2. Academic Validation
  3. Discovery of a Novel Target Inhibitor Theaflavin against UDP-Glucose Pyrophosphorylase 2 and Its Role in Attenuating the Malignant Phenotype of Liver Cancer Cells via Perturbation of Glucose Metabolism

Discovery of a Novel Target Inhibitor Theaflavin against UDP-Glucose Pyrophosphorylase 2 and Its Role in Attenuating the Malignant Phenotype of Liver Cancer Cells via Perturbation of Glucose Metabolism

  • J Agric Food Chem. 2025 Dec 17;73(50):31893-31905. doi: 10.1021/acs.jafc.5c07617.
Yuxin Zhou 1,  Nan Song 1,  Haonan Hu 1,  Yanli Wang 1,  Ziquan Zhao 1,  Chang Sun 1,  Siying Xie 1,  Ailing Yu 1,  Fanxing Xu 1,  Dahong Li 2,  Miao Chang 3,  Hao Cao 1
Affiliations

Affiliations

  • 1 School of Life Science and Biopharmaceutics, and Key Laboratory of Microbial Pharmaceutics, Liaoning Province, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 3 Department of Radiology, The First Hospital of China Medical University, 155 Nanjing North St, Heping District, Shenyang, Liaoning 110001, China.
PMID: 41363755 DOI: 10.1021/acs.jafc.5c07617
Abstract

UDP-glucose pyrophosphorylase 2 (UGP2), the unique mammalian enzyme converting glucose-1-phosphate to UDP-glucose, is upregulated in hepatocellular carcinoma (HCC) and Other malignancies. It promotes tumor progression through glycogen metabolism and glycosylation, thereby emerging as a promising yet undrugged therapeutic target. Utilizing high-throughput screening coupled with AI-based modeling, we identified Theaflavin, a food-derived natural product, as a targeted inhibitor of UGP2, exhibiting an IC50 of 27.24 μM. The results showed that Theaflavin, as a competitive inhibitor, mainly binds to the region of UGP2 centered around the key residues Lys396 and Asp253, and has minimal inhibitory effect on its homologous enzyme galactose-1-phosphate uridylyltransferase (GALT). Theaflavin inhibits UGP2-mediated UDPG synthesis and intracellular glycogen accumulation, attenuating malignant phenotypes (proliferation, migration, invasion) in HCC cells. Our findings identify Theaflavin as a selective UGP2 inhibitor, providing a novel dietary-derived candidate for HCC therapy targeting glucose metabolism and establishing UGP2 as its direct cellular target.

Keywords

UGP2; hepatocellular carcinoma (HCC); metabolic reprogramming; selective inhibitor; target drug; theaflavin.

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