EP909 - ECE_2236 - RNA-exosome dysregulation: core and PAXT complexes as novel mediators of MASLD-HCC oncogenesis

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Abstract Metabolic-associated steatotic liver disease (MASLD) has emerged as the primary chronic liver dysfunction worldwide, frequently culminating in the development of hepatocellular carcinoma (HCC). Emerging evidence underscores the critical importance of RNA metabolism and surveillance in liver pathophysiology, where the RNA-Exosome complex plays a decisive role. Nevertheless, the precise molecular mechanisms and the specific contributions of this machinery during the pathological transition from metabolic steatosis to malignancy remain to be fully elucidated. Our objective was to characterize the dysregulation of various RNA-Exosome complexes across the MASLD-HCC spectrum and to explore their subsequent clinical and functional implications. To this end, we evaluated the expression profile of the RNA-Exosome machinery across 18 independent cohorts (2 retrospective and 16 in silico) of MASLD, Metabolic Dysfunction-Associated Steatohepatitis (MASH), MASH-related HCC, HCC and control (normal or adjacent tissue) samples. To identify the most relevant alterations, we employed VIP-score (Variable Importance in Projection) ranking, selecting those complexes that exhibited the most significant dysregulation within tumor samples (Top-10 VIP-score). Clinical associations and Gene Set Enrichment Analysis (GSEA) were complemented by extensive in vitro and in vivo functional assays through the targeted molecular modulation of representative complex components. Our results demonstrate a profound and progressive dysregulation of the RNA-Exosome machinery, with a generalized overexpression from early MASLD to HCC. Specifically, the Core and PAXT complexes emerged as the most altered machineries across all cohorts. High expression of these complexes, represented by key components such as EXOSC4 (Core) and ZFC3H1 (PAXT), significantly correlated with poor overall survival, increased invasiveness, and the enrichment of oncogenic pathways like MYC targets and mTOR signaling. In vitro silencing of these specific components significantly reduced tumor aggressiveness parameters (cell proliferation, migration, colony formation, and sphere-forming capacity), whereas their overexpression promoted a more malignant phenotype. Crucially, in vivo studies confirmed the pro-tumorigenic potential of the machinery, where silencing Core components inhibited tumor growth, while its induction significantly increased tumor volume and progression. In conclusion, our findings demonstrate that the RNA-Exosome machinery, driven by its Core and PAXT complexes, is a critical regulator of the MASLD-HCC axis. This study highlights the entire RNA-Exosome machinery as a promising source of prognostic biomarkers and a novel therapeutic vulnerability in the context of metabolic dysregulations and, specifically, MASLD-HCC. Funding ISCIII (PI23/00652, co-funded by the European Union), JdA (PI-0046-2024, BIO-0139), FSEEN, CIBERobn and CIBERehd.

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