CXCR4 DRIVES HEPATOCYTE REPROGRAMMING IN ALCOHOL-RELATED LIVER DISEASE

Backgruound and aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). However, the mechanisms and the impact of hepatocyte reprogramming in liver disease are poorly understood. Here we show that both hepatocytes expressing KRT7 (hepatobiliary (HB) cells) and ductular reaction cells were increased in decompensated cirrhotic patients and AH, but only HB cells correlated with poor liver function, reduced liver synthetic capacity and poor outcome. Transcriptomic analysis of microdissected HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming together with inflammatory, stemness and cancer gene programs. In this context, CXCR4 pathway was highly enriched in HB cells, and CXCR4 correlated with disease severity and reduced expression of hepatocyte transcription factors and albumin. Mechanistically, TGFβ induced the expression of CXCR4 in primary hepatocytes, and its ligand CXCL12 promoted hepatocyte reprogramming. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte gene expression and promoted liver injury. Pharmacological inhibition of CXCR4 reverted hepatocyte loss of identity and reduced ductular reaction and fibrosis progression. Conclusions: This study shows the association of hepatocyte reprogramming with disease progression and poor outcome in AH. Moreover, we identify CXCR4 as a driver of hepatocyte reprogramming as well as a potential therapeutic target in chronic liver injury. KC were isolatrd from decompensated cirrhosis that underwent liver transplantation (n=4) and a control group of patients with liver tumours (except hepatocellular carcinoma) and without underlying liver disease (n=5). Morever, whole liver tissue from the same patients were aso sequenced.