Glycycoumarin protects mice against acetaminophen-induced liver injury predominantly via activating sustained autophagy.

<bold>Background and Purpose: </bold>Acetaminophen-induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Given the significant limitations associated with N-acetyl cysteine, the only antidote used to treat AILI, the development of novel therapeutic approaches that can offer a wide range of therapeutic time-windows is clearly needed. Glycycoumarin (GCM), a natural coumarin purified from liquorice, has been previously demonstrated to possess potent hepatoprotective effects. In the present study, we aimed to investigate the therapeutic potential of GCM against AILI.<bold>Experimental Approach: </bold>Acetaminophen (300 mg·kg-1 ) was administered to male C57BL/6 mice, with and without GCM. Serum transaminases, haematoxylin and eosin staining and Western blot were used to assess hepatic damage.<bold>Key Results: </bold>GCM (50 mg·kg-1 ) was highly effective against acetaminophen-induced hepatotoxicity. Moreover, GCM was superior to N-acetyl cysteine, in terms of the dosage and the therapeutic time-windows. Further mechanistic investigations revealed that the therapeutic action of GCM was not a result of inhibition of acetaminophen metabolic activation or associated with Nrf2. Instead, the protective effect of GCM appeared to be predominantly dependent on sustained activation of autophagy, which attenuated acetaminophen-induced mitochondrial oxidative stress and JNK activation.<bold>Conclusions and Implications: </bold>Collectively, our results indicate that GCM alleviated acetaminophen-induced oxidative stress through activating autophagy, thereby protecting against AILI. Our findings suggest that GCM has potential as a novel therapeutic agent for treating AILI. [ABSTRACT FROM AUTHOR]