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Background & Aims Liver diseases are caused by many factors, such as genetics, nutrition, and viruses. Therefore, it is important to delineate transcriptomic changes that occur in various liver diseases. Methods We performed high-throughput sequencing of mouse livers with diverse types of injuries, including cholestasis, diet-induced steatosis, and partial hepatectomy. Comparative analysis of liver transcriptome from mice and human samples of viral infections (HBV and HCV), alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH), and biliary atresia revealed distinct and overlapping gene profiles associated with liver diseases. We hypothesised that discrete molecular signatures could be utilised to assess therapeutic outcomes. We focused on cholestasis to test and validate the hypothesis using pharmacological approaches. Results Here, we report significant overlap in the expression of inflammatory and proliferation-related genes across liver diseases. However, cholestatic livers were unique and displayed robust induction of genes involved in drug metabolism. Consistently, we found that constitutive androstane receptor (CAR) activation is crucial for the induction of the drug metabolic gene programme in cholestasis. When challenged, cholestatic mice were protected against zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. These protective effects were diminished upon inhibition of CAR activity. Further, drug metabolic genes were also induced in the livers from a subset of biliary atresia patients, but not in HBV and HCV infections, AH, or NASH. We also found a higher expression of CYP2B6, a CAR target, in the livers of biliary atresia patients, underscoring the clinical importance of our findings. Conclusions Comparative transcriptome analysis of different liver disorders revealed specific induction of phase I and II metabolic genes in cholestasis. Our results demonstrate that CAR activation may lead to variations in drug metabolism and clinical outcomes in biliary atresia. Lay summary Transcriptomic analysis of diverse liver diseases revealed alterations in common and distinct pathways. Specifically, in cholestasis, we found that detoxification genes and their activity are increased. Thus, cholestatic patients may have an unintended consequence on drug metabolism and not only have a beneficial effect against liver toxicity, but also may require adjustments to their therapeutic dosage., Graphical abstract, Highlights • Cell cycle, inflammation, and glucose homeostasis are some of the common pathways altered in a variety of liver disorders. • Phase I and II metabolic genes are induced in Fxr−/−Shp−/− double knockouts (DKOs) and bile-acid-fed control mice. • Activation of xeno-sensor, constitutive androstane receptor (CAR), is observed in cholestasis. • Inhibiting CAR activity in DKO mice exacerbates zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. • A subset of patients with biliary atresia display increased expression of CAR target protein CYP2B6.