Xuefu Zhuyu decoction attenuates thoracic aortic dissection by regulating VSMC phenotypic switching and oxidative stress via the JAK2/STAT3/HIF-1α pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xuefu Zhuyu Decoction (XFZY), a classic formula for "blood stasis syndrome", has insufficient evidence for its thoracic aortic dissection (TAD) therapeutic efficacy and its underlying mechanism remains unclear.

AIM OF STUDY: This study aimed to elucidate the efficacy, mechanism, and key components of XFZY against TAD.

MATERIAL AND METHOD: Using a β-Aminopropionitrile (BAPN)-induced TAD mouse model, efficacy was assessed via survival, ultrasonography, and histology. Mechanisms were explored via integrated UPLC-Q-TOF-MS, clinical proteomics, bioinformatics, and molecular docking, with validation by western blotting and immunofluorescence.

RESULTS

In TAD mice, XFZY exerted significant therapeutic effects, as evidenced by reduced mortality (mortality: 40.0% in TAD vs. 13.3% in high-dose group), attenuated aortic dilation (maximum diameter: 1.49 ± 0.08 mm in TAD vs. 1.10 ± 0.04 mm in high-dose group), ameliorated histopathological changes, restored VSMC contractile phenotype, and mitigated oxidative stress. Proteomic analyses identified 339 dysregulated proteins, and pinpointed JAK2/STAT3/HIF-1α axis as core regulatory axis. XFZY dose-dependently inhibited JAK2/STAT3 activation and HIF-1α expression. Molecular docking identified Naringin, Kaempferol, Glycyrrhizic acid, and Saikosaponins A/D as key components, with anti-TAD efficacy confirmed in vivo.

CONCLUSION

XFZY attenuated aortic tissue remodeling and improved the survival rate in TAD mice. This therapeutic effect was achieved by rescuing the VSMC contractile phenotype (inhibition of the JAK2/STAT3 pathway) and alleviating oxidative stress (downregulation of HIF-1α expression). Naringin, Kaempferol, Glycyrrhizic acid, and Saikosaponins A/D were identified as key components and exhibit effects similar to those of the XFZY extract. These findings establish a solid experimental basis for its clinical application.