Buyang Huanwu Decoction attenuates vascular aging by suppressing the pathway of neutrophil extracellular trap formation via modulation of the HMGB1/TLR4/p38 signaling pathway

  • J Ethnopharmacol. 2026 May 10:362:121315. doi: 10.1016/j.jep.2026.121315.
Nan Xiao  1 ,  Jinsong Gao  2 ,  Yutong Yang  1 ,  Chenghui Li  3 ,  Xuejuan Shen  4 ,  Xiangyu Chen  1 ,  Xiaodie Chen  1 ,  Yanbin Pan  3 ,  Huiqun Huang  3 ,  Simin Yang  5 ,  Shuting Zeng  5 ,  Xiaodong Duan  5 ,  Yongan Deng  5 ,  Chengkai Chen  5 ,  Yixuan Huang  5 ,  Danping Huang  6 ,  Zunpeng Shu  7 ,  Li Zhang  8
Affiliations
  • 1. Cardiology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, Guangdong, 519087, China.
  • 2. Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China.
  • 3. Cardiology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, China.
  • 4. Nephrology and Rheumatology Department, The Affiliated TCM Hospital of Guangzhou Medical University, The Affiliated Guangzhou Hospital of TCM of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510630, China.
  • 5. Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, Guangdong, 519087, China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China.
  • 6. Department of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, China.
  • 7. Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, Guangdong, 519087, China. Electronic address: [email protected].
  • 8. Cardiology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, China. Electronic address: [email protected].
PMID: 41655726 DOI: 10.1016/j.jep.2026.121315
Abstract

Ethnopharmacological relevance: Vascular aging is a significant driver of age-related cardiovascular diseases, in which the immune-inflammatory response driven by excessive formation of neutrophil extracellular traps (NETs) is a core process accelerating this progression. Buyang Huanwu Decoction (BHD) is a classic traditional Chinese medicine (TCM) formula widely used for treating cardio-cerebrovascular diseases, but whether it acts through modulating NET-driven vascular aging is unknown.

Aim of the study: This study aims to investigate the mechanism by which BHD delays vascular aging, focusing on the NETs formation pathway.

Materials and methods: Based on a D-galactose-induced aging mouse model, this study focused on neutrophils and combined transcriptomics, network pharmacology and Molecular Biology methods to explore the mechanism of BHD in delaying vascular aging.

Results: The present study identified 23 major chemical constituents in BHD and demonstrated its efficacy in ameliorating aging phenotypes in a D-galactose-induced aging mouse model. BHD treatment significantly alleviated aortic structural degeneration, reduced oxidative stress and inflammatory cytokine levels, and downregulated key senescence markers including p16 and p21. Integrated multi-omics analysis implicated NET suppression as a primary mechanism underlying the Anti-aging benefits of BHD. Both in vivo and in vitro experiments confirmed that BHD inhibits NETosis by modulating the HMGB1/TLR4/p38 signaling pathway, leading to reduced expression of critical NET components. Notably, HMGB1 overexpression partially reversed the inhibitory effects of BHD on NETosis, establishing HMGB1 as a key effector molecule.

Conclusion: For the first time, our findings unveil a novel mechanism whereby BHD alleviates vascular aging by modulating the immune microenvironment through inhibition of the HMGB1-TLR4-p38-NETs cascade. These findings provide a novel immunomodulatory perspective on BHD and highlight its potential as a holistic therapeutic strategy against vascular aging.

Keywords
Buyang Huanwu decoction; HMGB1/TLR4/p38 signaling pathway; Neutrophil extracellular traps (NETs); Vascular senescence.
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