2. Academic Validation
  3. The total xanthones from Gentianella acuta alleviate acute myocardial infarction by targeting BRD4-mediated cardiomyocyte pyroptosis and inflammation

The total xanthones from Gentianella acuta alleviate acute myocardial infarction by targeting BRD4-mediated cardiomyocyte pyroptosis and inflammation

  • Phytomedicine. 2025 Aug 13:147:157156. doi: 10.1016/j.phymed.2025.157156.
Cheng Dai 1,  Jiahuan Sun 2,  Gaoshan Yang 2,  Chuang Zhang 1,  Yajing Zhang 3,  Qiuhang Song 1,  Xingchao Liu 4,  Xuhong Duan 5,  Hongxia Yang 6,  Aiying Li 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China.
  • 2 Department of Biochemistry and Molecular Biology, College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China; Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, 050091, Hebei, China; Hebei Higher Education Institute Applied Technology Research Center of TCM Development and Industrialization, Shijiazhuang, 050091, Hebei, China.
  • 3 College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China.
  • 4 Hebei Higher Education Institute Applied Technology Research Center of TCM Development and Industrialization, Shijiazhuang, 050091, Hebei, China; College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China.
  • 5 College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China. Electronic address: duanxuhong@hebcm.edu.cn.
  • 6 Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, 050091, Hebei, China; Hebei Higher Education Institute Applied Technology Research Center of TCM Development and Industrialization, Shijiazhuang, 050091, Hebei, China; Department of Epidemic Febrile Disease, College of Traditional Chinese Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China. Electronic address: yanghongxia@hebcm.edu.cn.
  • 7 Department of Biochemistry and Molecular Biology, College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China; Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Shijiazhuang, 050091, Hebei, China; Hebei Higher Education Institute Applied Technology Research Center of TCM Development and Industrialization, Shijiazhuang, 050091, Hebei, China. Electronic address: aiyingli1963@163.com.
PMID: 40845590 DOI: 10.1016/j.phymed.2025.157156
Abstract

Background: Gentianella acuta (G. acuta), a traditional remedy for cardiovascular ailments among the Ewenki people of China, has been reported to contain Xanthones as its primary bioactive components. However, the complete chemical composition of G. acuta's total Xanthones (TXG) and their therapeutic targets in the treatment of acute myocardial infarction (AMI) remain inadequately characterized.

Purpose: This study aims to investigate the chemical composition of TXG and identify its therapeutic targets in AMI, focusing on its role and mechanism in the suppression of pyroptosis-mediated inflammatory myocardial injury.

Methods and results: UPLC-Q/TOF-MS/MS analysis revealed 29 constituents in TXG, including Xanthones, Flavonoids, Lignans, Iridoids, and Coumarins. And 7 compounds (including 4 Xanthones) in TXG can be absorbed into the blood. Xanthones, which constituted 68.1% of TXG's total content as determined by high-performance liquid chromatography (HPLC), were the predominant compounds. Key Xanthones identified included swertianolin, norswertianolin, bellidifolin, demethylbellidifolin, and mangiferin. Network pharmacology analysis, supported by qRT-PCR, molecular docking, and surface plasmon resonance (SPR) experimental validation, revealed that TXG's anti-AMI effects are linked to the modulation of inflammatory responses. Key therapeutic targets identified include TLR4, NF-κB, and NLRP3, along with their associated signaling pathways. In vivo and in vitro experiments confirmed that TXG reduced BRD4 expression, thereby inhibiting TLR4/NF-κB/NLRP3 signaling. This inhibition attenuated cardiomyocyte Pyroptosis and inflammation, reduced infarct size, and improved functional and pathological outcomes in AMI.

Conclusions: This study demonstrates that Xanthones, the major constituents of G. acuta, are absorbed into the bloodstream and exert their therapeutic effects by inhibiting pyroptosis-mediated cardiac inflammation. The underlying mechanism involves multi-target inhibition of the BRD4/TLR4/NF-κB/NLRP3 pathway, underscoring the potential of G. acuta in AMI treatment.

Keywords

AMI; BRD4/TLR4/NF-κB/NLRP3 signaling; Network pharmacology; TXG; UPLC-Q/TOF-MS/MS and HPLC; cardiomyocyte pyroptosis.

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