AMBRA1-mediated nucleocytoplasmic control promotes early onset of liver cancer

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, largely driven by uncontrolled cell proliferation and the loss of tumor suppressor activity in the liver. By analyzing publicly available genome-wide CRISPR screening datasets, we identified AMBRA1 as a strong anti-proliferative candidate. Analysis of a clinical HCC patient cohort revealed that AMBRA1 expression was significantly reduced in tumor tissues, and its downregulation was tightly associated with poor patient outcomes. The downregulation of AMBRA1 was consistently validated in multiple HCC mouse models established through somatic mutations and high-fat diet challenge at early stages. Functionally, CRISPR-mediated knockout of AMBRA1 accelerated early spontaneous liver tumor initiation in vivo. AMBRA1 co-immunoprecipitated with key proteins involved in nucleocytoplasmic transport, suggesting a novel function for AMBRA1 in modulating nucleocytoplasmic trafficking in HCC. Collectively, our findings establish AMBRA1 as a bona fide tumor suppressor with clinical and functional importance in HCC.