FBP1 controls liver cancer evolution from senescent MASH hepatocytes.

Area of Science:

• Hepatology
• Oncology
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) arises from liver damage due to viruses or metabolic dysfunction-associated steatohepatitis (MASH).
• MASH induces hepatocyte senescence, a tumor-suppressive response, but the mechanisms by which this is bypassed to promote HCC remain unclear.
• Senescence is linked to DNA damage, and understanding its role in HCC development is crucial.

Purpose of the Study:

• To elucidate how the tumor-suppressive senescence response is circumvented in MASH-induced HCC.
• To identify key molecular players involved in the transition from MASH to HCC.
• To understand the role of fructose-1,6-bisphosphatase 1 (FBP1) in HCC pathogenesis.

Main Methods:

• Identification of FBP1 as a p53 target gene.
• Analysis of FBP1 expression in senescent MASH hepatocytes versus human HCCs.
• Investigation of the roles of AKT and NRF2 in regulating FBP1 and p53 degradation.
• Studies in mouse models and human samples to validate the findings.

Main Results:

• FBP1 is elevated in senescent MASH hepatocytes but suppressed in most human HCCs via promoter hypermethylation and proteasomal degradation.
• FBP1 levels decrease in premalignant hepatocytes and HCC progenitor cells, coinciding with AKT and NRF2 activation.
• AKT and NRF2 accelerate FBP1 and p53 degradation, promoting proliferation and metabolic activity of senescent HCC progenitors.
• A senescence-reversing metabolic switch involving NRF2, FBP1, AKT, and p53 facilitates DNA-damage accumulation for MASH-to-HCC progression.

Conclusions:

• The decline of FBP1, driven by AKT and NRF2, is a critical step in bypassing senescence and enabling HCC development from MASH.
• This NRF2-FBP1-AKT-p53 metabolic pathway promotes the accumulation of mutations necessary for liver cancer progression.
• Targeting this pathway could offer new therapeutic strategies for MASH-associated HCC.