Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease globally, encompassing the entire disease spectrum from metabolic dysfunction-associated steatotic liver (MASL, i.e., simple hepatic fat accumulation) to metabolic dysfunction-associated steatohepatitis (MASH). Among these, MASH is characterized by hepatocyte injury, inflammatory responses, and varying degrees of fibrosis, representing a critical stage of disease progression that can further develop into cirrhosis and even hepatocellular carcinoma.

The pathological process of MASLD is highly complex, involving a series of metabolic-immune interaction networks between hepatic parenchymal cells and various types of non-parenchymal cells, and there is currently a lack of targeted and effective clinical treatments. Although cutting-edge technologies like single-cell omics have provided important clues for understanding the cellular heterogeneity of MASLD, systematic studies on cell distribution, metabolic states, and intercellular interactions of human liver tissues within their true spatial structure remain significantly insufficient.

On November 24, 2025, Professor Fan Bai from the Biomedical Pioneering Innovation Center (BIOPIC) at Peking University/Peking-Tsinghua Center for Life Sciences, in collaboration with Professor Jin Chai from the First Affiliated Hospital of Army Medical University (Southwest Hospital), Professor Ming-Hua Zheng from the First Affiliated Hospital of Wenzhou Medical University, and Professor Xinshou Ouyang from Yale University School of Medicine, published a research paper online in Nature Genetics titled "Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease". The research team conducted a multi-modal joint analysis of single-cell, spatial transcriptomics, and spatial metabolomics on 61 liver samples from healthy controls, MASL, and MASH patients, constructing the largest human MASLD liver spatial multi-omics atlas to date (https://db.genomics.cn/stomics/hmsma/), and systematically revealing the spatial variation patterns of cellular composition, gene expression, and metabolic states during MASLD progression (Figure 1).

Figure 1: Collection of the human MASLD disease cohort and construction of the spatial multi-omics atlas

Previously, multiple studies have revealed that as MASLD progresses, the self-renewal capacity of liver-resident Kupffer cells (KCs) is impaired, and they are gradually replaced by monocyte-derived macrophage subsets. In areas of lipid accumulation and fibrosis, monocyte-derived lipid-associated macrophages (LAMs) are specifically enriched and exhibit significant lipid uptake and metabolic capabilities. By constructing a cell-type-specific gene regulatory network (GRN), this study identified for the first time that the microphthalmia-associated transcription factor (MITF) is the core transcription factor driving the lipid metabolism phenotype of LAMs (Figure 2).

Figure 2: MITF is a key regulatory factor controlling the lipid processing function of LAMs

Utilizing differential intercellular signal flow analysis, the study found that LAMs are an important source of hepatocyte growth factor (HGF) signaling, which is significantly enhanced during the MASH stage. In vitro experiments confirmed that LAM-conditioned medium can significantly promote hepatocyte proliferation and inhibit lipotoxic apoptosis, indicating that LAMs can promote hepatocyte repair and survival through the HGF–MET signaling axis, constituting a key macrophage-mediated hepatoprotective mechanism in MASLD progression. This result reveals that LAMs not only possess lipid clearance functions but also have a paracrine role in promoting tissue repair, redefining their role in MASLD pathology (Figure 3).

Figure 3: LAMs exert hepatoprotective effects via the HGF–MET signaling axis

By applying topic modeling to the spatial transcriptomic data, the study identified an extracellular matrix remodeling spatial gene module characterized by typical fibrosis-related genes such as COL1A1, COL1A2, LOXL1, LUM, and MFAP4, which is highly active in MASH patients at the F3–4 stages (severe fibrosis). Spatial mapping results showed that the activity distribution of this module is highly consistent with hepatic stellate cells (HSCs) and central vein endothelial cells. Further ligand-receptor interaction analysis revealed a potential pro-fibrotic signaling link between RSPO3 secreted by central vein endothelial cells and the receptor LGR6 expressed by HSCs, suggesting that cellular communication between the two may be an important driving factor in the formation of MASLD-associated fibrosis, providing new biological clues for dissecting the liver fibrosis microenvironment and developing anti-fibrotic therapeutic targets (Figure 4).

Figure 4: MASH-associated fibrosis-specific spatial gene expression modules and cellular interaction mechanisms

Spatial metabolomics analysis showed that phospholipid molecules containing ultra-long-chain fatty acids significantly accumulate in the liver tissues of MASLD patients, and their enrichment worsens with disease progression. Alignment with spatial transcriptomic images revealed that this area of abnormal phospholipid metabolism highly overlaps with the spatial enrichment area of LAMs, suggesting that LAMs are closely related to phospholipid metabolic remodeling in the lesion areas. Further analysis found that PLA2G7, which encodes lipoprotein-associated phospholipase A2 (Lp-PLA2), is specifically expressed in LAMs during MASLD and can be upregulated under oxidative phospholipid stimulation. Previous studies have shown that the intrahepatic accumulation of oxidative phospholipids can induce ferroptosis in KCs and promote fibrosis, while Lp-PLA2 helps reduce lipid peroxidation and inhibit ferroptosis. Based on this, the study infers that LAMs, under the regulation of MITF, acquire an intrinsic resistance to ferroptosis by upregulating PLA2G7, thereby exerting a stable metabolic regulatory role in the MASLD pathological microenvironment (Figure 5).

Figure 5: Spatial metabolomics reveals MASLD-specific phospholipid accumulation and metabolic remodeling

In summary, based on the multi-modal integrated analysis of single-cell, spatial transcriptomics, and spatial metabolomics, this study systematically depicts the remodeling rules of cellular composition, gene regulatory networks, and metabolic pathways in the livers of MASLD patients from a spatial dimension for the first time. At the mechanistic level, the study confirmed that MITF is the core transcription factor driving the lipid metabolism phenotype of LAMs and revealed the hepatoprotective effects mediated by LAMs through the HGF–MET signaling axis, expanding the functional understanding of this key macrophage subset in the disease. This research provides an important theoretical foundation and data resources for deeply understanding the pathological progression mechanisms of MASLD, identifying key intervention targets, and developing precise treatment strategies.

Ziyu Li (Ph.D. student at the School of Life Sciences/Biomedical Pioneering Innovation Center, Peking University), Dr. Gang Luo, Dr. Changpei Gan, Dr. Huayu Zhang, and Master's student Ling Li from Southwest Hospital are the co-first authors of this paper. Professor Jin Chai from Southwest Hospital, Professor Fan Bai from Peking University, Professor Ming-Hua Zheng from Wenzhou Medical University, and Professor Xinshou Ouyang from Yale University are the co-corresponding authors. The research was funded by the National Natural Science Foundation of China, the National Key Research and Development Program, the Project of Chongqing University Innovation Research Group/Outstanding Medical Research Group, the Beijing Natural Science Foundation, and the Xplorer Prize, among others.

Paper Link: https://www.nature.com/articles/s41588-025-02407-8