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

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.