FBP1 controls liver cancer evolution from senescent MASH hepatocytes

• 成果类型: Article
• 署名作者: Gu, Li; Zhu, Yahui; Nandi, Shuvro P.; Lee, Maiya; Watari, Kosuke; Bareng, Breanna; Ohira, Masafumi; Liu, Yuxiao; Sakane, Sadatsugu; Carlessi, Rodrigo; Sauceda, Consuelo; Dhar, Debanjan; Ganguly, Souradipta; Hosseini, Mojgan; Teneche, Marcos G.; Adams, Peter D.; Gonzalez, David J.; Kisseleva, Tatiana; Tirnitz-Parker, Janina E. E.; Simon, M. Celeste; Alexandrov, Ludmil B.; Karin, Michael
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; Sichuan University; Sichuan University; Chongqing University; Sichuan University; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; Curtin University; University of Western Australia; Harry Perkins Institute of Medical Research; Queen Elizabeth II Medical Centre; University of Western Australia; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; Sanford Burnham Prebys Medical Discovery Institute; University of Pennsylvania; University of Pennsylvania
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1468
• DOI: 10.1038/s41586-024-08317-9
• 发表日期: 2025-01-09
• 页码: 461-+
• 关键词: oncogene-induced senescence; hcc; progression; degradation; mouse

摘要

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 risk(2), MASH triggers p53-dependent hepatocyte senescence(3), 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, operativein mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression.