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‐HT 7 R antagonists). These findings position the 5‐HT system as a pivotal target for next‐generation precision therapeutics across multiple disease domains.