Astragaloside IV alleviates septic myocardial injury through DUSP1-Prohibitin 2 mediated mitochondrial quality control and ER-autophagy

• Interaction between DUSP1 and PHB2 significantly contributes to cardiomyocyte injury following SCM. • AS mitigated myocardial inflammatory damage and oxidative stress, enhanced myocardial cell energy metabolism, addressed cardiac structural abnormalities, and preserved cardiac function through modulating the DUSP1-PHB2 interaction. • AS normalizes mitochondrial quality control via the DUSP1-PHB2 interaction. Septic cardiomyopathy (SCM) is a complication of myocardial injury in patients with severe sepsis. This study highlights the potential of Astragaloside IV(AS) in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2-related mitochondria-ER interaction. Dual specificity phosphatase-1 (DUSP1)/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2 CKO ) /DUSP1 transgenic mice (DUSP1/PHB2 TG ) were used to generate LPS-induced sepsis models. The pathological mechanism by which AS-IV improves heart injury was detected using cardiac ultrasound, fluorescence staining, transmission electron microscopy, and western blotting. After siRNA treatment of cardiomyocytes with DUSP-1/PHB2, changes in mitochondrial function and morphology were determined using qPCR, western blotting, ELISA, and laser confocal microscopy, and the targeted therapeutic effects of AS-IV were further examined. SCM treatment leads to severe mitochondrial dysfunction. However, Astragaloside IV (AS) treatment normalizes mitochondrial homeostasis and ER function. Notably, the protective effect was blocked in DUSP1/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2 CKO ) but remained unaffected in DUSP1 transgenic mice (DUSP1/PHB2 TG ). This study highlights the potential of AS in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2 related mitochondria-ER interaction.