DB18 Dysregulation of the Liver-Adipose crosstalk in metabolic-driven hepatic oncogenesis
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major complication of obesity. Although the endocrine-crosstalk mediated by adipo- and hepatokines is crucial for metabolic homeostasis, its precise molecular involvement in the progressive transition toward steatohepatitis (MASH) and hepatocellular carcinoma (HCC) remains poorly characterized. This study aimed to comprehensively analyse these alterations throughout the MASLD-MASH-HCC continuum to identify non-invasive biomarkers and actionable therapeutic targets. We evaluated the expression profiles of 56 adipo- and hepatokines in normal and diseased hepatic tissues across 18 well-defined patient cohorts spanning MASLD, MASH, and HCC phenotypes. This integrated in-house retrospective tissue biopsies with extensive in silico transcriptomic datasets. Key candidates were further validated at protein level in patient serum by ELISA assays. Finally, their functional impact on tumour cell proliferation was assessed in vitro using Hep3B and SNU-387 human HCC cell lines. A progressive and consistent dysregulation of multiple adipo- and hepatokines was identified across the entire disease spectrum. Notably, ANGPTL2, ANGPT1, and ITLN1 exhibited the most robust, reproducible alterations across independent cohorts, which was successfully confirmed by circulating serum analysis. Functionally, treatment with ANGPTL2 and ITLN1 significantly reduced HCC cell proliferation. In sharp contrast, ANGPT1 administration markedly increased tumour cell proliferation, suggesting a distinct, divergent role in metabolic-driven hepatic tumour progression. These findings demonstrate a profound, stage-dependent disruption of the liver-adipose tissue axis during metabolic-driven hepatic oncogenesis, positioning ANGPTL2, ANGPT1, and ITLN1 as promising biomarkers and potential therapeutic targets in HCC. Funding: ISCIII(PI23/00652; DTS24/00093; co-financed UE), JdA(PI-0046-2024, BIO139), FSEEN & CIBERobn/ehd.