Esculetin Improves LPS/D-GalN Induced Acute Liver Injury Through AMPK/SIRT1/PGC-1α Signaling Pathway

The pathogenesis of acute liver injury (ALI) involves the loss of hepatic detoxification function, massive death of liver parenchymal cells within a short period, and excessive inflammatory responses. Studies have shown that Esculetin (Esc) possesses potent anti-inflammatory, antioxidant, and anti-tumor properties. In this study, we investigate whether Esc has a protective effect against ALI in mice and its potential mechanism. Esculetin markedly decreased ROS, MitoSOX, and apoptosis levels in AML12 cells and restored MMP. H&E staining demonstrated that Esc alleviated hepatic histopathological injury, and its intervention reduced serum ALT and AST levels. Moreover, Esc diminished ROS and apoptosis levels in the liver. Hepatic proteomic profiling identified the AMPK signaling pathway. Esc reduced the protein levels of p-AMPK/AMPK, PGC-1α, p-SIRT1/SIRT1, and BAX and upregulated the levels of Bcl-2 in liver tissue. Concomitantly, we added inhibitor Compound C (CC) to the AML12 cells to assess whether Esc acted through the AMPK pathway. The results showed that CC exacerbated the degree of liver injury, whereas Esc was able to reverse these phenomena, thus exerting an anti-liver injury effect. These findings provide mechanistic insights into the protective effects of Esc against ALI and support its potential as a therapeutic candidate for ALI.