Formononetin relieves chronic stress-related neointimal hyperplasia in mice by regulating HDAC6.

Authors

Shanqian Li, Wanhua Wu, Chaozhi Xu, Yue Huang, Guixian Wu, Hongyu Ding, Zongyi Zhang, Yulin Zhang, Meimei Zheng, Hongxian Wu, Lina Hu

Published in

Frontiers in cardiovascular medicine. Volume 13. Pages 1865656. Epub Oct 07, 2026.

Abstract

Chronic stress severely impairs physical and mental health and is a critical risk factor for cardiovascular diseases. Formononetin (FMN) has shown promising cardiovascular protective effects, yet its functional role and molecular mechanism in chronic stress-triggered arterial neointimal hyperplasia and concomitant mood disturbances remain poorly elucidated.
Network pharmacology was used to predict the underlying mechanisms of FMN against cardiovascular disease-depression comorbidity. A dual mouse model recapitulating chronic stress and carotid artery injury was established for in vivo validation. Histological staining, behavioral tests, Western blotting, β-galactosidase staining, and in vitro VSMC assays were performed to assess the effects of FMN and the HDAC6 inhibitor TubA.
Network pharmacology identified 111 overlapping targets, with functional enrichment and molecular docking revealing that FMN primarily regulates inflammation, apoptosis, and autophagy via binding to core hub proteins including HDAC6, Bcl-2, and AKT1. In vivo, chronic stress aggravated arterial intimal hyperplasia and aortic senescence, and induced anxiety- and depression-like behaviors. FMN treatment notably improved emotional disorders, reduced HDAC6 expression, activated autophagy (increased LC3B/A ratio), inhibited apoptosis (elevated Bcl-2/Bax ratio), attenuated NLRP3 and IL-6 expression, and alleviated intimal thickening. The HDAC6 inhibitor TubA recapitulated the vascular protective effects of FMN.
FMN attenuates chronic stress-induced vascular injury and emotional dysfunction via suppressing HDAC6 signaling to restore autophagy, inhibit inflammation, and reduce apoptosis. This study unveils the dual cardio-neuroprotective capacities of FMN and provides novel mechanistic insights for the treatment of chronic stress-related cardiocerebral comorbidities.

PMID:
42908797
Bibliographic data and abstract were imported from PubMed on 23 Oct 2026.

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