Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease
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 A<sub>2</sub>-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.
Authors
- Fan Bai (ORCID: https://orcid.org/0000-0001-6119-8936)
- Changpei Gan
- Jin Chai (ORCID: https://orcid.org/0000-0002-8543-4566)
- Ming‐Hua Zheng (ORCID: https://orcid.org/0000-0003-4984-2631)
- Ying Peng (ORCID: https://orcid.org/0000-0002-6459-3154)
- Simeng Hu (ORCID: https://orcid.org/0000-0002-2446-3929)
- Qiong Pan (ORCID: https://orcid.org/0000-0003-1033-3098)
- Jingjing Ding (ORCID: https://orcid.org/0000-0003-1508-7084)
- Xie Wei (ORCID: https://orcid.org/0000-0002-9396-3337)
- Xudong Xing (ORCID: https://orcid.org/0000-0003-0681-9378)
- Xiaozhi Jin
- Xiaoxun Zhang (ORCID: https://orcid.org/0000-0002-3892-7464)
- Giovanni Targher (ORCID: https://orcid.org/0000-0002-4325-3900)
- Xinshou Ouyang (ORCID: https://orcid.org/0000-0003-3423-0042)
- Gang Luo (ORCID: https://orcid.org/0000-0003-1544-1434)
- Christopher D. Byrne (ORCID: https://orcid.org/0000-0001-6322-7753)
- Ling Li (ORCID: https://orcid.org/0000-0002-9027-7307)
- Ziqian Xu
- Huayu Zhang (ORCID: https://orcid.org/0000-0003-1625-4067)
- Liangjun Zhang (ORCID: https://orcid.org/0000-0002-7053-8661)
- Xu Tan (ORCID: https://orcid.org/0009-0007-6126-6549)
- Zhuohan Li (ORCID: https://orcid.org/0009-0006-2927-8067)
Institutions
- Army Medical University (CN)
- Hebei University of Technology (CN)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Wenzhou Medical University (CN)
- Southampton General Hospital (GB)
- Beijing Institute of Genomics (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- University Hospital Southampton NHS Foundation Trust (GB)
- Yale University (US)
- Affiliated Hospital of Southwest Medical University (CN)
- Ospedale Sacro Cuore Don Calabria (IT)
- Xinqiao Hospital (CN)
- Southwest Hospital (CN)
- Beijing Advanced Sciences and Innovation Center (CN)
- University of Southampton (GB)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41588-025-02407-8
- Citations
- 4
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 3.22