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已发表论文
西黄丸通过调控缺氧诱导因子-1信号通路对免疫检查点抑制剂相关性心肌炎小鼠模型的保护作用
Authors Cao B, Xie H, Xu J, Yu N, Man Z, Zhao W, Li G, Li C, Han L
Received 10 March 2025
Accepted for publication 21 August 2025
Published 7 November 2025 Volume 2025:18 Pages 15511—15525
DOI https://doi.org/10.2147/JIR.S527372
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Durga Prasanna Misra
Bo Cao,1,* Huijuan Xie,1,* Jing Xu,2 Nuoxian Yu,3 Zhuo Man,4 Wenwen Zhao,4 Guohui Li,2 Chunyu Li,2 Li Han1
1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China; 2National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 3Department of Pharmacy, The First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 4SCIEX China, Beijing, 100015, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Chunyu Li; Li Han, Email licy@cicams.ac.cn; hanliyx@163.com
Background: Immune checkpoint inhibitor (ICIs)-associated cardiotoxicity is a significant cause of immune-related adverse events and mortality in cancer immunotherapy, lacking effective preventative or therapeutic strategies. Xihuang Pill (XHW), a traditional Chinese medicine with established anti-inflammatory properties and clinical use in cancer treatment and adverse event mitigation, merits investigation for its efficacy against ICIs-induced cardiac toxicity.
Purpose: To investigate XHW’s therapeutic effects on Immune checkpoint inhibitors (ICIs)-associated cardiotoxicity and its underlying mechanisms.
Methods: This study utilized mass spectrometry technology to identify the chemical components in XHW. The experimental model for ICIs-associated myocarditis was generated in BALB/c mice by immunizing them with murine cardiac troponin I (cTnI) peptide and administering anti-programmed death 1 (PD-1) antibodies to mice. Mice received varying XHW dosages (0.39, 0.78, and 1.56 mg/kg). Myocardial contractility and plasma cardiac injury markers (CK, CK-MB) were assessed. Metabolomics and transcriptomics identified key signaling pathways modulated by XHW, validated via real-time quantitative PCR (QT-PCR). In addition, a correlation analysis was conducted between key genes and differential metabolites.
Results: Mass spectrometry identified 171 components in XHW. Pharmacological studies demonstrated that XHW improved cardiac contractility, reduced plasma cardiac injury biomarkers, and attenuated myocardial injury in the myocarditis model. Integrated metabolomic and transcriptomic analyses revealed that XHW primarily modulates the HIF-1 signaling pathway, significantly upregulating HIF-1 mRNA expression and downregulating the mRNA expression of Nppa, Angpt1, Angpt2, and Trf. Correlation analysis identified significant associations between 16 metabolites, including 13-tetradecynoic acid, 1-pentadecanoylglycerol, and arginyl-glycyl-aspartic acid, and these genes.
Conclusion: These findings suggest that XHW may alleviate ICIs-associated myocarditis via HIF-1 signaling pathway, offering a promising therapeutic approach for ICIs-related cardiotoxicity.
Keywords: Xihuang pill, immune checkpoint inhibitors, cardiotoxicity, metabolomics, transcriptomic
1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China; 2National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 3Department of Pharmacy, The First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 4SCIEX China, Beijing, 100015, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Chunyu Li; Li Han, Email licy@cicams.ac.cn; hanliyx@163.com
Background: Immune checkpoint inhibitor (ICIs)-associated cardiotoxicity is a significant cause of immune-related adverse events and mortality in cancer immunotherapy, lacking effective preventative or therapeutic strategies. Xihuang Pill (XHW), a traditional Chinese medicine with established anti-inflammatory properties and clinical use in cancer treatment and adverse event mitigation, merits investigation for its efficacy against ICIs-induced cardiac toxicity.
Purpose: To investigate XHW’s therapeutic effects on Immune checkpoint inhibitors (ICIs)-associated cardiotoxicity and its underlying mechanisms.
Methods: This study utilized mass spectrometry technology to identify the chemical components in XHW. The experimental model for ICIs-associated myocarditis was generated in BALB/c mice by immunizing them with murine cardiac troponin I (cTnI) peptide and administering anti-programmed death 1 (PD-1) antibodies to mice. Mice received varying XHW dosages (0.39, 0.78, and 1.56 mg/kg). Myocardial contractility and plasma cardiac injury markers (CK, CK-MB) were assessed. Metabolomics and transcriptomics identified key signaling pathways modulated by XHW, validated via real-time quantitative PCR (QT-PCR). In addition, a correlation analysis was conducted between key genes and differential metabolites.
Results: Mass spectrometry identified 171 components in XHW. Pharmacological studies demonstrated that XHW improved cardiac contractility, reduced plasma cardiac injury biomarkers, and attenuated myocardial injury in the myocarditis model. Integrated metabolomic and transcriptomic analyses revealed that XHW primarily modulates the HIF-1 signaling pathway, significantly upregulating HIF-1 mRNA expression and downregulating the mRNA expression of Nppa, Angpt1, Angpt2, and Trf. Correlation analysis identified significant associations between 16 metabolites, including 13-tetradecynoic acid, 1-pentadecanoylglycerol, and arginyl-glycyl-aspartic acid, and these genes.
Conclusion: These findings suggest that XHW may alleviate ICIs-associated myocarditis via HIF-1 signaling pathway, offering a promising therapeutic approach for ICIs-related cardiotoxicity.
Keywords: Xihuang pill, immune checkpoint inhibitors, cardiotoxicity, metabolomics, transcriptomic