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, Xueli Zhang, Naiqi Zhang, Bo-Tai Li, Lili Zhu, Jun Li, Mingxuan Feng, Yunchen Gao, Jie Chen, Xiaona Hu, Jiaofeng Wang, Chongyi Jiang, Cun Wang, Helen He Zhu, Lin‐Tai Da, Jianguang Ji, Zhigang Zhang, Zhijun Bao, Shu‐Heng Jiang
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.