Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease
Zhuohan 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, Xiaozhi Jin, Xie Wei, Xinshou Ouyang, Ming‐Hua Zheng, Fan Bai, Jin Chai
Abstract
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. Spatially resolved transcriptomic, metabolomic and proteomic analyses of human liver samples highlight the role of lipid-associated macrophages in metabolic dysfunction-associated steatotic liver disease.