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

作者：Huiling Rao, Xiaotong An, Xiaoyan Qu, Juan Yu, Jin Xie, Jing Ke, Zhixin Liu, Lei You, Zhenpeng Qiu, Lin Tian, Weixing Du, Wanrong Li, Jie Jia, D. Liu, Shan Li · 发表于：Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · 年份：2025 · DOI：10.1016/j.bbadis.2025.167805 · 被引用次数：4 · 研究领域：Diabetes Treatment and Management、Pancreatic function and diabetes、Metabolism, Diabetes, and Cancer

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 ...