Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis
Abstract Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis and limited therapeutic options. Leukemic stem cells (LSCs), which drive disease progression and confer resistance to therapy, pose a significant challenge to conventional treatment strategies. In thi...
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07831-6 |
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| author | Zhenghao Li Guangci Liu Ziren Chen Keming Li Zhe Yu Chao He Xinyu Ying Danling Huang Chengtian Tao Sajid Khan Yimeng Wang Fang-Lin Zhang Huan Li Yun Chen Jingfeng Zhou Li Yu Thomas J. Kipps Yongxian Cheng Suping Zhang |
| author_facet | Zhenghao Li Guangci Liu Ziren Chen Keming Li Zhe Yu Chao He Xinyu Ying Danling Huang Chengtian Tao Sajid Khan Yimeng Wang Fang-Lin Zhang Huan Li Yun Chen Jingfeng Zhou Li Yu Thomas J. Kipps Yongxian Cheng Suping Zhang |
| author_sort | Zhenghao Li |
| collection | DOAJ |
| description | Abstract Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis and limited therapeutic options. Leukemic stem cells (LSCs), which drive disease progression and confer resistance to therapy, pose a significant challenge to conventional treatment strategies. In this study, we identified and characterized the inhibitory mechanisms of TH37, a small molecule derived from traditional Chinese medicine, which selectively targets AML blasts and LSCs. Our analyses identified peroxiredoxin 1 (PRDX1), an enzyme that catalyzes the breakdown of hydrogen peroxide (a reactive oxygen species), as the primary molecular target of TH37. We demonstrated that TH37 directly interacts with PRDX1, inhibiting its enzymatic activity and thereby elevating intracellular reactive oxygen species levels in AML cells. PRDX1 was found to be overexpressed in AML, and its expression correlated with poor prognosis and the activation of AML- and cancer-associated pathways. Targeting PRDX1, either through lentiviral short-hairpin RNA-mediated silencing or TH37 treatment, induced apoptosis, reduced colony formation, and impaired the engraftment and growth of AML cells in immunodeficient mouse models. Furthermore, TH37 synergized with conventional chemotherapeutic agent to significantly reduce the viability and colony-forming capacity of AML cells. These findings demonstrate the critical role of PRDX1 in AML pathogenesis and highlight its potential as a key therapeutic target to improve clinical outcomes for AML patients. |
| format | Article |
| id | doaj-art-1583dc14361d496bacb072cc7cc492dd |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-1583dc14361d496bacb072cc7cc492dd2025-08-24T11:54:22ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111210.1038/s41419-025-07831-6Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasisZhenghao Li0Guangci Liu1Ziren Chen2Keming Li3Zhe Yu4Chao He5Xinyu Ying6Danling Huang7Chengtian Tao8Sajid Khan9Yimeng Wang10Fang-Lin Zhang11Huan Li12Yun Chen13Jingfeng Zhou14Li Yu15Thomas J. Kipps16Yongxian Cheng17Suping Zhang18Shenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityDepartment of Hematology, Shenzhen University General HospitalShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityDepartment of Hematology, Shandong Provincial Third Hospital, Shandong UniversityCentral Laboratory, Jiangsu University Affiliated Fourth HospitalDepartment of Clinical Laboratory, Ningbo Medical Centre Lihuili Hospital, Affiliated Hospital of Ningbo UniversityShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversitySchool of Chemistry, Chemistry Engineering and Life Sciences, Wuhan University of TechnologyShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityDepartment of Immunology, Nanjing Medical UniversityShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityDepartment of Hematology, Shenzhen University General HospitalMoores Cancer Center, University of California San DiegoShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityShenzhen University International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Marshall Laboratory of Biomedical Engineering, Institute for Inheritance-Based Innovation of Chinese Medicine, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, School of Basic Medical Sciences, School of Pharmacy, Shenzhen University Medical School, Shenzhen UniversityAbstract Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis and limited therapeutic options. Leukemic stem cells (LSCs), which drive disease progression and confer resistance to therapy, pose a significant challenge to conventional treatment strategies. In this study, we identified and characterized the inhibitory mechanisms of TH37, a small molecule derived from traditional Chinese medicine, which selectively targets AML blasts and LSCs. Our analyses identified peroxiredoxin 1 (PRDX1), an enzyme that catalyzes the breakdown of hydrogen peroxide (a reactive oxygen species), as the primary molecular target of TH37. We demonstrated that TH37 directly interacts with PRDX1, inhibiting its enzymatic activity and thereby elevating intracellular reactive oxygen species levels in AML cells. PRDX1 was found to be overexpressed in AML, and its expression correlated with poor prognosis and the activation of AML- and cancer-associated pathways. Targeting PRDX1, either through lentiviral short-hairpin RNA-mediated silencing or TH37 treatment, induced apoptosis, reduced colony formation, and impaired the engraftment and growth of AML cells in immunodeficient mouse models. Furthermore, TH37 synergized with conventional chemotherapeutic agent to significantly reduce the viability and colony-forming capacity of AML cells. These findings demonstrate the critical role of PRDX1 in AML pathogenesis and highlight its potential as a key therapeutic target to improve clinical outcomes for AML patients.https://doi.org/10.1038/s41419-025-07831-6 |
| spellingShingle | Zhenghao Li Guangci Liu Ziren Chen Keming Li Zhe Yu Chao He Xinyu Ying Danling Huang Chengtian Tao Sajid Khan Yimeng Wang Fang-Lin Zhang Huan Li Yun Chen Jingfeng Zhou Li Yu Thomas J. Kipps Yongxian Cheng Suping Zhang Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis Cell Death and Disease |
| title | Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis |
| title_full | Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis |
| title_fullStr | Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis |
| title_full_unstemmed | Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis |
| title_short | Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis |
| title_sort | targeting prdx1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis |
| url | https://doi.org/10.1038/s41419-025-07831-6 |
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