A human single-cell atlas identifies OLR1+ scar-associated macrophages as a potential therapeutic target for chronic liver disease

Abstract Chronic liver disease (CLD) results in liver fibrosis, leading to adverse clinical outcomes. Macrophages regulate fibrosis and represent an attractive therapeutic target. However, the specific macrophage subpopulation that drives fibrosis in CLD remains unclear. Here we generate a liver single-cell atlas comprising 649,295 cells from 42 healthy and 35 CLD patients, identifying 125 transcriptionally distinct cellular states. We resolve two types of disease-expanded TREM2 + scar-associated macrophages (SAMac), including a pro-inflammatory subpopulation that expresses the scavenger receptor OLR1 and spatially accumulates in the CLD fibrotic niche. High hepatic OLR1 expression was associated with increased fibrosis across multiple CLD etiologies and adverse patient outcomes in metabolic dysfunction-associated steatotic liver disease. Corollary pro-inflammatory OLR1 + SAMac expanded in mouse CLD, while targeting of macrophage OLR1 attenuated fibrogenic activity in human coculture and multilineage spheroid models. Overall, our atlas provides a reference to study disease-associated cell states in CLD and identifies OLR1 as a potential therapeutic target to attenuate liver fibrosis.

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Journal
Nature Genetics
Published
2026-09-28
DOI
https://doi.org/10.1038/s41588-026-02774-w
Primary Topic
Single-cell and spatial transcriptomics
Type
article
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article

A human single-cell atlas identifies OLR1+ scar-associated macrophages as a potential therapeutic target for chronic liver disease

Elisa Pose, Catalina A. Vallejos, Juliet Luft, Prakash Ramachandran et al.
Nature Genetics
Single-cell and spatial transcriptomics
article

A human single-cell atlas identifies OLR1+ scar-associated macrophages as a potential therapeutic target for chronic liver disease

Elisa Pose, Catalina A. Vallejos, Juliet Luft, Prakash Ramachandran, Max Hammer, Jayamary Divya Ravichandar, Alvile Kasarinaite, Sebastian J. Wallace, Elena F. Sutherland, Tabitha Turner‐Stokes, Volker Martin Lauschke, Stefan Veizades, Eleni Papachristoforou, Calum C. Bain, Fabio Colella, Timothy James Kendall, Jonathan Andrew Fallowfield, John R. Wilson‐Kanamori, Neil Cowan Henderson, Malgorzata Grzelka, James Christopher Lee, Ayma Asif, Laura J. Pallett, Ines Battle, Ginerva Pistocchi, Pak Kwan Qui, Ailish McCafferty-Brown, Gareth-Rhys Jones, Jacky Tam, Anna Zagorska, Yingxin Liang, Josepmaria Argemi, Kexin Kong, Ravi Parhar, Grant Budas, George Finney, Raktaprabal Kashyap, Ashis Mukhopadhya, David Lopez, Ramon Bataller, Theresa Kuschnereit, Keshav Rao, David C. Hay
article en

Abstract

Abstract Chronic liver disease (CLD) results in liver fibrosis, leading to adverse clinical outcomes. Macrophages regulate fibrosis and represent an attractive therapeutic target. However, the specific macrophage subpopulation that drives fibrosis in CLD remains unclear. Here we generate a liver single-cell atlas comprising 649,295 cells from 42 healthy and 35 CLD patients, identifying 125 transcriptionally distinct cellular states. We resolve two types of disease-expanded TREM2 + scar-associated macrophages (SAMac), including a pro-inflammatory subpopulation that expresses the scavenger receptor OLR1 and spatially accumulates in the CLD fibrotic niche. High hepatic OLR1 expression was associated with increased fibrosis across multiple CLD etiologies and adverse patient outcomes in metabolic dysfunction-associated steatotic liver disease. Corollary pro-inflammatory OLR1 + SAMac expanded in mouse CLD, while targeting of macrophage OLR1 attenuated fibrogenic activity in human coculture and multilineage spheroid models. Overall, our atlas provides a reference to study disease-associated cell states in CLD and identifies OLR1 as a potential therapeutic target to attenuate liver fibrosis.

Nature Genetics
Karolinska University Hospital (SE), Central South University (CN), Aberdeen Royal Infirmary (GB), The Francis Crick Institute (GB), The Royal Free Hospital (GB), Karolinska Institutet (SE), MRC Centre for Regenerative Medicine (GB), Navarre Institute of Health Research (ES), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Gilead Sciences (United States) (US), Centre for Inflammation Research (GB), Second Xiangya Hospital of Central South University (CN), Institute of Genetics and Cancer (GB), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), MRC Human Genetics Unit, University College London (GB), Imperial College London (GB), Zhejiang University (CN), University of Tübingen (DE), Universidad de Navarra (ES), University of Edinburgh (GB)
Good health and well-being
Openalex Percentile: Top 19%
Single-cell and spatial transcriptomics
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