Dysosoma versipellis induces cholestatic hepatotoxicity via FXR-SHP-CYP7A1/BSEP-MRP2 axis disruption: A multi-omics-driven mechanistic investigation based on the toxicological evidence chain (TEC) concept
To elucidate the mechanisms underlying Dysosoma versipellis (DV)-induced cholestatic hepatotoxicity, which limits its clinical application despite its broad-spectrum antitumor potential.Using a toxicological evidence chain (TEC) framework, Sprague-Dawley rats were administered 1.2 g/kg DV ethanol extract for three consecutive days. Multi-modal investigations included phenotypic assessments (organ coefficients, serum biochemistry, histopathology), toxicokinetic profiling of podophyllotoxin derivatives via UPLC-MS/MS, bile acid metabolomics using LC-MS, transcriptomic analysis of hepatic FXR pathway regulators, and mechanistic validation through RT-PCR and Western blot.Phenotypic assessments revealed characteristic cholestasis manifestations,including an 11.3% reduction in liver weight, elevated serum biomarkers (ALT, AST,TBA), and bile duct proliferation. Toxicokinetic profiling identified five hepatotoxic podophyllotoxiderivatives, with podophyllotoxin exhibiting the highest systemic exposure. Bile acid metabolomics demonstrated significant perturbations, showing a 6.9-fold increase in TCDCA and a 78% decrease in GCDCA. Transcriptomic analysis revealed suppression of the FXR-SHP axis, leading to CYP7A1 upregulation and concurrent downregulation of canalicular transporters. Mechanistic validationconfirmed FXR inhibition and corresponding alterations in downstream effectors.