Hepatoprotective effects of wine-steamed <i>Schisandra sphenanthera</i> fruit in alleviating APAP-induced liver injury <i>via</i> the gut–liver axis

Drug-induced liver injury (DILI) is a common adverse drug reaction that can result in liver injury, particularly in cases of paracetamol (APAP) abuse. <i>Schisandra sphenanthera</i> Rehd. et Wils. has attracted attention due to its hepatoprotective properties, and the underlying mechanism is unclear. In this study, a mouse model of APAP-induced liver injury was employed to evaluate network pharmacology analysis, histopathological analysis, the gut microbiota, and fecal metabolome to investigate the mechanism by which <i>S. sphenanthera</i> fruit extract (SFE) alleviates DILI. Network pharmacology indicated that the SFE can attenuate APAP-induced liver injury <i>via</i> key targets, including MAPK3 and CASP3. Furthermore, SFE effectively alleviated APAP-induced oxidative stress (MDA, SOD, and GSH) and inflammation (IL-6, TNF-α, and IL-1β). Further analysis of gut microbiota and fecal metabolites revealed that SFE promoted the growth of Bacteroidales and Erysipelotrichales, and decreased the growth of Lactobacillales, leading to increased production of tryptophan metabolites. Correlation analysis showed that the increase in gut microbiota by SFE was positively correlated with improved antioxidant ability and improved liver and gut function. In conclusion, SFE pretreatment can alleviate APAP-induced liver injury by targeting the gut-liver axis, and provides a valuable reference for the clinical use of SFE in the prevention or treatment of DILI.