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

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.