Single-Cell Transcriptomic Analysis Reveals Distinct Pathogenic Subtypes in Hepatocyte- and Cholangiocyte-Directed Autoimmune Liver Injury
- 1Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
Abstract
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.
Related
- Integrated Transcriptomic Analysis Reveals Distinct Molecular and Immune Microenvironment Features of Peutz–Jeghers Syndrome-Associated Lobular Endocervical Glandular Hyperplasia and Gastric-Type Endocervical Adenocarcinoma
- Distinct Clinical Patterns Associated with HLA-DRB1 Genotypes in Pediatric Autoimmune Liver Diseases
- Escherichia coli ST131 isolates are rare in human meningitis but belong to a distinct O25b-fimH22 clade B lineage shared with avian pathogenic Escherichia coli
- Metabolic transcriptomic subtyping defines distinct immunogenomic and clinical landscapes in non–small cell lung cancer
- Ductular reaction as a spatial fibrogenic niche: cholangiocyte-macrophage-fibroblast crosstalk in chronic liver disease.
BibTeX
@article{zhao2026singlecell,
title = {{Single-Cell Transcriptomic Analysis Reveals Distinct Pathogenic Subtypes in Hepatocyte- and Cholangiocyte-Directed Autoimmune Liver Injury}},
author = {Peiyi Zhao and Li Zhao and Huayang Zhang and Xiting Pu and Jun Qian and Yudong Zhao and Zhengrui You and Xiong Ma},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209323},
url = {https://www.mdpi.com/1422-0067/27/20/9323},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Single-Cell Transcriptomic Analysis Reveals Distinct Pathogenic Subtypes in Hepatocyte- and Cholangiocyte-Directed Autoimmune Liver Injury
AU - Peiyi Zhao
AU - Li Zhao
AU - Huayang Zhang
AU - Xiting Pu
AU - Jun Qian
AU - Yudong Zhao
AU - Zhengrui You
AU - Xiong Ma
PY - 2026
DA - 2026/10/20
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209323
UR - https://www.mdpi.com/1422-0067/27/20/9323
AB - 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.
SN - 1422-0067
ER -