Yinchenhao decoction alleviates obstructive jaundice liver injury by modulating epidermal growth factor receptor and constitutive androstane receptor signaling

BACKGROUND Yinchenhao decoction (YCHD) is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice (OJ). Although YCHD has demonstrated protective effects against liver damage, reduced apoptosis, and mitigated oxidative stress in OJ, the precise molecular mechanisms involved remain poorly understood. AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms. METHODS The active constituents of YCHD were identified using liquid chromatography-tandem mass spectrometry, and their potential targets for OJ treatment were predicted through network pharmacology. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. An OJ rat model was established by common bile duct ligation. Rats were divided into three groups: Sham surgery (S Group), model (O Group), and YCHD (Y Group). YCHD was administered to Group Y for one week. Bilirubin levels, liver function parameters, and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay. The bile acid renal clearance rate (Clr) was calculated. Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining. Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues. The expression of the constitutive androstane receptor (CAR) and its nuclear localization were evaluated by immunohistochemistry. Molecular docking studies identified the epidermal growth factor receptor (EGFR) as a potential target of YCHD's active components. An OJ cell model was created using human liver (L02) and renal tubular epithelial (HK-2) cells, which were treated with YCHD-containing serum. Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation. RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ. In vivo experiments showed that YCHD improved liver function, reduced OJ-induced pathology in liver and kidney tissues, and decreased serum bile acid content by enhancing bile acid Clr and urine output. YCHD also increased CAR expression and nuclear heterotopy, upregulating proteins involved in bile acid metabolism and transport, including CYP3A4, UGT1A1, MRP3, and MRP4 in the liver, and MRP2 and MRP4 in the kidneys. In vitro, YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells, an effect that was reversed by EGFR agonists. CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys, ameliorating liver damage caused by OJ. These effects are likely mediated by the upregulation of CAR and its nuclear translocation.