Serotonin (5-Hydroxytryptamine): Metabolism, Signaling, Biological Functions, Diseases, and Emerging Therapeutic Opportunities

Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is an evolutionarily conserved monoamine neurotransmitter that plays critical roles in various physiological systems, functioning as a neurotransmitter, hormone, and paracrine signaling molecule. This review synthesizes current research on 5-HT metabolism (biosynthesis, transport, and degradation), 5-HT receptor-mediated signaling pathways (seven receptor families and 14 subtypes), and broad biological functions of 5-HT. We emphasize the roles of 5-HT in both health and disease, with a particular focus on its emerging significance in the tumor immune microenvironment. Studies have shown that dysregulated 5-HT signaling is associated with various pathological conditions, including functional gastrointestinal disorders, psychiatric diseases, metabolic disorders, and cancer progression. Notably, this review describes novel mechanisms by which 5-HT modulates tumor immunity, including its effects on macrophage polarization, dendritic cell function, T cell activity, and PD-L1 expression, and it explores the therapeutic potential of targeting 5-HT-associated pathways. Promising therapeutic strategies that target 5-HT include combining selective serotonin reuptake inhibitors with immune checkpoint inhibitors, inhibiting key metabolic enzymes (e.g., Tph1 and MAO-A), and developing receptor subtype-specific agents (e.g., 5-HT₇R antagonists). These findings position the 5-HT system as a pivotal target for next-generation precision therapeutics across multiple disease domains.

Keywords

5-hydroxytryptamine (5-HT) / 5-HT receptor (5-HTR) / serotonin / signaling pathways / therapeutic potential / tumor immune microenvironment

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