Restoration of cyclin A2 by glabridin reverses pathological cell cycle arrest and drives cardiac repair in HFpEF.

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a pervasive clinical syndrome characterized by complex and elusive pathogenic mechanisms. In this study, we identify aberrant cardiomyocyte cell cycle arrest as a previously unrecognized pathological driver of HFpEF that hinders tissue repair. Using in vivo and in vitro models, we further demonstrate that Glabridin (Gla), a bioactive isoflavone, can induce cardiac repair and alleviate myocardial hypertrophy and fibrosis in HFpEF by targeting the cell cycle arrest pathway. Mechanistically, Gla exerts its protective effects by specifically inhibiting the degradation of Cyclin A2 (CCNA2) and mitigating cardiomyocyte oxidative damage. This stabilization of CCNA2 effectively abrogates cell cycle arrest and drives cardiomyocyte cell cycle re-entry, an effect that was successfully recapitulated by CCNA2 gain-of-function experiments. This reparative response is intrinsically coupled with the restoration of metabolic homeostasis and the attenuation of oxidative stress, as evidenced in both cardiac and hepatic cells. Collectively, our findings define cell cycle arrest as a novel target and position Gla as a potent inducer of CCNA2-mediated cardiac repair for HFpEF treatment.