Detailed Liver Atlas Links Macrophage Activity to MASH Progression

Long before fibrosis reshapes the liver’s architecture, subtle cellular conversations begin to determine whether steatosis will remain benign or progress toward more serious disease. New high-resolution data suggested that these interactions—particularly those involving immune cells and lipid metabolism—played a defining role in metabolic dysfunction–associated steatohepatitis (MASH), offering potential clues for future therapeutic targeting.1

Liver disease | Image credit: Aliaksandr Marko - stock.adobe.com

Investigators reported the creation of a spatially resolved, multi-omics atlas of human metabolic dysfunction–associated steatotic liver disease (MASLD), including MASH, integrating single-cell transcriptomics, spatial transcriptomics, and spatial metabolomics across disease stages. The analysis, published in Nature Genetics, characterized how immune and parenchymal cells were organized within liver tissue and identified molecular programs associated with disease severity.

MASLD, formerly referred to as nonalcoholic fatty liver disease, represents a spectrum ranging from isolated steatosis to MASH, a more severe form marked by inflammation and fibrosis that can progress to cirrhosis and hepatocellular carcinoma.2 Although prior single-cell sequencing studies improved understanding of cellular heterogeneity in MASLD, they largely lacked spatial context, limiting insight into how cell populations interacted within specific liver microenvironments.1

The authors noted that liver biology is inherently zonated, with metabolic and immune functions varying along the portal-to-central axis of the hepatic lobule. Without spatial resolution, critical region-specific mechanisms—particularly those driving fibrosis and inflammation—could be missed. The study aimed to address this gap by combining multiple high-resolution approaches to map gene expression, immune composition, and metabolite distribution within intact human liver tissue.

The analysis included liver samples from 61 individuals: 10 controls without MASLD, 17 with metabolic dysfunction–associated steatotic liver (MASL), and 34 with MASH. Samples were obtained from liver biopsies or surgical resections and classified by histologic criteria.

Single-cell RNA sequencing generated transcriptomic profiles for 540,216 cells across 29 livers, whereas spatial transcriptomics analyzed 47,864 tissue spots from 35 livers. Spatial metabolomics using mass spectrometry imaging was performed on a subset of 27 tissue sections. These datasets were integrated to produce a spatial multi-omics map spanning disease progression.

One of the central findings involved lipid-associated macrophages (LAMs), a subset of immune cells enriched in fatty liver disease. The authors observed that LAMs increased in abundance with disease severity and were particularly expanded in individuals with MASH compared with those with MASL. Spatial analysis localized these cells predominantly to pericentral regions, areas known to be vulnerable to hypoxia and metabolic stress.

The investigators identified microphthalmia-associated transcription factor (MITF) as a key regulator of the lipid-handling phenotype of LAMs. MITF activity was selectively elevated in LAMs and was highest in samples from individuals with MASH. Gene ontology analysis showed that MITF-regulated genes were enriched for lipid metabolism pathways, including triglyceride and lipoprotein processing.

Experimental overexpression of MITF in a human monocyte cell line increased expression of canonical LAM markers and lipid metabolism genes, while MITF knockdown had the opposite effect. These results suggested a causal role for MITF in shaping macrophage function in MASLD.

In addition to immune remodeling, spatial transcriptomics identified a fibrosis-associated gene program enriched in advanced MASH. This program reflected coordinated signaling between central vein endothelial cells and hepatic stellate cells within fibrotic regions, supporting the concept of localized profibrotic niches rather than diffuse liver-wide activation.

Spatial metabolomics further revealed MASLD-specific accumulation of phospholipids, which the authors linked to altered phospholipid metabolism mediated by LAMs, including pathways involving lipoprotein-associated phospholipase A2.

According to the investigators, integrating spatial and molecular data was essential for understanding disease mechanisms. “This spatially resolved multi-omics atlas of human MASLD provides a valuable resource for mechanistic and therapeutic studies,” the authors wrote, emphasizing that the dataset allows researchers to interrogate gene and metabolite expression within defined tissue microenvironments.

The study had several limitations. The sample size, although large for a spatial multi-omics analysis, remained modest, particularly for control tissues. Not all samples were analyzed across every modality, which may have limited some integrative comparisons. Additionally, the cross-sectional design precluded conclusions about temporal disease progression within individuals.

The authors also noted that certain immune cell populations, such as neutrophils and mast cells, were underrepresented due to technical challenges associated with tissue dissociation and RNA degradation.

Although the study was not designed to assess clinical outcomes or treatment response, its findings may have implications for therapeutic development in MASH. By identifying spatially localized immune and metabolic programs associated with disease severity, the atlas may help prioritize cell-specific or pathway-targeted interventions.

References

1. Li Z. Luo G, Gan C, et al. Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease. Nat Genet. 2025;57(12):3112-3125. doi:10.1038/s41588-025-02407-8

2. Metabolic dysfunction-associated steatotic liver disease (MASLD). Children’s Hospital of Philadelphia. Accessed January 16, 2026. https://www.chop.edu/conditions-diseases/metabolic-dysfunction-associated-steatotic-liver-disease-masld