SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1
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<sup>high</sup> 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.
Authors
- Naiqi Zhang (ORCID: https://orcid.org/0000-0002-0668-7822)
- Kang He (ORCID: https://orcid.org/0000-0002-7270-8118)
- Li-Peng Hu (ORCID: https://orcid.org/0000-0002-5941-3825)
- Jianguang Ji (ORCID: https://orcid.org/0000-0003-0324-9496)
- Yunchen Gao
- Shu‐Heng Jiang (ORCID: https://orcid.org/0000-0001-8516-6234)
- Lin‐Tai Da (ORCID: https://orcid.org/0000-0002-1589-5754)
- Jiaofeng Wang
- Helen He Zhu (ORCID: https://orcid.org/0000-0003-0290-5527)
- Bo-Tai Li
- Shan Zhang
- Zhigang Zhang (ORCID: https://orcid.org/0000-0002-4974-5850)
- Qing Li (ORCID: https://orcid.org/0000-0002-3579-5494)
- Mingxuan Feng
- Kaiyuan Song (ORCID: https://orcid.org/0000-0001-9889-824X)
- Cun Wang (ORCID: https://orcid.org/0000-0002-4977-2189)
- Xueli Zhang (ORCID: https://orcid.org/0000-0001-8306-0639)
- Zhijun Bao (ORCID: https://orcid.org/0000-0003-4445-8737)
- Lili Zhu
- Fangyuan Dong (ORCID: https://orcid.org/0000-0001-9323-9026)
- Chongyi Jiang
- Xiaona Hu
- Luju Jiang
- Jie Chen (ORCID: https://orcid.org/0009-0006-5545-2495)
- Jun Li (ORCID: https://orcid.org/0009-0004-1683-5130)
Institutions
- Shanghai International Studies University (CN)
- Shanghai Medical College of Fudan University (CN)
- Shanghai Jiao Tong University (CN)
- Lund University (SE)
- University of Macau (MO)
- Fudan University (CN)
- Huadong Hospital (CN)
- Shanghai Cancer Institute (CN)
- YangPu Geriatric Hospital (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114818
- Citations
- 20
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 5.70
Funders
- Natural Science Foundation of Shanghai
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Shanghai Jiao Tong University