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<p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide. We generated single-cell and spatial transcriptomic and metabolomic maps from 61 human livers, including controls (<i>n</i> = 10), metabolic dysfunction-associated steatotic liver (MASL) (<i>n</i> = 17) and metabolic dysfunction-associated steatohepatitis (MASH) (<i>n</i> = 34). We identified microphthalmia-associated transcription factor (MITF) as a key regulator of the lipid-handling capacity of lipid-associated macrophages (LAMs), and further revealed a hepato-protective role of LAMs mediated through hepatocyte growth factor secretion. Unbiased deconvolution of spatial transcriptomics delineated a fibrosis-associated gene program enriched in advanced MASH, suggesting profibrotic crosstalk between central vein endothelial and hepatic stellate cells within fibrotic regions. Mass spectrometry imaging-based spatial metabolomics demonstrated MASLD-specific accumulation of phospholipids, potentially linked to lipoprotein-associated phospholipase A<sub>2</sub>-mediated phospholipid metabolism in LAMs. This spatially resolved multi-omics atlas of human MASLD, which can be queried at the <a href="http://db.genomics.cn/stomics/hmsma/">Human Masld Spatial Multiomics Atlas</a>, provides a valuable resource for mechanistic and therapeutic studies.</p>

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Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • Ziyu Li,
  • Gang Luo,
  • Changpei Gan,
  • Huayu Zhang,
  • Ling Li,
  • Xiaoxun Zhang,
  • Xudong Xing,
  • Simeng Hu,
  • Xu Tan,
  • Jingjing Ding,
  • Liangjun Zhang,
  • Ying Peng,
  • Ziqian Xu,
  • Qiong Pan,
  • Christopher D. Byrne,
  • Giovanni Targher,
  • Xiao-Zhi Jin,
  • Wei Xie,
  • Xinshou Ouyang,
  • Ming-Hua Zheng,
  • Fan Bai,
  • Jin Chai

摘要

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide. We generated single-cell and spatial transcriptomic and metabolomic maps from 61 human livers, including controls (n = 10), metabolic dysfunction-associated steatotic liver (MASL) (n = 17) and metabolic dysfunction-associated steatohepatitis (MASH) (n = 34). We identified microphthalmia-associated transcription factor (MITF) as a key regulator of the lipid-handling capacity of lipid-associated macrophages (LAMs), and further revealed a hepato-protective role of LAMs mediated through hepatocyte growth factor secretion. Unbiased deconvolution of spatial transcriptomics delineated a fibrosis-associated gene program enriched in advanced MASH, suggesting profibrotic crosstalk between central vein endothelial and hepatic stellate cells within fibrotic regions. Mass spectrometry imaging-based spatial metabolomics demonstrated MASLD-specific accumulation of phospholipids, potentially linked to lipoprotein-associated phospholipase A2-mediated phospholipid metabolism in LAMs. This spatially resolved multi-omics atlas of human MASLD, which can be queried at the Human Masld Spatial Multiomics Atlas, provides a valuable resource for mechanistic and therapeutic studies.