‌Case Study: FBP1 Controls Liver Cancer Evolution from Senescent MASH Hepatocytes

FBP1 Controls Liver Cancer Evolution from Senescent MASH Hepatocytes

Published in Nature (2025), DOI: 10.1038/s41586-024-08317-9

Research Background

Hepatocellular carcinoma (HCC) often arises from hepatocytes undergoing compensatory proliferation in livers damaged by metabolic-dysfunction-associated steatohepatitis (MASH). While MASH triggers p53-dependent hepatocyte senescence, the mechanisms bypassing this tumor-suppressive response to enable HCC progression were unclear. This study identifies fructose-1,6-bisphosphatase 1 (FBP1) as a key mediator linking senescence reversal to oncogenic mutagenesis in MASH-driven HCC.

Methods

Human and mouse models

Analyzed 83 human HCC tumors and adjacent non-tumor tissues for FBP1, p53, and senescence markers.
Utilized MUP-uPA mice fed high-fructose diets to model MASH-HCC progression.
Generated hepatocyte-specific Fbp1 and Trp53 knockout mice to validate mechanistic roles.

Molecular analysis

Immunohistochemistry and immunoblotting quantified protein expression (FBP1, ALDOB, AKT, NRF2).
snRNA-seq identified disease-associated hepatocytes and HCC progenitors in human MASH and mouse models.
Whole genome sequencing and duplex sequencing to characterize mutational signatures (C>T transitions in HFrD-induced HCCs, T>C transitions in NRASG12V-driven tumors).

Functional validation

Reconstituted Fbp1^ΔHep livers with Fbp1-WT or Fbp1^E98A, suppressing HCC via AKT inhibition.
Used MK-2206 and nutlin-3a to reverse senescence, assessing AKT and p53 roles in tumorigenesis.
Lineage tracking in mT/mG mice demonstrated that oncogenic mutations first arise in stressed and DNA-damaged hepatocytes.

Key Results

71% of human HCCs showed FBP1 loss, linked to AKT pathway activation and p53/p21 suppression.
FBP1 promoter hypermethylation (63% of HCCs) and TP53 mutations further lead to loss of FBP1 expression.
FBP1 deficiency triggered AKT/NRF2 signaling, leading to p53 inactivation and proliferation of senescent HCC precursors.
Lineage tracing confirmed HCC emergence from DNA-damaged, reversibly senescent hepatocytes.
AKT and MDM2 inhibitors suppressed tumor progression in mouse models.

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References

This study demonstrates that FBP1 loss, driven by epigenetic silencing and NRF2/ERK-mediated degradation, is a hallmark of human HCC, promoting AKT activation and p53 suppression. This enables senescence escape in DNA-damaged hepatocytes, which then elucidates the molecular link between metabolic deregulation and tumorigenesis, offering insights for HCC treatment.

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