Cell-specific Y-box binding protein-1 drives liver-kidney injury in cholestasis

Acute kidney injury is a frequent, life-threatening complication of liver disease. The stress-responsive DNA- and RNA-binding protein Y-box-binding protein 1 (YB-1) regulates gene expression and modulates liver-kidney crosstalk, with partial systemic YB-1 deficiency protecting the liver but worsening kidney injury in a murine bile duct ligation (BDL) model. To further define cell-specific roles of YB-1, its expression was selectively reduced in kidney and immune cells, and the effects on primary liver and secondary kidney injury were evaluated. Conditional Ybx1 knockout mice targeting tubular ( Pax8 cre xYbx1 fl ) and myeloid ( LysM cre xYbx1 fl ) cells were used to study YB-1 function during BDL-induced cholestasis and kidney damage. Organ injury and fibrosis were evaluated by histology, gene expression, and serum markers. Tubular YB-1 deficiency was associated with reduced kidney injury and fibrosis. This was accompanied by a decreased expression of the bile acid uptake transporter ASBT and an increased expression of the efflux transporter OSTβ. These changes are consistent with a coordinated detoxification response limiting intracellular bile acid accumulation. However, this deficiency aggravated liver damage after BDL. In contrast, myeloid YB-1 deficiency reduced serum markers of liver injury but worsened renal inflammation and injury, mirroring findings in whole-body Ybx1 haploinsufficient mice. These findings identify YB-1 as a crucial regulator of organ-specific responses in cholestatic liver disease, with opposing, cell type-dependent effects on liver and kidney injury, highlighting its central role in inter-organ communication.