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

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.