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Kynurenic Acid/GPR35 Signaling Protects the Infarcted Heart by Suppressing Macrophage mtDNA-Triggered cGAS-STING
Yuyuan Mao1,2,3, Jiao Jiao1,2,3, Xinyu Zhu1,2,3
1Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Antioxidants (Basel, Switzerland)
|March 28, 2026
Summary
Kynurenic acid (KynA) protects the heart after myocardial infarction (MI) by reducing inflammation. This tryptophan metabolite targets G protein-coupled receptor 35 (GPR35) on macrophages, offering a potential new therapy for heart attack recovery.
Area of Science:
- Immunology
- Cardiology
- Metabolism
Background:
- Kynurenic acid (KynA), a tryptophan metabolite, modulates immune responses via G protein-coupled receptor 35 (GPR35).
- Its specific role in post-myocardial infarction (MI) cardiac immunity remains unclear.
Purpose of the Study:
- To investigate the cardioprotective effects of KynA in a murine MI model.
- To elucidate the underlying mechanisms involving macrophage response and GPR35 signaling.
Main Methods:
- Established a murine MI model and administered KynA.
- Assessed cardiac function, ventricular remodeling, and macrophage infiltration.
- Utilized macrophage depletion and GPR35-targeted siRNA for mechanistic studies.
- Investigated mitochondrial pathways and inflammatory signaling in macrophages.
Main Results:
- KynA administration improved cardiac function and reduced infarct size and fibrosis post-MI.
- KynA suppressed pro-inflammatory macrophage infiltration, a protective effect abolished by macrophage depletion.
- Mechanistically, KynA inhibited mitochondrial DNA release and downregulated the cGAS/STING pathway in macrophages.
Conclusions:
- The KynA/GPR35 axis confers cardioprotection following MI by mitigating pro-inflammatory macrophage responses.
- KynA presents a promising therapeutic target for managing cardiac injury after myocardial infarction.
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