Astragaloside IV inhibits MAPK pathway and promotes mitochondrial autophagy in rats with heart failure.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with mitochondrial dysfunction and impaired mitophagy recognized as key contributors to its progression. Astragaloside IV (AS-IV), a major active component of Astragalus membranaceus, has shown multiple biological effects, but its role in mitochondrial homeostasis in HF remains unclear. In this study, a rat model of HF was induced by abdominal aortic constriction, and AS-IV was administered at doses of 20 mg/kg and 80 mg/kg. We found AS-IV treatment significantly reduced myocardial fibrosis and hypertrophy, improved mitochondrial function by increasing ATP and manganese superoxide dismutase levels, reducing reactive oxygen species, and upregulating PGC-1α and TFAM. It also enhanced mitochondrial autophagy. Moreover, AS-IV markedly inhibited the activation of the p38 MAPK pathway. AS-IV suppresses autophagy and mitochondrial function via targeting MAPK pathway in H9c2 cells. These findings suggest that AS-IV alleviates HF by promoting mitophagy and preserving mitochondrial function through suppression of the MAPK pathway, highlighting its potential as a novel therapeutic agent for HF.