THBS1+ macrophages fuel pathogenic inflammation in alcohol-associated liver disease.

Authors

Wentao Xu, Shanshan Wu, Jia Gao, Chen Cheng, Conghan Li, Shaocheng Hong, Jianshang Huang, Jinjing Zhang, Chenchen An, Miaomiao Wu, Xiang Li, Xin Wang, Yan Zhang, Hua Wang, Derun Kong, Wei He

Published in

Hepatology communications. Volume 10. Issue 10. Oct 01, 2026. Epub Sep 18, 2026.

Abstract

Alcohol-associated liver disease (ALD) is one of the most common chronic liver diseases worldwide, with a pathological spectrum ranging from simple steatosis to steatohepatitis and, ultimately, cirrhosis. Severe alcohol-associated hepatitis (sAH) arises acutely within this continuum as a rapidly developing inflammatory condition associated with high mortality and poor prognosis.
To investigate important cellular subpopulations, we integrated single-cell RNA sequencing (scRNA-seq) data from the peripheral blood and liver tissues of healthy individuals and patients with ALD (including those with alcoholic cirrhosis and sAH). A murine metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease (MetALD)-like model was established by combining a metabolic dysfunction-associated steatohepatitis-inducing diet with controlled ethanol exposure. The model was used for histopathological analyses, and CD45+ cells from peripheral blood and liver tissues were isolated for scRNA-seq. Analyses included cell composition profiling, differential expression, pathway enrichment, pseudotime trajectory inference, transcriptional regulatory network reconstruction, and cell-cell communication analysis. In parallel, we generated THBS1‑KO and IL15‑KO immortalized bone marrow-derived macrophages cell lines in vitro and conducted functional assays to validate their roles.
ScRNA-seq data revealed significant enrichment of IL15+ monocytes and THBS1+​​​​ monocyte-derived macrophages (moMFs) in patients with sAH, both exhibiting highly proinflammatory characteristics. Pseudotime analysis indicated that circulating IL15+ monocytes could dynamically differentiate into hepatic THBS1+ moMFs. Pathological staining and scRNA-seq data from the MetALD mouse model yielded similar results, further confirming the dynamic evolution of IL15+​​​​ monocytes into THBS1+​​​​ moMFs. In vitro cellular experiments also substantiated the proinflammatory roles of THBS1 and IL15.
Our study reveals that circulating IL15+​​​​ monocytes dynamically differentiate into hepatic THBS1+​​​​ moMFs, and the combined proinflammatory action of these subsets accelerates the progression of ALD.

PMID:
42758867
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.

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