Drug‐induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP‐induced DILI. In this study, wolfberry promoted the proliferation of activated‐A. muciniphila in vitro and in vivo. For the first time, we detected that the activated‐A. muciniphila but not the killed‐A. muciniphila increased the expression level of Yes‐associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP‐induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP‐induced DILI mice, which promoted the recovery of APAP‐induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.

Background and Aims. Artemisia annua (Qinghao) and Sophora flavescens (Kushen) are traditional Chinese medicines (TCMs). They are widely used in disease therapy, including hepatocellular carcinoma (HCC). However, their key compounds and targets for HCC treatment are unclear. This article mainly analyzed the vital active compounds and the mechanism of Qinghao-Kushen acting on HCC. Methods. First, we chose a traditional Chinese medicine, which has an excellent clinical effect on HCC by network meta-analysis. Then, we composed the Qinghao-Kushen herb pair and prepared the medicated serum. The active compounds of Qinghao-Kushen were verified by the LC-MS method. Next, we detected key targets from PubChem, SymMap, SwissTargetPrediction, DisGeNET, and GeneCards databases. Subsequently, the mechanism of Qinghao-Kushen was predicted by network pharmacology strategy and primarily examined in HuH-7 cells, HepG2 cells, and HepG2215 cells. Results. The effect of the Qinghao-Kushen combination was significantly better than that of single Qinghao or single Kushen in HepG2 and HuH-7 cells. Qinghao-Kushen increased the expression of activated caspase-3 protein than Qinghao or Kushen alone in HepG2 and HepG2215 cells. Network analyses and the LC-MS method revealed that the pivotal compounds of Qinghao-Kushen were matrine and scopoletin. GSK-3β was one of the critical molecules related to Qinghao-Kushen. We confirmed that Qinghao-Kushen and matrine-scopoletin decreased the expression of GSK-3β in HepG2 cells while increased GSK-3β expression in HepG2215 cells. Conclusions. This work not only illustrated that the practical components of Qinghao-Kushen on HCC were matrine and scopoletin but shed light on the inhibitory of Qinghao-Kushen and matrine-scopoletin on liver cancer cells. Moreover, Qinghao-Kushen and matrine-scopoletin had a synergistic effect over the drug alone in HuH-7, HepG2, or HepG2215 cells. GSK-3β may be a potential target for HCC therapy.