CoChat
Sign Up
Cited by 1Immune cells in cancerCancer Immunotherapy and BiomarkersHepatocellular Carcinoma Treatment and Prognosis

The DOI matches its Crossref record; the references it cites are not checked yet.

Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs

Open access
Dong, Fangyuan, Zhang, Shan, Song, Kaiyuan, Jiang, Luju, Hu, Li-Peng, Li, Qing, Zhang, Xue-Li, Li, Jun, Feng, Mingxuan, Cai, Zhi-Wei, Yao, Hong-Fei, Li, Rong-Kun, Li, Hui, Chen, Jie, Hu, Xiaona, Wang, Jiaofeng, Jiang, Chongyi, Zhu, Helen He, Wang, Cun, Da, Lin-Tai, Zhang, Zhi-Gang, Bao, Zhijun, Wang, Xu, Jiang, Shu-Heng·2026·eLife
DOI 10.7554/elife.103016.4

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Administration of selective serotonin reuptake inhibitors (SSRIs) is associated with a reduced cancer risk and shows significant anti-tumor effects across multiple tumor types, suggesting the potential for repurposing SSRIs in cancer therapy. Nonetheless, the specific molecular target and mechanism of action of SSRIs remain to be fully elucidated. Here, we reveal that citalopram exerts an immune-dependent anti-tumor effect in hepatocellular carcinoma (HCC). Interestingly, the anti-HCC effects of citalopram are not reliant on its conventional target, the serotonin transporter. Through various drug repurposing approaches, including global reverse gene expression profiling, drug affinity responsive target stability assay, and molecular docking, the complement component 5a receptor 1 (C5aR1) is identified as a new target of citalopram. C5aR1 is predominantly expressed by tumor-associated macrophages, and citalopram treatment enhances local macrophage phagocytosis and elicits CD8 + T anti-tumor immunity. C5aR1 deficiency or depletion of CD8 + T cells hinders the anti-HCC effects of citalopram. Collectively, our study reveals the immunomodulatory roles of citalopram in inducing anti-tumor immunity and provides a basis for considering the repurposing of SSRIs as promising anticancer agents for HCC treatment.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.7554/elife.103016.4

