Calycosin attenuates mitochondrial damage and pyroptosis in heart failure via the Nrf2/ROS/TXNIP pathway.

Abstract

Heart failure (HF) is a key public health concern worldwide due to its high morbidity and mortality rates. Calycosin (CA) is a flavonoid natural product that effectively treats HF with cardioprotective effects; however, its mechanism of action remains unclear. The present study aimed to investigate the therapeutic effect of CA on HF and its mechanism through in vivo and in vitro experiments, and to reveal the roles of pyroptosis and mitochondrial dysfunction in the pathophysiology of HF. The HF model was constructed 4 weeks after ligation of the left anterior descending artery in rats. Myocardial ischemia‑reperfusion injury was simulated using a hypoxia‑reoxygenation model and nuclear factor erythroid 2‑related factor (Nrf2) was silenced by transfection using small interfering RNA to further explore the therapeutic mechanism of CA. The results revealed that CA treatment improved cardiac function and myocardial injury, suppressed oxidative stress levels and improved mitochondrial ultrastructure in HF‑induced rats. CA downregulated the expression of relevant pyroptosis proteins via the Nrf2/reactive oxygen species (ROS)/thioredoxin‑interacting protein (TXNIP) pathway. In vitro experiments demonstrated consistent results confirming that CA ameliorated mitochondrial damage by reducing levels of ROS and inhibiting mitochondrial gasdermin D N‑terminal fragments activation. Silencing Nrf2 partially reversed the cardioprotective effects of CA, confirming the key therapeutic role of CA in Nrf2‑mediated anti‑pyroptosis. In conclusion, CA inhibits pyroptosis and improves mitochondrial damage in HF through the Nrf2/ROS/TXNIP pathway, which may disrupt the crosstalk between mitochondrial damage and pyroptosis, thereby exerting cardioprotective effects.