Astragaloside IV Alleviates Acute Hepatic Injury by Regulating Macrophage Polarization and Pyroptosis via Activation of the AMPK/SIRT1 Signaling Pathway

ABSTRACT Acute hepatic injury (AHI) is associated with poor prognosis in sepsis patient; however, to date, no specific therapeutic approach has been established for this disease. Therefore, we aimed to explore the effects and action mechanisms of Astragaloside IV (AS) on AHI. C57BL/6 mice, RAW264.7 cells, and bone marrow‐derived macrophages were used in this study. Sepsis‐associated AHI model mice were established using lipopolysaccharide + D‐galactosamine. Pathological examination of liver tissues and serum alanine aminotransferase/aspartate aminotransferase was performed to evaluate the liver function. Moreover, inflammatory cytokine levels, proportion of M1/M2 macrophages and their marker levels, and cell pyroptosis‐related indicator levels were determined in the liver of the AHI model mice with or without AS treatment. AMP‐activated protein kinase (AMPK)/sirtuin 1 (SIRT1) expression was determined after AS treatment. Additionally, inflammatory cytokine levels, liver injury, and macrophage polarization were evaluated after inhibiting the AMPK/SIRT1 pathway. AS alleviated lipopolysaccharide + D‐galactosamine‐induced AHI and inhibited inflammatory reactions in the blood and liver of mice. AS also promoted the M1‐to‐M2 phenotypic transformation of macrophages in the liver of AHI model mice and in vitro, thereby decreasing the pro‐inflammatory cytokine levels and increasing the anti‐inflammatory cytokine levels. AS increased AMPK and SIRT1 levels in the liver and macrophages. Furthermore, AS improved liver injury by elevating the expression of the AMPK/SIRT1 signaling pathway and inhibiting pyroptosis in macrophages. Overall, AS alleviated AHI by promoting M1‐to‐M2 macrophage transformation and inhibiting macrophage pyroptosis via activation of the AMPK/SIRT1 signaling pathway.