Cites

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

The citation lists haven’t been fetched yet

References 53 · Cited by 1

Research works printed but not linked: 53

  1. Ajona, 2018, Blockade of the complement C5a/C5aR1 axis impairs lung cancer bone metastasis by CXCL16-mediated effects, American Journal of Respiratory and Critical Care Medicine, 197, 1164, 10.1164/rccm.201703-0660OC · DOI
  2. Beach, 2023, Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1, The Journal of Clinical Investigation, 133, 10.1172/JCI168277 · DOI
  3. Bhagavathula, 2022, Selective serotonin reuptake inhibitor use and the risk of hepatocellular carcinoma: a systematic review and dose-response analysis of cohort studies with one million participants, European Journal of Clinical Pharmacology, 78, 547, 10.1007/s00228-021-03264-0 · DOI
  4. Bi, 2021, Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug, Cell Reports, 37, 10.1016/j.celrep.2021.109957 · DOI
  5. Cao, 2023, Effects of altered glycolysis levels on CD8+ T cell activation and function, Cell Death & Disease, 14, 10.1038/s41419-023-05937-3 · DOI
  6. Carlson, 2023, Integrative oncology care of symptoms of anxiety and depression in adults with cancer: society for integrative oncology-ASCO guideline, Journal of Clinical Oncology, 41, 4562, 10.1200/JCO.23.00857 · DOI
  7. Chen, 2017, SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin, Nature, 544, 493, 10.1038/nature22076 · DOI
  8. Coleman, 2016, X-ray structures and mechanism of the human serotonin transporter, Nature, 532, 334, 10.1038/nature17629 · DOI
  9. Costa, 2020, Can selective serotonin reuptake inhibitors have a neuroprotective effect during COVID-19?, European Journal of Pharmacology, 889, 10.1016/j.ejphar.2020.173629 · DOI
  10. Custódio, 2021, Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family, Life Science Alliance, 4, 10.26508/lsa.202000858 · DOI
  11. Ding, 2020, C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation, Theranostics, 10, 8619, 10.7150/thno.45058 · DOI
  12. Dong, 2024, SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1, Cell Reports, 43, 10.1016/j.celrep.2024.114818 · DOI
  13. Du, 2022, Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma, Acta Pharmaceutica Sinica B, 12, 558, 10.1016/j.apsb.2021.09.019 · DOI
  14. Eslam, 2020, A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement, Journal of Hepatology, 73, 202, 10.1016/j.jhep.2020.03.039 · DOI · Paper page
  15. Fischer, 2022, Selective serotonin reuptake inhibitors associated with increased mortality risk in breast cancer patients in Northern Israel, International Journal of Epidemiology, 51, 807, 10.1093/ije/dyac004 · DOI
  16. Fluyau, 2022, Selective serotonin reuptake inhibitors in the treatment of depression, anxiety, and post-traumatic stress disorder in substance use disorders: a Bayesian meta-analysis, European Journal of Clinical Pharmacology, 78, 931, 10.1007/s00228-022-03303-4 · DOI
  17. Foretz, 2023, Metformin: update on mechanisms of action and repurposing potential, Nature Reviews. Endocrinology, 19, 460, 10.1038/s41574-023-00833-4 · DOI
  18. Forli, 2016, Computational protein-ligand docking and virtual drug screening with the AutoDock suite, Nature Protocols, 11, 905, 10.1038/nprot.2016.051 · DOI
  19. Hochrein, 2022, The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming, Cell Metabolism, 34, 516, 10.1016/j.cmet.2022.02.015 · DOI
  20. Huang, 2023, Antidepressant use and mortality among patients with hepatocellular carcinoma, JAMA Network Open, 6, 10.1001/jamanetworkopen.2023.32579 · DOI
  21. Hwang, 2021, Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein, Autophagy, 17, 2783, 10.1080/15548627.2020.1841953 · DOI
  22. Jiang, 2017, Increased serotonin signaling contributes to the warburg effect in pancreatic tumor cells under metabolic stress and promotes growth of pancreatic tumors in mice, Gastroenterology, 153, 277, 10.1053/j.gastro.2017.03.008 · DOI
  23. Jiang, 2019, GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner, Gut, 68, 1994, 10.1136/gutjnl-2018-317479 · DOI
  24. Jiang, 2021, The physiology, pathology and potential therapeutic application of serotonylation, Journal of Cell Science, 134, 10.1242/jcs.257337 · DOI
  25. Lee, 2021, Association between selective serotonin reuptake inhibitors and kidney cancer risk: a nationwide population-based cohort study, International Journal of Cancer, 148, 1331, 10.1002/ijc.33307 · DOI
  26. Li, 2024, C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer, Nature Communications, 15, 10.1038/s41467-024-48637-y · DOI
  27. Li, 2025, Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis, Cell, 188, 3823, 10.1016/j.cell.2025.04.032 · DOI
  28. Liu, 2018, Orthosteric and allosteric action of the C5a receptor antagonists, Nature Structural & Molecular Biology, 25, 472, 10.1038/s41594-018-0067-z · DOI
  29. Llovet, 2022, Immunotherapies for hepatocellular carcinoma, Nature Reviews. Clinical Oncology, 19, 151, 10.1038/s41571-021-00573-2 · DOI · Paper page
  30. Lomenick, 2009, Target identification using drug affinity responsive target stability (DARTS), PNAS, 106, 21984, 10.1073/pnas.0910040106 · DOI
  31. Luan, 2024, Blockade of C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8+ T cell activity, Molecular Therapy, 32, 469, 10.1016/j.ymthe.2023.12.010 · DOI
  32. Macintyre, 2014, The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function, Cell Metabolism, 20, 61, 10.1016/j.cmet.2014.05.004 · DOI
  33. Medler, 2018, Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy, Cancer Cell, 34, 561, 10.1016/j.ccell.2018.09.003 · DOI
  34. Mirdita, 2022, ColabFold: making protein folding accessible to all, Nature Methods, 19, 679, 10.1038/s41592-022-01488-1 · DOI · Paper page
  35. Morris, 2009, AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility, Journal of Computational Chemistry, 30, 2785, 10.1002/jcc.21256 · DOI
  36. Ou, 2021, C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1, Cell Death & Disease, 12, 10.1038/s41419-021-04028-5 · DOI
  37. Pio, 2019, Complementing the cancer-immunity cycle, Frontiers in Immunology, 10, 10.3389/fimmu.2019.00774 · DOI
  38. Pushpakom, 2019, Drug repurposing: progress, challenges and recommendations, Nature Reviews. Drug Discovery, 18, 41, 10.1038/nrd.2018.168 · DOI · Paper page
  39. Robertson, 2018, Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727, Nature, 553, 111, 10.1038/nature25025 · DOI
  40. Schipper, 2022, Can drug repurposing accelerate precision oncology?, Cancer Discovery, 12, 1634, 10.1158/2159-8290.CD-21-0612 · DOI
  41. Schneider, 2021, Attenuation of peripheral serotonin inhibits tumor growth and enhances immune checkpoint blockade therapy in murine tumor models, Science Translational Medicine, 13, 10.1126/scitranslmed.abc8188 · DOI
  42. Singh, 2023, Structure-based discovery of conformationally selective inhibitors of the serotonin transporter, Cell, 186, 2160, 10.1016/j.cell.2023.04.010 · DOI
  43. Tang, 2019, GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis, Nucleic Acids Research, 47, W556, 10.1093/nar/gkz430 · DOI
  44. Wang, 2023, SAP deficiency aggravates periodontitis possibly via C5a-C5aR signaling-mediated defective macrophage phagocytosis of Porphyromonas gingivalis, Journal of Advanced Research, 50, 55, 10.1016/j.jare.2022.10.003 · DOI
  45. Wang, 2023, Revealing the signaling of complement receptors C3aR and C5aR1 by anaphylatoxins, Nature Chemical Biology, 19, 1351, 10.1038/s41589-023-01339-w · DOI
  46. Wang, 2024, A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity, Molecular Cell, 84, 760, 10.1016/j.molcel.2023.12.015 · DOI
  47. Zhang, 2019, Landscape and dynamics of single immune cells in hepatocellular carcinoma, Cell, 179, 829, 10.1016/j.cell.2019.10.003 · DOI · Paper page
  48. Zhang, 2021, Combined use of aspirin and selective serotonin reuptake inhibitors is associated with lower risk of colorectal cancer: a nested case-control study, American Journal of Gastroenterology, 116, 1313, 10.14309/ajg.0000000000001192 · DOI
  49. Zhao, 2024, Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner, Cell Death & Disease, 15, 10.1038/s41419-024-06500-4 · DOI
  50. Zheng, 2021, The progress of immune checkpoint therapy in primary liver cancer, Biochimica et Biophysica Acta. Reviews on Cancer, 1876, 10.1016/j.bbcan.2021.188638 · DOI
  51. Wang XW. 2019. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. NCBI Gene Expression Omnibus. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE125449. GSE125449.
  52. Jiang SH. 2024. RNA sequencing analysis in HCC-LM3 cells upon citalopram or fluvoxamine treatment. NCBI BioProject. https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1084911. PRJNA1084911.
  53. He Y, Zhang Q, Zhang Z, Ren X, Liu K. 2019. Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma. NCBI Gene Expression Omnibus. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE140228. GSE140228.

