2. Academic Validation
  3. Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis

Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis

  • Cell Death Dis. 2025 Jul 25;16(1):562. doi: 10.1038/s41419-025-07882-9.
Zimei Cheng # 1 2,  Kexin Wang # 1 2,  Yixue Wang # 1,  Tingyan Liu 1,  Jingjing Li 1,  Yaodong Wang 1,  Weiming Chen 1,  Reyihangu Awuti 1,  Hetian Zhou 1,  Wenjia Tong 3,  Zhenhao Yu 1,  Yao Wang 4,  Guoyun Su 5,  Weiguo Yang 5,  Yufeng Zhou 6 7 8,  Guoping Lu 9 10 11,  Caiyan Zhang 12 13
Affiliations

Affiliations

  • 1 Department 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 University, 200032, Shanghai, China.
  • 2 National Health Commission Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
  • 3 Department of Pediatric Critical Care Unit, Anhui Provincial Children's Hospital, Hefei, China.
  • 4 Center for Molecular Medicine, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
  • 5 Pediatric Intensive Care Unit, Shenzhen Children's Hospital, Shenzhen, China.
  • 6 Department 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 University, 200032, Shanghai, China. yfzhou1@fudan.edu.cn.
  • 7 National Health Commission Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China. yfzhou1@fudan.edu.cn.
  • 8 Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital (Children's Hospital of Fudan University at Xiamen), Xiamen, China. yfzhou1@fudan.edu.cn.
  • 9 Department 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 University, 200032, Shanghai, China. lgp@fudan.edu.cn.
  • 10 National Health Commission Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China. lgp@fudan.edu.cn.
  • 11 Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital (Children's Hospital of Fudan University at Xiamen), Xiamen, China. lgp@fudan.edu.cn.
  • 12 Department 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 University, 200032, Shanghai, China. zhangcy17@fudan.edu.cn.
  • 13 National Health Commission Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China. zhangcy17@fudan.edu.cn.
  • # Contributed equally.
PMID: 40715082 DOI: 10.1038/s41419-025-07882-9
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/ ).

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