AUTHOR=Zhang Jiaqi , Zhao Licong , Hu Cheng , Wang Tao , Lu Juan , Wu Chenqu , Chen Long , Jin Mingming , Hu Hao , Ji Guang , Cao Qin , Jiang Yuanye 

TITLE=Fisetin Prevents Acetaminophen-Induced Liver Injury by Promoting Autophagy

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00162

DOI=10.3389/fphar.2020.00162

ISSN=1663-9812

ABSTRACT=<p>Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinical and hospital settings. Fisetin (FST) is a phenolic compound derived from natural products such as fruit and vegetables. Our research investigated the protective mechanisms of FST in APAP-induced hepatic injury <italic>in vitro</italic> and <italic>vivo</italic>. Assessment of mouse serum levels of alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) demonstrated the protective effects of FST toward APAP-induced liver injury. FST also reversed an APAP-induced decrease in mouse L-02 cell line viability. Our results also showed that FST significantly promoted APAP-induced autophagy and inhibited inflammasome activation both <italic>in vivo</italic> and <italic>in vitro</italic>. We also found that silencing ATG5, using si-ATG5, reduced the protective effects of FST against APAP-induced hepatotoxicity and reversed the effects on autophagy. Finally, we used the autophagy inhibitor, 3-methyladenine (3-MA) to validate the involvement of autophagy in FST against APAP-induced hepatotoxicity <italic>in vitro</italic>. We demonstrated that FST prevented APAP-induced hepatotoxicity by increasing ATG5 expression, thereby promoting autophagy and inhibiting inflammasome activation.</p>