美国加州大学圣迭戈分校Michael Karin等研究人员合作发现，FBP1通过衰老的MASH肝细胞调控肝癌的演化。相关论文于2025年1月1日在线发表在《自然》杂志上。

研究人员表示，肝细胞癌（HCC）源自于在病毒或代谢功能障碍相关脂肪性肝炎（MASH）损伤的肝脏中，经过补偿性增殖的分化肝细胞。

尽管MASH增加了HCC的风险，它会触发依赖p53的肝细胞衰老，研究人员发现这种衰老过程与超营养引起的DNA断裂并行。然而，如何绕过这种抑制肿瘤的反应，从而许可致癌突变并推动HCC演化，之前尚不清楚。

研究人员鉴定了糖异生酶果糖-1,6-二磷酸酶1（FBP1）作为p53靶基因，其在衰老样的MASH肝细胞中升高，但在大多数人类HCC中通过启动子过度甲基化和蛋白酶体降解被抑制。

FBP1首先在代谢压力下的前恶性病变相关肝细胞和HCC祖细胞中下降，并与促肿瘤的AKT和NRF2的激活并行。通过加速FBP1和p53的降解，AKT和NRF2增强了先前衰老的HCC祖细胞的增殖和代谢活性。NRF2–FBP1–AKT–p53代谢开关在小鼠和人类中均发挥作用，反转衰老并支持增殖，同时促进了DNA损伤诱导的体细胞突变积累，这是MASH向HCC进展所必需的。

附：英文原文

Title: FBP1 controls liver cancer evolution from senescent MASH hepatocytes

Author: 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

Issue&Volume: 2025-01-01

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.

DOI: 10.1038/s41586-024-08317-9

Source: https://www.nature.com/articles/s41586-024-08317-9