2. Academic Validation
  3. L-Kynurenine regulates immune response in ICIs-associated myocarditis via JAK/STAT pathway

L-Kynurenine regulates immune response in ICIs-associated myocarditis via JAK/STAT pathway

  • Int Immunopharmacol. 2025 May 27:156:114676. doi: 10.1016/j.intimp.2025.114676.
Xiaozhen He 1,  Jian Zhang 1,  Yerui Zhang 1,  Huishan Li 2,  Yifan Chen 1,  Hui Zhang 1,  Jianan Pan 1,  Yan Zhou 3,  Shilong Zhang 4,  Leilei Cheng 5
Affiliations

Affiliations

  • 1 Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, China.
  • 2 Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: slzhang15@fudan.edu.cn.
  • 5 Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, China. Electronic address: cheng.leilei@zs-hospital.sh.cn.
PMID: 40267722 DOI: 10.1016/j.intimp.2025.114676
Abstract

Background: Immune checkpoint inhibitor associated myocarditis (ICIAM) is a drug-induced myocarditis characterized by the infiltration of immune cells into cardiac. However, the mechanisms are unknown and effective drug therapies are lacking in clinical practice. This study aims to explore the relationship between plasma metabolites and the treatment of ICIAM.

Methods: Human plasma metabolites were analyzed using untargeted metabolomics for characteristic metabolites. For in vivo experiments, Male Balb/c mice were divided into six groups: PBS, L-Kynurenine, cTNI+PD-1 inhibitor (ICIs), ICIs+L-Kynurenine, ICIs+RO8191, ICIs+RO8191+L-Kynurenine. On day 21 post-modeling, echocardiography, ELISA and histopathology were employed to evaluate the therapeutic effect of L-Kynurenine. Flow cytometry was used to determine the proportion of immune cells in the heart and spleen. Bulk-RNAseq was conducted to analyze differential genes, and q-PCR, immunofluorescence and western blot were performed for validation experiments.

Results: Untargeted metabolomics verified that indoleamine 2,3 dioxygenase-1 (IDO1)-derived L-Kynurenine level was higher in the serum of ICIAM compared to non-ICIAM patients. Meanwhile, in vitro and in vivo experiments showed that L-Kynurenine exhibited a therapeutic ability in ICIAM by inhibiting the pro-inflammatory polarization of immune cells and the secretion of pro-inflammatory cytokines. Mechanistically, L-Kynurenine improved cardiac functions majorly by the inhibition of the JAK1/STAT3 signaling pathway.

Conclusion: L-Kynurenine exhibits significant therapeutic potential in ICIAM. The multi-roles of L-Kynurenine in regulating immune responses make it possible to be used as a targeted drug for ICIAM therapy.

Keywords

ICIs-associated myocarditis; Immune checkpoint inhibitors; JAK/STAT pathway; L-Kynurenine; Macrophage polarization.

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