FBP1 controls liver cancer evolution from senescent MASH hepatocytes

Li Gu (), Yahui Zhu (), Shuvro P. Nandi, Maiya Lee, Kosuke Watari, Breanna Bareng, Masafumi Ohira, Yuxiao Liu, Sadatsugu Sakane, Rodrigo Carlessi, Consuelo Sauceda, Debanjan Dhar, Souradipta Ganguly, Mojgan Hosseini, Marcos G. Teneche, Peter D. Adams, David J. Gonzalez, Tatiana Kisseleva, Janina E. E. Tirnitz-Parker, M. Celeste Simon, Ludmil B. Alexandrov and Michael Karin ()
Additional contact information
Li Gu: University of California San Diego (UCSD)
Yahui Zhu: Chongqing University
Shuvro P. Nandi: UCSD
Maiya Lee: University of California San Diego (UCSD)
Kosuke Watari: University of California San Diego (UCSD)
Breanna Bareng: University of California San Diego (UCSD)
Masafumi Ohira: University of California San Diego (UCSD)
Yuxiao Liu: University of California San Diego (UCSD)
Sadatsugu Sakane: UCSD
Rodrigo Carlessi: Curtin University
Consuelo Sauceda: UCSD
Debanjan Dhar: UCSD
Souradipta Ganguly: UCSD
Mojgan Hosseini: UCSD
Marcos G. Teneche: Sanford Burnham Prebys Medical Discovery Institute
Peter D. Adams: Sanford Burnham Prebys Medical Discovery Institute
David J. Gonzalez: UCSD
Tatiana Kisseleva: UCSD
Janina E. E. Tirnitz-Parker: Curtin University
M. Celeste Simon: University of Pennsylvania
Ludmil B. Alexandrov: UCSD
Michael Karin: University of California San Diego (UCSD)

Nature, 2025, vol. 637, issue 8045, 461-469

Abstract: Abstract Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH)1. While increasing HCC risk2, MASH triggers p53-dependent hepatocyte senescence3, which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed premalignant disease-associated hepatocytes and HCC progenitor cells4,5, paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and p53 degradation, AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing and proliferation-supportive NRF2–FBP1–AKT–p53 metabolic switch, operative in mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression.

Date: 2025
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DOI: 10.1038/s41586-024-08317-9

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