Butein Attenuates Cardiac Hypertrophy by Restoring Redox–Mitochondrial Homeostasis Through Nrf2–Sirt3 Signaling

ABSTRACT

Butein (3,4,2′,4′‐tetrahydroxychalcone) is a bioactive chalcone with antioxidant, anti‐inflammatory, and cytoprotective properties. However, its effects on pathological cardiac hypertrophy and the underlying molecular mechanisms remain unclear. In this study, neonatal rat ventricular cardiomyocytes stimulated with phenylephrine and mouse models of transverse aortic constriction (TAC) at 2 and 8 weeks were used to investigate the protective effects of butein in vitro and in vivo. Butein markedly reduced cardiomyocyte hypertrophy, decreased intracellular and mitochondrial reactive oxygen species, preserved mitochondrial membrane potential, and restored mitochondrial bioenergetic status. Mechanistically, butein enhanced nuclear accumulation of Nrf2, restored antioxidant gene expression, and reactivated AMPK–Sirt3–FoxO3a signaling while reversing SOD2 hyperacetylation. In vivo, butein suppressed cardiac hypertrophy during the early compensated stage (2week TAC) and alleviated cardiac remodeling, fibrosis, and functional deterioration during the advanced pathological stage (8‐week TAC). Notably, genetic silencing of Nrf2 or Sirt3 and pharmacological inhibition of Nrf2 attenuated the protective effects of butein, supporting the involvement of Nrf2–Sirt3 signaling both in vitro and in vivo. Collectively, these findings demonstrate that butein mitigates pathological cardiac hypertrophy by restoring redox and mitochondrial homeostasis through coordinated Nrf2–Sirt3 signaling.