Gut microbiota depletion and FXR inhibition exacerbates zonal hepatotoxicity of sunitinib

<b>Rationale:</b> Sunitinib is a small-molecule tyrosine kinase inhibitor associated with the side-effect of liver injury. The impaired cell type in liver and the hepatotoxicity mechanisms is still unclear. <b>Methods:</b> Spatial metabolomics, transmission electron microscopy, immunofluorescence co-staining, and isolation of bile duct cells and liver sinusoidal endothelial cells (LSECs) were used to evaluate the zonated hepatotoxicity of sunitinib. Farnesoid X receptor (FXR) conditional knockout mice, metagenomics analysis, bacteria clearance, bacterial culture, <i>Parabacteroides distasonis</i> and 3-oxolithocholic acid supplementation were used to evaluate the hepatotoxicity mechanisms of sunitinib. <b>Results:</b> Phenotype analysis found that hepatic autophagy, apoptosis, and mitochondrial injury were observed <i>in vivo</i> or <i>in vitro</i> after sunitinib treatment. By using spatial metabolomics and isolation of bile duct cells and LSECs, the zonated drug toxicity was observed around the portal vein. Hepatocytes, bile duct cells, and LSECs were damaged after sunitinib treatment. FXR inhibition and gut microbiota depletion aggravated sunitinib-induced liver injury. For diurnal variation, sunitinib-induced liver injury was enhanced at night compared with that at day, and FXR and gut microbiota participated in circadian rhythmic hepatotoxicity induced by sunitinib. <b>Conclusions:</b> Our data suggested activation of FXR and <i>Parabacteroides distasonis</i> supplementation may be used to improve sunitinib-induced hepatotoxicity.