APAP is one of the most commonly used
antipyretic and
pain medications, but excessive use can cause liver toxicity and damage.
3,4-dihydroxyphenylethyl alcohol glycoside (DAG) is a component isolated from Sargentodoxa cuneata known to have anti-apoptotic, anti-oxidation and anti-inflammatory effects. However, the effects of DAG on
acute liver failure (ALF) are largely unknown. The purpose of this study is to study the protective effects and mechanism of DAG on
APAP-induced ALF in mice. We established an ALF model in adult male pathogen-free C57BL/6 mice treated with
APAP (300 mg/kg) by
intraperitoneal injection and resolved by 24 h.
Hematoxylin and
eosin (HE) staining was used to evaluate the pathological changes in mouse liver tissue. The infiltration of neutrophils in liver tissue and
reactive oxygen species (ROS) in AML12 cells were analyzed by flow cytometry. The levels of
alanine aminotransferase (ALT),
aspartate aminotransferase (AST),
glutathione (GSH),
malondialdehyde (MDA),
catalase (CAT), and
superoxide dismutase (SOD) were analyzed using relevant kits. Our results show that DAG reduced
APAP-induced serum ALT and AST levels, histopathological changes, liver neutrophil infiltration and proinflammatory
cytokines production, also attenuated the accumulation of MDA and the exhaustion of GSH, CAT and SOD. In vitro experiment indicated that DAG dose-dependently inhibited
APAP-induced the levels of pro-inflammatory factors (IL-1β and
IL18), and
reactive oxygen species (ROS) and preventing GSH depletion in mouse AML12 hepatocytes. More interestingly, DAG inhibited the expression of ERK, HO-1, NLRP3, Caspase1 (p20) and Gasdermin-D and upregulated the expression of GPX4 in liver tissues and AML12hepatocytes. Therefore, our results indicate that DAG may act as a potential agent to treat ALF induced by
APAP by inhibiting hepatocyte ferroptosis and pyroptosis.