Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis
Abstract Acute thymic involution (ATI) is frequently observed during sepsis, however the underlying mechanisms remain poorly understood. This study demonstrates that ferroptosis plays a crucial role in sepsis-associated ATI. We found that pediatric sepsis patients showed significantly elevated kynur...
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| Format: | Article |
| Language: | English |
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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/s41419-025-07882-9 |
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| author | Zimei Cheng Kexin Wang Yixue Wang Tingyan Liu Jingjing Li Yaodong Wang Weiming Chen Reyihangu Awuti Hetian Zhou Wenjia Tong Zhenhao Yu Yao Wang Guoyun Su Weiguo Yang Yufeng Zhou Guoping Lu Caiyan Zhang |
| author_facet | Zimei Cheng Kexin Wang Yixue Wang Tingyan Liu Jingjing Li Yaodong Wang Weiming Chen Reyihangu Awuti Hetian Zhou Wenjia Tong Zhenhao Yu Yao Wang Guoyun Su Weiguo Yang Yufeng Zhou Guoping Lu Caiyan Zhang |
| author_sort | Zimei Cheng |
| collection | DOAJ |
| description | Abstract Acute thymic involution (ATI) is frequently observed during sepsis, however the underlying mechanisms remain poorly understood. This study demonstrates that ferroptosis plays a crucial role in sepsis-associated ATI. We found that pediatric sepsis patients showed significantly elevated kynurenine (Kyn)/tryptophan (Trp) ratios, indicating increased indoleamine 2,3-dioxygenase 1 (IDO1) activity, along with higher Kyn levels compared to controls. Moreover, Kyn levels were negatively correlated with thymus-to-thorax ratio. Further mechanistic analysis revealed that the enhanced expression of IDO1, induced by inflammatory signals, drives the accumulation of Kyn and subsequent activation of the aryl hydrocarbon receptor (AhR), triggering lipid oxidation-related gene transcription and ferroptosis in thymocytes during sepsis. Treatment with 1-methyltryptophan (IDO1 inhibitor) effectively restore thymic function and improve survival in septic mice. Our findings reveal a novel role for the IDO1/Kyn/AhR pathway in ferroptosis, suggesting that targeting this pathway may offer a promising therapeutic strategy for sepsis. Created with BioRender ( https://app.biorender.com/ ). |
| format | Article |
| id | doaj-art-61a3b9314fc04d54be75f714e0c463d3 |
| 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-61a3b9314fc04d54be75f714e0c463d32025-08-20T04:02:44ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111410.1038/s41419-025-07882-9Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsisZimei Cheng0Kexin Wang1Yixue Wang2Tingyan Liu3Jingjing Li4Yaodong Wang5Weiming Chen6Reyihangu Awuti7Hetian Zhou8Wenjia Tong9Zhenhao Yu10Yao Wang11Guoyun Su12Weiguo Yang13Yufeng Zhou14Guoping Lu15Caiyan Zhang16Department of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Pediatric Critical Care Unit, Anhui Provincial Children’s HospitalDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityCenter for Molecular Medicine, Children’s Hospital of Fudan University, National Children’s Medical CenterPediatric Intensive Care Unit, Shenzhen Children’s HospitalPediatric Intensive Care Unit, Shenzhen Children’s HospitalDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityDepartment of Emergency and Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai Institute of Infectious Disease and Biosecurity, and Institutes of Biomedical Sciences Fudan UniversityAbstract Acute thymic involution (ATI) is frequently observed during sepsis, however the underlying mechanisms remain poorly understood. This study demonstrates that ferroptosis plays a crucial role in sepsis-associated ATI. We found that pediatric sepsis patients showed significantly elevated kynurenine (Kyn)/tryptophan (Trp) ratios, indicating increased indoleamine 2,3-dioxygenase 1 (IDO1) activity, along with higher Kyn levels compared to controls. Moreover, Kyn levels were negatively correlated with thymus-to-thorax ratio. Further mechanistic analysis revealed that the enhanced expression of IDO1, induced by inflammatory signals, drives the accumulation of Kyn and subsequent activation of the aryl hydrocarbon receptor (AhR), triggering lipid oxidation-related gene transcription and ferroptosis in thymocytes during sepsis. Treatment with 1-methyltryptophan (IDO1 inhibitor) effectively restore thymic function and improve survival in septic mice. Our findings reveal a novel role for the IDO1/Kyn/AhR pathway in ferroptosis, suggesting that targeting this pathway may offer a promising therapeutic strategy for sepsis. Created with BioRender ( https://app.biorender.com/ ).https://doi.org/10.1038/s41419-025-07882-9 |
| spellingShingle | Zimei Cheng Kexin Wang Yixue Wang Tingyan Liu Jingjing Li Yaodong Wang Weiming Chen Reyihangu Awuti Hetian Zhou Wenjia Tong Zhenhao Yu Yao Wang Guoyun Su Weiguo Yang Yufeng Zhou Guoping Lu Caiyan Zhang Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis Cell Death and Disease |
| title | Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis |
| title_full | Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis |
| title_fullStr | Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis |
| title_full_unstemmed | Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis |
| title_short | Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis |
| title_sort | ferroptosis mediated by the ido1 kyn ahr pathway triggers acute thymic involution in sepsis |
| url | https://doi.org/10.1038/s41419-025-07882-9 |
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