Endocrine Abstracts

JOINT1763

Metabolic-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease and can progress to hepatocellular carcinoma (HCC). Understanding the molecular mechanisms underlying MASLD progression to HCC is essential for developing effective therapeutic strategies. Previous studies have suggested that RNA processing and metabolic machinery, including the RNA-Exosome complex, may play a pivotal role in MASLD-HCC progression. However, the specific role and contributions of the RNA-Exosome complex in HCC development remain poorly understood. The aim of this study was to characterize the dysregulation and putative role of the RNA-exosome machinery, specifically the component EXOSC4, in MASLD-HCC progression to identify new diagnostic/prognostic biomarkers and/or potential therapeutic targets. Bioinformatic approaches were implemented to analyze the dysregulation of the RNA-exosome machinery and to characterize, in silico, the expression of EXOSC4 at mRNA/protein levels in MASLD, MASLD-related HCC, Metabolic Dysfunction-Associated Steatohepatitis (MASH), HCC and control (normal or adjacent tissue) samples in 16 cohorts (2 retrospective and 14 in silico). Correlations between EXOSC4 expression and clinical parameters relevant to MASLD-HCC progression were evaluated. Pathway enrichment analyses were performed to identify associated cellular and molecular processes. Finally, the role of EXOSC4 was characterized <i>in vitro</i>(proliferation, migration, clonogenic and tumorosphere formation assays) by modulating its expression (silencing and overexpression) in two liver-derived cell lines (Hep3B and SNU-387) and in vivo through a preclinical model of Hep3B-induced xenograft tumors. These analyses revealed that the RNA-exosome machinery is dysregulated in MASLD and HCC. Specifically, the EXOSC4 component was consistently overexpressed in the cohorts studied, wherein high EXOSC4 expression was associated with clinical parameters of malignancy, such as poor survival, increased invasion and recurrence capacity. Consistently, high EXOSC4 expression was associated with the enrichment of oncogenic pathways, such as cell cycle regulation or DNA repair. Consistent with these results, <i>in vitro</i>assays demonstrated that EXOSC4 silencing reduced classical parameters tumor aggressiveness, while EXOSC4 overexpression increased malignancy. Furthermore, in vivo studies confirmed the pro-tumorigenic potential of EXOSC4 by inducing tumor growth in murine models. In conclusion, our results reveal a critical role of the RNA-Exosome machinery, particularly the EXOSC4 component in MASLD-CHC progression. These results suggest that EXOSC4 may serve as a potential biomarker and/or therapeutic target for this pathology. Fundings: ISCIII (PI20/01301, PI23/00652, co-funded by the European Union), JdA(PI-0046-2024, PEMP-0036-2020, BIO-0139), FSEEN y CIBERobn/ehd