ArticleThe Journal of clinical investigation2025
5-HT orchestrates histone serotonylation and citrullination to drive neutrophil extracellular traps and liver metastasis.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- Neuroscience in prostate cancer.Prostate cancer and prostatic diseases · 2026Review
- Targeting the nervous system: Mechanistic insights into neuro-tumor communication and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- Neutrophil extracellular traps promote liver metastasis by impairing NK cell-dependent tumor surveillance via CCDC25.Nature communications · 2026Article
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- Review
- Mechanisms and therapeutic targets in distant metastasis of lung adenocarcinoma.Signal transduction and targeted therapy · 2026Article
- Epigenetic Alterations in Hepatocellular Carcinoma: Mechanisms and Biomarkers for Precision Therapy.Cancers · 2026Review
- Cell death crosstalk in NET-Driven inflammation: mechanisms, disease contexts, and therapeutic perspectives.Biomarker research · 2026Review
- Neurotransmitters in cancer: how receptor signaling and posttranslational modifications modulate tumor progression and offer new therapeutic targets.Cell communication and signaling : CCS · 2026Review
- Roles of neutrophil extracellular traps in cancer immunotherapy resistance and therapeutic targeting.Biomarker research · 2026Review
- GABRD promotes hepatocellular carcinoma progression via the IL-10RA/JAK2-STAT3 signaling axis.Cell death & disease · 2026Article
- Histone modifications across cancers: mechanisms, therapy and clinical translation.Molecular cancer · 2026Review
- Neuroendocrine tumours through an epigenetic lens: Emerging insights for diagnosis and treatment.Journal of neuroendocrinology · 2026Review
- Gastric Cancer: Pathobiology and Therapeutics.MedComm · 2026Review
- Neutrophil extracellular traps: A central player in liver diseases.Hepatology communications · 2026Review
- Liver-nervous system axis: pathways, dysregulation, and translational perspectives.Journal of neuroinflammation · 2026Review
- Platelet-neutrophil cooperation in cancer: mechanisms of metastatic niche formation and implications for prognostic stratification and therapy.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Beyond neurotransmission: the roles of serotonylation in physiological and pathological processes.Cellular & molecular biology letters · 2026Review
- Single-cell transcriptomics unveils the immunologic landscape of anti-PD-1-associated indirect drug-induced liver injury.Journal of gastroenterology · 2026Article
- TGM2-mediated serotonylation of GPX4 confers ferroptosis resistance to promote gastric tumorigenesis.Cell discovery · 2026Article
Corrections and comments
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Authors and funding
23 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Serotonin (5-HT) is a neurotransmitter that has been linked to tumorigenesis. Whether and how 5-HT modulates cells in the microenvironment to regulate tumor metastasis is largely unknown. Here, we demonstrate that 5-HT was secreted by neuroendocrine prostate cancer (NEPC) cells to communicate with neutrophils and to induce the formation of neutrophil extracellular traps (NETs) in the liver, which in turn facilitated the recruitment of disseminated cancer cells and promoted liver metastasis. 5-HT induced histone serotonylation (H3Q5ser) and orchestrated histone citrullination (H3cit) in neutrophils to trigger chromatin decondensation and facilitate the formation of NETs. Interestingly, we uncovered in this process a reciprocally reinforcing effect between H3Q5ser and H3cit and a crosstalk between the respective writers enzyme transglutaminase 2 (TGM2) and peptidylarginine deiminase 4 (PAD4). Genetic ablation or pharmacological targeting of TGM2, or inhibition of the 5-HT transporter (SERT) with the FDA-approved antidepressant drug fluoxetine reduced H3Q5ser and H3cit modifications, suppressed NET formation, and effectively inhibited NEPC, small-cell lung cancer, and thyroid medullary cancer liver metastasis. Collectively, the 5-HT-triggered production of NETs highlights a targetable neurotransmitter/immune axis that drives liver metastasis of NE cancers.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.