Integrated transcriptome and metabolome analysis reveals the therapeutic mechanism of Huang-Qi-Si-Wu-Tang in experimental pulmonary arterial hypertension

Ye Wang; Zhuangjie Guo; Xinqi Ma; Qing Xu; Dandan Li; Jie Yang; Xiaoxuan Lu; Peiran Yang; Hongchun Zhang; Hongmei Zhao; Chen Wang

doi:10.1016/j.phymed.2025.157058

Integrated transcriptome and metabolome analysis reveals the therapeutic mechanism of Huang-Qi-Si-Wu-Tang in experimental pulmonary arterial hypertension

Phytomedicine. 2025 Jul 7:145:157058. doi: 10.1016/j.phymed.2025.157058. Online ahead of print.

Authors

Ye Wang¹, Zhuangjie Guo², Xinqi Ma³, Qing Xu³, Dandan Li⁴, Jie Yang², Xiaoxuan Lu², Peiran Yang⁵, Hongchun Zhang⁶, Hongmei Zhao⁷, Chen Wang⁸

Affiliations

¹ China-Japan Friendship Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100029, China.
² State Key Laboratory of Respiratory Health and Multimorbidity, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
³ Core Facilities Centre, Capital Medical University, Beijing 100069, China.
⁴ Department of Respiratory and Critical Care Medicine,Children's Hospital Hebei Province, Hebei 050031, China.
⁵ State Key Laboratory of Respiratory Health and Multimorbidity, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China. Electronic address: peiran.yang@foxmail.com.
⁶ National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address: 13701226664@139.com.
⁷ National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address: Lucy0500@163.com.
⁸ State Key Laboratory of Respiratory Health and Multimorbidity, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China; National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address: wangchen@pumc.edu.c.

PMID: 40651300
DOI: 10.1016/j.phymed.2025.157058

Abstract

Background: Pulmonary arterial hypertension is a complex vascular disease involving pathological remodeling of vascular cells, inflammatory cells, and the extracellular matrix. Current PAH therapies, which are primarily vasodilators, cannot reverse the disease pathogenesis or cure PAH. Novel therapeutic agents targeting the core process of vascular remodeling are desperately needed, and their mechanisms warrant systematic investigation.

Purpose: This study aimed to investigate the therapeutic potential of Huang-Qi-Si-Wu-Tang (HQSWT), a traditional Chinese herbal formula, in experimental models of PAH and to elucidate its underlying mechanisms.

Methods: We used monocrotaline-induced PAH in rats as an experimental model. We assessed the effect of HQSWT on disease prevention, as well as its effect in mitigating established disease. We employed RNA sequencing, integrated metabolomics and transcriptomics analysis, and validated findings by multiplex immunohistochemistry and quantitative PCR.

Results: HQSWT dose-dependently prevented monocrotaline-induced PAH development and mitigated established PAH, right ventricular hypertrophy, and pulmonary vascular remodeling. Transcriptomic analysis revealed HQSWT's action on extracellular matrix pathways, including Fn1 and Thbs2. Furthermore, we observed modulation of arachidonic acid metabolism via the ALOX5-LTB₄ axis. HQSWT reduced ALOX5 expression in lung tissue and perivascular macrophages.

Conclusion: Our results demonstrate that HQSWT is effective in treating experimental PAH. Through omics analysis, we have identified a novel mechanism of action whereby HQSWT may exert its protective effects by simultaneously targeting the extracellular matrix and inflammation-mediated pulmonary vascular remodeling, suggesting its potential as a new therapy for PAH.

Keywords: Multi-target therapy; Pulmonary arterial hypertension; Traditional Chinese medicine formula; Vascular remodeling.