Cardamonin Reduces Acetaminophen-Induced Acute Liver Injury in Mice via Activating Autophagy and NFE2L2 Signaling

• Published in: Frontiers in pharmacology Vol. 11; p. 601716
• Main Authors: Xu, Qiushi, Fan, Yunhui, Loor, Juan J., Liang, Yusheng, Sun, Xudong, Jia, Hongdou, Zhao, Chenxu, Xu, Chuang
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 13.11.2020
• Subjects: acetaminophen; acute liver injury; autophagy; cardamonin; NFE2L2; Pharmacology; acetaminophen; autophagy; cardamonin; NFE2L2; acute liver injury
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2020.601716

Cardamonin (CD), a naturally occurring chalcone derived from the Alpinia species, has been shown to exert antioxidant and anti-inflammatory activity, but its role in the prevention of acetaminophen- (APAP-) induced hepatotoxicity remains elusive. The objective of this study was to determine the protective effects of CD against APAP-induced acute liver injury (ALI) and the underlying mechanisms. Wild-type or transcription factor nuclear factor erythroid 2-related factor 2- (NFE2L2-) deficient mice were treated with CD (50 or 100 mg/kg, i.p.) or vehicle for 24 h. Subsequently, these mice were challenged with APAP (400 mg/kg, i.p.) for 6 h. Liver and blood samples were collected to evaluate liver injury and protein abundance. Treatment with CD significantly reduced APAP-induced hepatotoxicity. Furthermore, CD effectively reduced APAP-induced inflammation by inhibiting high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and NOD-like receptor protein 3 (NLRP3) signaling. In addition, CD induced activation of sequestosome 1 (p62) and NFE2L2 signaling and facilitated autophagy. By applying autophagy inhibitor 3-methyladenine (3-MA; 20 mg/kg, i.p.), further mechanistic exploration revealed that NFE2L2 deficiency promoted autophagic activity induced by CD treatment, which was conducive to the hepatoprotective effect of CD against APAP-induced hepatoxicity in NFE2L2 −/− mice. Overall, data suggest that CD has hepatoprotective effect against APAP-induced ALI, which might contribute to the activation of NFE2L2 and autophagy.