Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis

Abstract

Immune cells play a central yet poorly understood role in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), a global cause of liver disease with limited treatment. Limited access to human livers and lack of studies across MASLD/MASH stages thwart identification of stage-specific immunological targets. Here we provide a unique single-cell RNA sequencing atlas of paired peripheral blood and liver fine-needle aspirates from a full-spectrum MASLD/MASH human cohort. Our findings included heightened immunoregulatory programs with MASH progression, such as enriched hepatic regulatory T cells, monocytic myeloid-derived suppressor cells, TREM2⁺S100A9⁺ macrophages and S100^hiHLA^lo type 2 conventional dendritic cells. Hepatic cytotoxic T cell functions increased with inflammation, but decreased with fibrosis, while acquiring an exhausted signature, whereas natural killer cell-driven toxicity intensified. Our dataset proposes immunological mechanisms for increased fibrogenesis and vulnerability to liver cancer and infections in MASH and provides a basis for a deeper understanding of human immunological dysfunction in chronic liver disease and a roadmap to new targeted therapies.