Gut microbiota depletion and FXR inhibition exacerbates zonal hepatotoxicity of sunitinib.

ABSTRACT: Rationale: 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. Methods: 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, Parabacteroides distasonis and 3-oxolithocholic acid supplementation were used to evaluate the hepatotoxicity mechanisms of sunitinib. Results: Phenotype analysis found that hepatic autophagy, apoptosis, and mitochon

SUBMITTER: Zhao Q 

PROVIDER: S-EPMC11610149 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature