SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1

Fangyuan Dong, Kang He, Shan Zhang, Kaiyuan Song, Luju Jiang, Li-Peng Hu, Qing Li, Xue-Li Zhang, Naiqi Zhang, Bo-Tai Li, Li-Li Zhu, Jun Li, Mingxuan Feng, Yunchen Gao, Jie Chen, Xiaona Hu, Jiaofeng Wang, Chongyi Jiang, Cun Wang, Helen He ZhuLin-Tai Da, Jianguang Ji, Zhi-Gang Zhang, Zhijun Bao, Shu-Heng Jiang

Research output: Contribution to journalArticlepeer-review

Abstract

Selective serotonin reuptake inhibitors (SSRIs) have shown promise in cancer therapy, particularly for hepatocellular carcinoma (HCC), but their molecular targets and mechanisms remain unclear. Here, we show that SSRIs exhibit significant anti-HCC effects independent of their classical target, the serotonin reuptake transporter (SERT). Using global inverse gene expression profiling, drug affinity responsive target stability assays, and in silico molecular docking, we demonstrate that citalopram targets glucose transporter 1 (GLUT1), resulting in reduced glycolytic flux. A mutant GLUT1 variant at the citalopram binding site (E380) diminishes the drug's inhibitory effects on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth of GLUT1 high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis reveals that SSRI use correlates with a lower risk of metastasis among patients with HCC. Our study describes a role for SSRIs in cancer metabolism, establishing a rationale for their repurposing as potential anti-cancer drugs for HCC.

Original languageEnglish
Article number114818
JournalCell Reports
Volume43
Issue number10
Early online date2024 Oct 9
DOIs
Publication statusPublished - 2024

Bibliographical note

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Subject classification (UKÄ)

  • Cancer and Oncology

Fingerprint

Dive into the research topics of 'SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1'. Together they form a unique fingerprint.

Cite this