Targeting mitochondrial morphofunctional homeostasis and oxidative stress: Iristectorigenin A protects against cardiac remodeling via SIRT6/FOXO1 signaling.

Myocardial remodeling, an essential pathological development in cardiovascular disease, is largely determined by disruptions in redox homeostasis and mitochondrial bioenergetic function. Iristectorigenin A (ITG), a naturally occurring isoflavone, exhibits a variety of pharmacological effects, including antioxidant and anti-inflammatory activities. While so many protective effects, its specific effect on cardiac remodeling has not been reported previously. In this study, we aims to investigate the role of ITG in pressure overload-induced cardiac remodeling with a particular focus on mitochondrial function and oxidative stress. We revealed that ITG mitigated TAC-induced cardiac remodeling and improved cardiac function, with the 20 mg/kg dose showing optimal efficacy; further escalation to 40 mg/kg provided no additional benefit. ITG attenuated cardiomyocyte hypertrophy and inhibited activation of fibroblasts in vitro. Additionally, ITG treatment effectively suppressed oxidative stress and inflammation in the hearts of TAC mice, while improving mitochondrial morphology and the integrity of inner membrane structure. Notably, surface plasmon resonance (SPR) analysis indicated a direct interaction between SIRT6 and ITG with micromolar affinity. Besides, sustained TAC- or PE-stimulation impaired cardiac sirtuin 6 (SIRT6) protein levels, which were partially reversed by ITG. More importantly, silencing SIRT6 and SIRT6 knockdown separately inhibited the protective effects of ITG in vitro and in vivo. Mechanistically, ITG promotes SIRT6 levels by inhibiting its ubiquitination degradation. Furthermore, the cardioprotective effect of ITG was concomitant with SIRT6 upregulation, deacetylation and dephosphorylation of forkhead box protein O1 (FOXO1) and the subsequent increased transcription of antioxidant genes. Collectively, we firstly discover that ITG inhibits oxidative stress and safeguards mitochondrial morphofunctional homeostasis in response to pathological stress through activating SIRT6/FOXO1 axis, suggesting the therapeutic potential of ITG in the treatment of cardiac hypertrophy and remodeling, providing a promising avenue for future research and potential clinical application. Schematic illustration of ITG's potential protective mechanism against cardiac hypertrophy.