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FBP1 controls liver cancer evolution from senescent MASH hepatocytes

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机构： [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. ligu@scu.edu.cn. [2]Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. ligu@scu.edu.cn. [3]Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China. ligu@scu.edu.cn. [4]School of Medicine, Chongqing University, Chongqing, China. zhuyahui861106@foxmail.com. [5]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. zhuyahui861106@foxmail.com. [6]Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA, USA. [7]Department of Bioengineering, UCSD, La Jolla, CA, USA. [8]Moores Cancer Center, UCSD, La Jolla, CA, USA. [9]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. [10]Division of Endocrinology &amp [11] Metabolism, UCSD, La Jolla, CA, USA. [11]Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia. [12]Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia. [13]Department of Pharmacology, UCSD, La Jolla, CA, USA. [14]Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, CA, USA. [15]Department of Medicine, UCSD, La Jolla, CA, USA. [16]Department of Pathology, UCSD, La Jolla, CA, USA. [17]Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. [18]Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [19]Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [20]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. karinoffice@ucsd.edu.

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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.© 2025. The Author(s), under exclusive licence to Springer Nature Limited.

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第一作者：

第一作者机构： [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. ligu@scu.edu.cn. [2]Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. ligu@scu.edu.cn. [3]Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China. ligu@scu.edu.cn.

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通讯作者：

通讯机构： [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. ligu@scu.edu.cn. [2]Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. ligu@scu.edu.cn. [3]Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China. ligu@scu.edu.cn. [4]School of Medicine, Chongqing University, Chongqing, China. zhuyahui861106@foxmail.com. [5]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. zhuyahui861106@foxmail.com.

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