cardiac or hepatic toxicity, which was associated with an elevated level of ferroptosis and a significantly decreased peroxidase activity. Collectively, our findings elucidate the molecular mechanism by which ART induces ferroptosis through direct interaction with PRDX1 or PRDX2 and highlight these PRDXs as potential therapeutic targets for DLBCL.https://doi.org/10.1038/s41419-025-07822-7 |
| spellingShingle | Xiaohui Liu Liyi Zeng Jing Liu Yulun Huang Hua Yao Jinman Zhong Jiewen Tan Xuenjuan Gao Dan Xiong Langxia Liu Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2 Cell Death and Disease |
| title | Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2 |
| title_full | Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2 |
| title_fullStr | Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2 |
| title_full_unstemmed | Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2 |
| title_short | Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2 |
| title_sort | artesunate induces ferroptosis in diffuse large b cell lymphoma cells by targeting prdx1 and prdx2 |
| url | https://doi.org/10.1038/s41419-025-07822-7 |
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