Dysosma versipellis is associated with cholestatic hepatotoxicity potentially involving FXR-SHP-CYP7A1/BSEP-MRP2 axis disruption: A multi-omics-driven mechanistic investigation based on the toxicological evidence chain (TEC) concept.

Dysosma versipellis (DV), despite its broad-spectrum antitumor potential, faces clinical limitations due to cholestatic hepatotoxicity, prompting investigation into its mechanisms and environmental health implications. Using a toxicological evidence chain (TEC) approach in Sprague–Dawley rats administered 1.2 g/kg DV ethanol extract for 3 days, integrated analyses revealed characteristic cholestatic injury, including significantly reduced liver weight (P < 0.01), elevated serum biomarkers (ALT, AST, TBA; P < 0.01), and bile duct hyperplasia. Toxicokinetic profiling identified five hepatotoxic podophyllotoxin derivatives (podophyllotoxin, 4'-demethylpodophyllotoxin, α-peltatin, β-peltatin, deoxypodophyllotoxin), with podophyllotoxin showing the highest systemic exposure (AUC₀₋ₜ). Bile acid metabolomics demonstrated profound dysregulation, notably a 6.9-fold increase in taurochenodeoxycholic acid (TCDCA) and a 78% decrease in glycocholic acid (GCA). Transcriptomics and mechanistic validation (RT-qPCR/Western blot) revealed suppression of the hepatic Farnesoid X Receptor (FXR)-Small Heterodimer Partner (SHP) axis, driving cholesterol 7α-hydroxylase (CYP7A1) upregulation and concurrent downregulation of canalicular transporters bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). These findings indicate that DV-induced cholestasis is mediated by podophyllotoxin derivatives through dual mechanisms: CYP7A1-driven bile acid overproduction via FXR-SHP inhibition and BSEP/MRP2-mediated excretion impairment, providing a molecular basis for detoxification strategies and environmental risk assessment of phytotoxin exposure.