Dihydromyricetin alleviates acetaminophen-induced liver injury via the regulation of transformation, lipid homeostasis, cell death and regeneration

Aims We previously reported that Hovenia dulcis Thunb. extract, a traditional Chinese medicine rich in dihydromyricetin (DHM), exhibited a significant hepatoprotective effect against acetaminophen (APAP)-induced liver injury. However, whether DHM plays a protective role in APAP hepatotoxicity and what mechanisms are involved remain unclear. In this study, we evaluated the hepatoprotective effects of DHM against APAP-induced liver injury. Main methods Male C57BL/6 mice were used for the experiment. LC-MS, q-PCR, immunochemistry and western blot analysis were employed to mechanism analysis. Key findings DHM exhibited a protective effect against APAP-induced liver injury. Further mechanistic investigations revealed that the protective effect of DHM against APAP hepatotoxicity had multi-target and multi-pathway characteristics involving APAP metabolism, lipid regulation, and hepatocyte death and regeneration. DHM pretreatment resulted in cytochrome P450 2E1 inhibition and UDP-glucuronosyltransferase 1A1 activation, affecting APAP biotransformation. Moreover, DHM pretreatment significantly ameliorated lipid dysregulation via peroxisome proliferator-activated receptor and sterol regulatory element-binding protein-1c (SREBP-1c) signalling pathways. Furthermore, DHM regulated the expression of cell death- and liver regeneration-associated proteins. Significance These results suggested that DHM alleviated APAP-induced liver injury in mice by inhibiting hepatocyte death, promoting p53-related regeneration, and regulating lipid homeostatic imbalance and APAP transformation. Based on these findings, DHM provides a potential and novel approach for preventing and treating APAP-induced liver damage, and SREBP-1c signalling might be a new therapeutic target for APAP hepatotoxicity.