As reported on Bioengineer and ScienMag, a new spatial transcriptomics study has provided fresh insight into how different regions of the liver are remodeled during metabolic dysfunction-associated steatohepatitis (MASH). By preserving the tissue’s architecture during analysis, researchers demonstrated that hepatocytes, hepatic stellate cells, and immune-cell-rich areas each undergo unique metabolic and inflammatory changes as fibrosis progresses.
Published in Genome Medicine, the investigation analyzed liver samples from 16 individuals with MASH representing multiple stages of fibrosis, alongside eight control samples from people without the disease. Using the GeoMx Digital Spatial Profiler, researchers examined gene activity within specific tissue compartments rather than averaging signals across whole liver specimens. Immunofluorescence-guided pathology was used to identify regions enriched for hepatocytes, stellate cells, or immune cells, enabling compartment-specific molecular profiling.
The findings revealed that disease-associated alterations vary substantially by location. One of the most notable observations was widespread suppression of cytochrome P450 (CYP450) genes, which are involved in metabolic processing and detoxification. Reduced CYP450 expression was detected not only in hepatocyte-dominant regions but also in stellate cell- and immune cell-rich areas. At the same time, expression patterns showed an inverse relationship between CYP450 genes and pathways linked to inflammation and nuclear receptor signaling, suggesting a coordinated shift from metabolic functions toward inflammatory activity during disease progression.
As fibrosis advanced, nonparenchymal compartments exhibited evidence of significant mitochondrial impairment. These results indicate that energy-producing pathways become compromised in stromal and immune populations during later stages of MASH, extending metabolic dysfunction beyond hepatocytes alone.
The spatial approach also enabled researchers to examine communication networks between neighboring cell populations. Analysis of ligand-receptor interactions suggested that MASH is associated with the loss of potentially protective signaling pathways and an increase in interactions that may promote fibrosis. The data highlighted altered cross-talk involving macrophages and other cellular populations, changes that may be difficult to detect using conventional single-cell methods that require tissue dissociation.
Among the genes identified, IL32 emerged as a particularly consistent marker. Unlike many molecular changes that were restricted to specific compartments, IL32 expression increased across hepatocyte-, stellate cell-, and immune-cell-enriched regions, making it one of the few disease-associated signals shared throughout the liver microenvironment.
To strengthen their findings, the investigators compared the spatial transcriptomic data with multiple publicly available single-cell RNA sequencing datasets. The key molecular signatures were reproduced across these independent datasets, supporting the robustness of the observations. The team also identified 19 genes associated with MASH whose expression correlated with clinical and histologic measures, including fibrosis severity.
Importantly, expression of these genes shifted in the opposite direction following bariatric surgery, suggesting that at least some disease-associated molecular programs may be reversible. This observation provides clinical context for the spatial findings and raises the possibility that targeted interventions could partially restore healthier gene-expression patterns.
Further validation at the protein level confirmed altered hepatic expression of several key markers, including CYP1A2, IL32, and S100A8/9, reinforcing that the observed transcriptomic changes were reflected beyond RNA measurements.
While the study was observational and based on a relatively small collection of tissue samples, it offers one of the most detailed spatial views of human MASH to date. The results underscore the importance of compartment-specific metabolic suppression, immune activation, disrupted intercellular signaling, and fibrosis-related remodeling. They also identify IL32 and other consistently altered genes as promising candidates for future mechanistic and therapeutic research.
Overall, the work provides a framework for understanding how distinct liver cell populations coordinate their responses during MASH progression and how these changes may evolve with disease severity or improve following weight-loss interventions.
