2. Academic Validation
  3. Beneficial effects of aryl hydrocarbon receptor activation on post-infarction myocardial metabolism, inflammation and fibrosis: implications from multi-omics

Beneficial effects of aryl hydrocarbon receptor activation on post-infarction myocardial metabolism, inflammation and fibrosis: implications from multi-omics

  • J Mol Cell Cardiol. 2025 Oct 21:209:104-118. doi: 10.1016/j.yjmcc.2025.10.006.
Yong Chu 1,  Jiang Zhu 2,  Shuaijie Chen 1,  Xiaoyan Lin 3,  Zhongxing Zhou 1,  Ruming Shen 1,  Hongzhuang Wang 1,  Longqing Chen 1,  Jinxiu Lin 2,  Hailin Zhang 4,  Dajun Chai 5
Affiliations

Affiliations

  • 1 Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Key Laboratory of Metabolic Heart Disease in Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
  • 2 Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Clinical Research Center for Metabolic Heart Disease of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
  • 3 Ultrasonography Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
  • 4 Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Clinical Research Center for Metabolic Heart Disease of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Cardiovascular Department, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China. Electronic address: hailinzhang-fy@fjmu.edu.cn.
  • 5 Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Key Laboratory of Metabolic Heart Disease in Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Clinical Research Center for Metabolic Heart Disease of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Cardiovascular Department, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China. Electronic address: dajunchai-fy@fjmu.edu.cn.
PMID: 41130496 DOI: 10.1016/j.yjmcc.2025.10.006
Abstract

Background: Post-infarction metabolism changes, inflammatory responses, and fibrosis are crucial contributors to adverse cardiac remodeling. 2-(1'H-indole-3'‑carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), the Aryl Hydrocarbon Receptor (AHR) ligand, has demonstrated effective AHR activation, yet its impact and mechanisms in myocardial infarction (MI) remain unclear.

Methods: The MI model was established by ligating left anterior coronary artery, and ITE was administered for 4 weeks. Echocardiography and hemodynamic monitoring were used to assess cardiac structure and function. Hematoxylin-eosin and Masson's trichrome were used to examine morphology and Collagen deposition. Transmission electron microscopy was employed to examine mitochondrial morphology. The transcriptome and metabolome were used to screen for key targets and pathways. Hypoxic neonatal rat cardiomyocytes and fibroblasts models combined with adenoviral AHR knockdown were used to verify key targets and pathways.

Results: ITE intervention significantly improved cardiac structure and function, mitochondrial morphology, fibrosis and inflammation in MI rats. Multi-omics revealed that differentially expressed genes and metabolites were enriched in glucose metabolism related pathways and identified a key target, HK2. Compared to MI group, ITE significantly improved the expression of key Enzymes in glucose metabolism after MI. In vitro, AHR activation by ITE and tapinarof significantly ameliorated hypoxia-induced abnormalities in HK2, CISY, OGDH, fibrosis, and inflammatory markers, while Hexokinase Inhibitor eliminated the beneficial effects of ITE. Moreover, AHR knockdown impairs glucose metabolism and promotes inflammation and fibrosis.

Conclusion: The AHR activation by ITE mitigates inflammation and fibrosis, improves cardiac structure and function by promoting HK2 and glucose metabolism after MI.

Keywords

Aryl hydrocarbon receptor agonist; Fibrosis; Glucose metabolism; Inflammatory response; Multi-omics analysis; Myocardial infarction.

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