Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease, characterised by hepatocyte death, ballooning, and inflammation, potentially leading to advanced fibrosis or cirrhosis and end-stage disease or hepatocellular carcinoma (HCC). In the steatotic liver, metabolic alterations and redox perturbations in hepatocytes result in an excess production of reactive oxygen species (ROS). This is accompanied initially by an upregulation of NFE2L2-orchestrated antioxidant defence pathways, but these eventually fail and decline facilitating the transition to MASH and fibrosis.
Prior work in our group has demonstrated that the increase in ROS in hepatocytes can oxidise and inactivate protein tyrosine phosphatases (PTPs), causing enhanced STAT-1 phosphorylation, which leads to the expression of chemoattractants and subsequent T cell accumulation. Ongoing work (see poster - Wiede et al.) shows that hepatocyte-derived ROS can also act in a paracrine manner on T cells and other neighbouring immune populations in the mouse liver, to promote CD8+ T cell activation and the progression to MASH/fibrosis and HCC. Using computational analyses of publicly available scRNA and snRNA datasets from human patients, we show that both hepatocytes and CD8+ T cells show a signature of oxidative distress in human MASH, consistent with exposure to increased ROS. Spatial transcriptomics of a human MASH cohort revealed a disease-specific ‘niche’ characterised by the spatial association of monocytes, T cells and NK cells. These cells, together with hepatocytes, colocalize with the spatially enriched expression of the ROS-detoxifying gene SOD2, as well as inflammatory markers and STAT target genes. Together, these findings lend support to the translatability of our discoveries in the mouse model to the pathology of MASH in a clinical setting.