Ferulic acid ameliorates acetaminophen-induced acute liver injury by promoting AMPK-mediated protective autophagy

Acetaminophen (APAP), one of the most widely used antipyretics and analgesics, principally results in acute liver injury (ALI) in developed countries when taken overdose. Ferulic acid (FA) is a natural polyphenol compound existing in many Plants that has free radical scavenging, anti-inflammatory, and liver-protective properties. However, the effect and underlying mechanism of FA in treating APAP-induced ALI have not been fully elucidated. Herein, we established a mouse model of APAP-induced ALI and used APAP-stimulated MPHs for biochemical assessment of molecular parameters. After constructing networks and obtaining predicted targets from public databases, we further verified the putative pathways using immune-blotting assays both in vivo and in vitro. The reign of liver necrosis, serum levels of ALT and AST, and oxidative stress in livers significantly elevated after APAP treatment, which were almost recovered back to normal levels by FA administration. In addition, FA significantly upregulated the APAP-induced downregulation of hepatic specific markers, including HNF4a, Foxa2, and ALB. Then, the results of functional enrichment indicated the possible signaling pathways of FA against APAP challenge, mainly including AMPK, Autophagy, Apoptosis, and Other metabolic process. Furthermore, FA markedly reversed the APAP-induced decline of mitochondria membrane potential, increased ratio of Bax/BCL2 and Caspase 3 expression, and promoted Autophagy flux of hepatocytes by upregulating AMPK phosphorylation, which were abrogated by a specific AMPK Inhibitor, compound C. Overall, the hepatoprotective effect of FA on APAP-induced ALI might be associated with anti-oxidant and anti-apoptosis, which were at least partly attributed to AMPK-mediated protective Autophagy.