Abstract
Cholestatic liver diseases are characterized by excessive bile acid accumulation in the liver. Endothelial cells (ECs) shape the local microenvironment in both normal conditions and liver injury, yet their role in cholestasis is unclear. Through a comparative analysis of single-cell RNA sequencing data from various murine models of liver injury, we identify distinctive Myc activation within ECs during obstructive cholestasis resulting from bile duct ligation (BDL). Myc overexpression in ECs significantly upregulates P-selectin, increasing neutrophil infiltration and worsening cholestatic liver injury. This process occurs through the FXR, activated by chenodeoxycholic acid (CDCA) and its conjugate TCDCA. Inhibiting P-selectin with PSI-697 reduces neutrophil recruitment and alleviates injury. Cholestatic patient liver samples also show elevated Myc and P-selectin in ECs, along with increased neutrophils. The findings identify ECs as key drivers of cholestatic liver injury through a Myc-driven program and suggest that targeting the CDCA/FXR/Myc/P-selectin axis may offer a therapeutic approach.