Researchers writing in Nature Communications have uncovered a molecular pathway linking high blood sugar to accelerated liver cancer, identifying transcription factor C/EBPβ as a primary driver and potential therapeutic target.
The study showed that C/EBPβ is significantly upregulated in hepatocellular carcinoma patients who were previously diagnosed with diabetes. High glucose levels trigger C/EBPβ transcription through ROS-dependent PERK-eIF2α-ATF4 signaling. Once activated, specific LAP isoforms of C/EBPβ—unlike the LIP isoform—upregulate key glycolytic effectors GLUT1 and LDHA along with the HRAS oncoprotein, accelerating glycolysis and liver cancer cell proliferation.
Therapeutic Interventions
Experiments in male mice revealed that hyperglycemia-driven hepatocellular glycometabolism and cancer progression were prevented through two interventions. Gene editing that caused hepatocyte-specific C/EBPβ deletion stopped the progression. Administration of Lucicebtide, also known as ST101—a clinical phase-II C/EBPβ inhibitory peptide—produced similar protective effects against high glucose-fueled tumor growth.
Human C/EBPβ isoform LAP1 mimicked the impact of high glucose, boosting hepatocellular glycometabolism and driving tumor growth on its own. The authors noted that while hyperglycemia accelerates cancer, mechanics targeting glucose-fueled pathways had previously stalled in development.
Study Details and Funding
Yifan Luo and Zhengjiang Qian contributed equally to the study, working alongside lead researcher Keqiang Ye. The research involved collaborations across Chinese institutions, including the Brain Cognition and Brain Disease Institute at the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, and the Shenzhen University of Advanced Technology.
Funding for the project came from several state and regional bodies, including the National Natural Science Foundation of China, the Shenzhen Science and Technology Program, the Shenzhen Medical Research Fund, and the Guangdong Basic and Applied Basic Research Foundation. The authors declared no competing financial interests in the published report.
