2. Academic Validation
  3. SGLT2i delays c-Myc-induced HCC progression via targeting mTOR

SGLT2i delays c-Myc-induced HCC progression via targeting mTOR

  • Biochim Biophys Acta Mol Basis Dis. 2025 Mar 18;1871(5):167805. doi: 10.1016/j.bbadis.2025.167805.
Huiling Rao 1,  Xiaotong An 2,  Xinyang Qu 2,  Juan Yu 3,  Jin Xie 2,  Jing Ke 4,  Zhixin Liu 5,  Lei You 4,  Zhenpeng Qiu 6,  Lin Tian 7,  Weixing Du 7,  Wanrong Li 2,  Jie Jia 8,  Danwen Liu 9,  Shan Li 10
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Department of Medical Engineering, The First Affiliated Hospital of Army Medical University, Chongqing 400000, People's Republic of China.
  • 2 School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
  • 3 School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Department of Anesthesiology, People's Hospital of Yunxi County of Hubei Province, Yunxi 442600, People's Republic of China.
  • 4 Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
  • 5 Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
  • 6 College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China.
  • 7 Department of Pathology, Renming Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
  • 8 School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China. Electronic address: jiajie@hbmu.edu.cn.
  • 9 School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China. Electronic address: liudanwen@hbmu.edu.cn.
  • 10 School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China. Electronic address: lishan@hbmu.edu.cn.
PMID: 40113049 DOI: 10.1016/j.bbadis.2025.167805
Abstract

Background: Hepatocellular carcinoma (HCC) stands as a primary malignant liver tumor characterized by metabolic reprogramming. The oncogene c-Myc exerts substantial influence by driving the transcription of numerous genes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in the treatment of type 2 diabetes and has recently attracted attention for its potential anti-cancer effects. This study aims to unravel the complex interplay among c-Myc, EMPA, and the mammalian target of rapamycin (mTOR) in HCC development and progression.

Methods: HCC induction in mice utilized high-pressure hydrodynamic transfection of the c-Myc plasmid. QPCR and immunohistochemistry experiments were performed to detect the expression of SGLT2 in HCC tissues. In vivo experiments were conducted to corroborate the upregulation of SGLT2 following c-Myc transfection. In invo and vitro investigations were conducted to evaluate the anti-cancer effects of two SGLT2i: EMPA and canagliflozin (CANA). Network pharmacology, molecular docking analyses, CETSA experiments, and additional western blot experiments were used to reveal EMPA's interaction inhibition with mTOR.

Results: The study identified an increase in SGLT2 expression in HCC tissues as a result of c-Myc overexpression. In vitro experiments confirmed the upregulation of SGLT2 following c-Myc transfection. Notably, the administration of SGLT2i effectively curtailed liver Cancer progression, and reduced hepatic fat accumulation in mice. EMPA exhibited significant suppression of cell proliferation in c-Myc-transfected cells. In vitro experiments unveiled EMPA's interaction and with inhibition the activation of mTOR.

Conclusion: Our study highlights EMPA's potential as a therapeutic agent in delaying the development and progression of HCC.

Keywords

HCC; SGLT2; c-Myc; mTOR.

Figures
Products