Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis

Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fi-brosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus tran-scriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mice and humans. At the nonalcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which were mainly demarcated by receptor tyrosine kinase ephrin type B receptor 2 (EphB2). EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomous inflam-mation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH. Thus, EphB2-expressing hepatocytes contribute to NASH progression and may serve as a potential therapeu-tic target.

Automated summary

Current therapeutic strategies for NASH have been ineffective in alleviating liver fibrosis. This study used single-nucleus transcriptomics and epigenomics to characterize liver cell types during NASH development in mice and humans. The progression of hepatocyte trajectory with NASH was conserved between the two species. Hepatocytes exhibited metabolic adaptation at the NAFL stage, while at the NASH stage, a subset of hepatocytes showed enrichment in cell adhesion and migration signatures, mainly through the receptor tyrosine kinase EphB2. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH, suggesting EphB2 as a potential therapeutic target.