Endocrine Abstracts

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the main hepatic manifestation of obesity. MASLD was recently defined as liver steatosis in the presence of at least one cardiometabolic risk factor and reduced or absent alcohol intake. MASLD prevalence is rapidly increasing, thus becoming the fastest growing aetiology of the most common primary liver cancer, hepatocellular carcinoma (HCC), and the leading cause of liver transplantation in HCC patients. Currently, there is no EMA/FDA approved drug specifically for MASLD treatment. In this scenario, neuroendocrine control regulatory systems, such as the ghrelin system, have been previously proven to be a reliable source of biomarkers and therapeutic opportunities in multiple endocrine-related cancer types (e.g., breast, prostate and pituitary tumours). Therefore, the purpose of this work was to assess the expression and possible clinical relevance of ghrelin system components (GSCs: ligands, receptors, etc.) in the MASLD-HCC progression. To achieve this, we analysed GSCs mRNA expression in 2 internal retrospective cohorts of chronic liver disease (CLD) and HCC [Retrospective-1: HCC vs non-tumoral adjacent tissue (NTAT) (n=80); Retrospective-2: HCC vs NTAT (n=58), cirrhotic (n=33) and healthy liver tissue (n=5)], 10 in silico cohorts [7 MASLD, 3 HCC; n=(45-369)], 4 diet-based mice models recapitulating MASLD-HCC progression (C57BL/6J, n=119) and 3 human cell lines modelling healthy liver (THLE-2) and HCC (Hep3B, SNU-387). Statistical associations with key clinical features of HCC were performed. In the HCC cell lines, the impact of GSCs administration on important tumour aggressiveness parameters was evaluated using different functional assays (proliferation, migration, colony and hepatosphere formation). Some GSCs showed a progressively increasing expression according to MASLD stage, followed by a drastic downregulation in HCC. This pattern was consistently observed through every cohort and in vivo and in vitro model, suggesting a biphasic GSCs expression regulation in CLD. Moreover, the inhibition of key GSCs in HCC was associated with several clinical features of tumoral aggressiveness such as histological differentiation, survival and recurrence rate, microvascular invasion and tumour nodule number and size. Remarkably, the in vitro administration of certain ligands of the GSC strongly hindered HCC cells proliferation and colony and hepatosphere formation. In contrast, healthy liver cells viability rate was not affected by these GSC ligands, suggesting a clinically safe approach. In conclusion, GSCs could be major players in the physiopathology of CLD as drivers of MASLD-derived hepatocarcinogenesis and the ghrelin system could represent a novel, yet unexplored origin of biomarkers and therapeutic options for CLD.