Front Cardiovasc Med. 2026 Oct 7;13:1865656. doi: 10.3389/fcvm.2026.1865656. eCollection 2026.
ABSTRACT
INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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.
DISCUSSION: 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 | PMC:PMC13683145 | DOI:10.3389/fcvm.2026.1865656