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<p>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, <i>TREM2</i><sup><i>+</i></sup><i>S100A9</i><sup><i>+</i></sup> macrophages and <i>S100</i><sup><i>hi</i></sup><i>HLA</i><sup><i>lo</i></sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月29日

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  • Owen P. Martin,
  • Michael S. Wallace,
  • Christopher Oetheimer,
  • Hailey B. Patel,
  • Michael D. Butler,
  • Lai Ping Wong,
  • Pinzhu Huang,
  • Joshua Elbaz,
  • Charlotte Costentin,
  • Shadi Salloum,
  • Zoe Reinus,
  • Adaeze Obinelo,
  • Ulandt Kim,
  • Stuti Shroff,
  • Kathleen E. Corey,
  • Yury V. Popov,
  • Edgar D. Charles,
  • Ruslan I. Sadreyev,
  • Raymond T. Chung,
  • Nadia Alatrakchi

摘要

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 S100hiHLAlo 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.