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; Liver Cancer Collaborative; Janina E E Tirnitz-Parker; M Celeste Simon; Ludmil B Alexandrov; Michael Karin

doi:10.1038/s41586-024-08317-9

FBP1 controls liver cancer evolution from senescent MASH hepatocytes

Nature. 2025 Jan 1. doi: 10.1038/s41586-024-08317-9. Online ahead of print.

Authors

Li Gu^#^{1

2

3}, Yahui Zhu^#^{4

5

6}, Shuvro P Nandi^{7

8

9}, Maiya Lee¹⁰, Kosuke Watari¹⁰, Breanna Bareng¹⁰, Masafumi Ohira¹⁰, Yuxiao Liu¹⁰, Sadatsugu Sakane¹¹, Rodrigo Carlessi^{12

13}, Consuelo Sauceda^{14

15}, Debanjan Dhar¹⁶, Souradipta Ganguly¹⁶, Mojgan Hosseini¹⁷, Marcos G Teneche¹⁸, Peter D Adams¹⁸, David J Gonzalez^{14

15}, Tatiana Kisseleva¹¹; Liver Cancer Collaborative; Janina E E Tirnitz-Parker^{12

13}, M Celeste Simon^{19

20}, Ludmil B Alexandrov^{7

8

9}, Michael Karin²¹

Collaborators

Liver Cancer Collaborative:
Janina E E Tirnitz-Parker, Peter J Leedman, Michael C Wallace, Louise N Winteringham, Benjamin J Dwyer, Jonathan Tibballs, Kim W Carter, Alistair R R Forrest

Affiliations

¹ Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA. [email protected].
² Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. [email protected].
³ Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China. [email protected].
⁴ Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA. [email protected].
⁵ School of Medicine, Chongqing University, Chongqing, China. [email protected].
⁶ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. [email protected].
⁷ Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA, USA.
⁸ Department of Bioengineering, UCSD, La Jolla, CA, USA.
⁹ Moores Cancer Center, UCSD, La Jolla, CA, USA.
¹⁰ Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA.
¹¹ Division of Endocrinology & Metabolism, UCSD, La Jolla, CA, USA.
¹² Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia.
¹³ Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia.
¹⁴ Department of Pharmacology, UCSD, La Jolla, CA, USA.
¹⁵ Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, CA, USA.
¹⁶ Department of Medicine, UCSD, La Jolla, CA, USA.
¹⁷ Department of Pathology, UCSD, La Jolla, CA, USA.
¹⁸ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹⁹ Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁰ Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²¹ Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA. [email protected].

^# Contributed equally.

PMID: 39743585
DOI: 10.1038/s41586-024-08317-9

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 cells^4,5, 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.