Single-Cell Transcriptomic Analysis Reveals Distinct Pathogenic Subtypes in Hepatocyte- and Cholangiocyte-Directed...

Autoimmune liver diseases (AILDs) involve a group of distinct disorders, but the differences in pathogenic subpopulations that drive hepatocyte or bile duct injury remain unclear. This study characterizes immune niche heterogeneity across AILD subtypes using single-cell RNA sequencing and verifies findings with animal models. We identified distinct immune cell states and functions by analyzing the heterogeneity of T cell and macrophage subsets and the impact of non-immune cell-derived signals on macrophage identity. This allowed us to characterize two distinct immunopathogenic ecotypes between hepatitis and cholestatic phenotypes. Mechanistic analysis predicted the Bmp-Acvrl1/Eng-Fosb signaling axis as a critical transcriptional regulator driving the repair phenotype of macrophages. Notably, Eng (endoglin) emerged as a regulatory receptor controlling macrophage phenotypic transition, especially during the recovery phase of cholestatic disease. Collectively, this study provides a comprehensive atlas of immune cell niches across AILDs, offering new mechanistic insights into disease heterogeneity and identifying macrophage maturation as a promising target for stratified therapeutic intervention in cholestatic disease.