Metadata

Authors
Dong, F., Zhang, S., Song, K., Jiang, L., Hu, L.-P., Li, Q., Zhang, X.-L., Li, J., Feng, M., Cai, Z.-W., Yao, H.-F., Li, R.-K., Li, H., Chen, J., Hu, X., Wang, J., Jiang, C., Zhu, H. H., Wang, C., Da, L.-T., Zhang, Z.-G., Bao, Z., Wang, X., & Jiang, S.-H.
Affiliations
  • Huadong Hospital (CN)
  • Shanghai Cancer Institute (CN)
  • Shanghai Jiao Tong University (CN)
  • State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University
  • Renji Hospital (CN)
  • Department of General Surgery, Hepato-biliary-pancreatic Center, Huadong Hospital, Fudan University
  • Affiliated Hospital of Jiangsu University (CN)
Corresponding author
Jiang, Shu-Heng
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2026-02-09
Volume
14
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.103016.4
OpenAlex
W4403546925
Cited by
1
References
53
Citations by year
2026: 1
FWCI
2.65
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
Funders
  • National Natural Science Foundation of China (82472883)
  • Basic Research-Shanghai Jiao Tong University (21TQ1400225)
  • China Foundation for Youth Entrepreneurship and Employment (P24062487785)
  • Clinical Medicine Research Center Construction Project of Huadong Hospital (LCZX2202)
  • Shanghai Outstanding Young Medical Personnel Training Program & Excellence Project of Shanghai Municipal Health Commission (20224Z0009)
  • Key Specialized Diseases Construction of Huadong Hospital (ZDZB2225)
  • Key Areas Research and Development Programs of Guangdong Province (2023B1111050009)
  • Shanghai Oriental Talent Program – Youth Project (QNWS2024017)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
citalopram, selective serotonin reuptake inhibitors, drug repurposing, hepatocellular carcinoma, C5aR1, tumor-associated macrophages, macrophage phagocytosis, CD8+ T cells, antitumor immunity, immunomodulation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review