2. Academic Validation
  3. Demethoxycurcumin suppresses HK2-mediated glycolysis by targeting PTEN/Akt signaling

Demethoxycurcumin suppresses HK2-mediated glycolysis by targeting PTEN/Akt signaling

  • Cancer Gene Ther. 2025 Oct 2. doi: 10.1038/s41417-025-00972-y.
Jinzhuang Liao # 1 2,  Shiming Tan # 1 3,  Shuangze Han 1 4,  Ruirui Wang 1,  Pengfei Guo 1,  Wei Zheng 1,  Xinfang Yu 5 6,  Wei Li 7
Affiliations

Affiliations

  • 1 Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 2 Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, China.
  • 6 Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China.
  • 7 Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China. weililx@csu.edu.cn.
  • # Contributed equally.
PMID: 41039015 DOI: 10.1038/s41417-025-00972-y
Abstract

Aerobic glycolysis is a hallmark of tumor cells, with the expression of glycolytic Enzymes often being upregulated in many cancers, leading to enhanced metabolic activity. Among the key rate-limiting Enzymes in this process, Hexokinase 2 (HK2) plays a crucial role in sustaining the biological activities of human cancers. Therefore, HK2 is considered a potential therapeutic target, although effective targeted drugs for oral squamous cell carcinoma (OSCC) treatment are currently lacking. To confirm potent anti-tumor agents that inhibit HK2 expression, we screened a library of 639 natural products and discovered that Demethoxycurcumin (Deme) was the most effective anti-tumor agent via inhibiting HK2-mediated glycolysis in OSCC cells, inducing intrinsic Apoptosis. Mechanistically, Deme enhanced the interaction between USP13 and PTEN, leading to the stabilization of PTEN and consequent downregulation of HK2 via the PTEN/Akt/HK2 pathway. Notably, HK2 overexpression reversed the inhibitory effect of Deme on OSCC cells. Furthermore, at the tumor-inhibitory dose, Deme showed no effect on non-tumor HaCat cells. In vivo, Deme significantly suppressed tumor growth without apparent toxicity to vital organs. Together, these data suggest that Deme is a promising and safe anti-tumor compound that downregulates HK2 expression, providing a potential therapeutic strategy for OSCC treatment.

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