2. Academic Validation
  3. Kynurenic Acid/GPR35 Signaling Protects the Infarcted Heart by Suppressing Macrophage mtDNA-Triggered cGAS-STING Activation

Kynurenic Acid/GPR35 Signaling Protects the Infarcted Heart by Suppressing Macrophage mtDNA-Triggered cGAS-STING Activation

  • Antioxidants (Basel). 2026 Feb 27;15(3):300. doi: 10.3390/antiox15030300.
Yuyuan Mao 1 2 3,  Jiao Jiao 1 2 3,  Xinyu Zhu 1 2 3,  Wenhu Liu 1 2 3,  Shujie He 1 2 3,  Nana Li 1 2 3,  Haoyi Yang 1 2 3,  Jingyong Li 1 2 3,  Tingting Tang 1 2 3,  Ni Xia 1 2 3,  Xiang Cheng 1 2 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2 Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 3 Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
PMID: 41897447 DOI: 10.3390/antiox15030300
Abstract

Kynurenic acid (KynA), a tryptophan metabolite that regulates immune homeostasis via G protein-coupled receptor 35 (GPR35), has an undefined role in post-myocardial infarction (MI) immune responses. To clarify this role, we established a murine MI model and administered KynA intraperitoneally to evaluate cardiac function and ventricular remodeling. Macrophage infiltration was assessed, and macrophages were depleted via clodronate liposomes to confirm their contribution to KynA-mediated cardioprotection. In bone marrow-derived macrophages (BMDMs), GPR35-targeted siRNA verified the receptor-dependent action of KynA. KynA improved cardiac function, reduced infarct scarring and fibrosis, and suppressed pro-inflammatory macrophage infiltration in MI mice, with these cardioprotective effects abrogated by macrophage depletion. Mechanistically, KynA inhibited voltage-dependent anion channel 1 oligomerization, prevented mitochondrial DNA leakage, and downregulated the cGAS/STING/TBK1/IκBα/P65 pathway in macrophages, while exogenous mitochondrial DNA counteracted this inhibition. Collectively, the KynA/GPR35 axis exerts cardioprotective effects against MI by attenuating macrophage pro-inflammatory responses, highlighting its potential as a novel therapeutic target.

Keywords

GPR35; STING; cGAS; kynurenic acid; macrophage; myocardial infarction.

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