The Role of the OSM/OSMRβ Axis in Chronic Liver Disease Progression and Hepatocellular Carcinoma Development: A Focus on MASLD/MASH

: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the emerging leading cause of Chronic Liver Disease (CLD) worldwide, with a global prevalence of approximately 30% in the general population that parallels global rates of obesity and Type 2 Diabetes (T2D). Although two drugs (Resmetirom and Semaglutide) have been recently approved for clinical use, their ability to block or slow down disease progression to metabolic dysfunction-associated Steatohepatitis (MASH) and liver fibrosis is limited to a subset of patients, and no data are available at present for the efficacy of these drugs in compensated cirrhosis or in relation to hepatocellular carcinoma (HCC) development. Moreover, there is a lack of reliable biomarkers able to identify MASH patients at risk of disease progression and/or HCC development. In line with the knowledge that pro-inflammatory cytokines play a key role in MASLD/MASH progression and HCC development, in this review, we will discuss the role in this disease and other CLDs of Oncostatin M (OSM), a cytokine belonging to the IL6 family, and of pathways involving OSM and its receptor β (OSM/OSMRβ axis). OSM and related pathways are emerging as selective in sustaining disease progression by promoting chronic inflammation and fibrogenesis. The OSM/OSMRβ axis is proposed to be involved in MASH-related HCC development by affecting proliferation, angiogenesis, invasiveness and metastasis as well as by reshaping the MASH-related tumor immune microenvironment. OSM and the OSM/OSMRβ axis are emerging as a candidate biomarker and putative MASH-related therapeutic target.