Targeting Tryptophan Metabolism via Serotonin and Kynurenine Pathways in Neuropsychiatric, Neurological, and Neuro-Oncological Disorders

Tryptophan is a biologically and pharmacologically relevant amino acid involved in multiple pathways that influence central nervous system (CNS) function, immune regulation, tumour biology, and behaviour. Although widely recognized as a precursor of serotonin, most tryptophan is metabolized through the kynurenine pathway, leading to the production of bioactive metabolites such as kynurenic acid, quinolinic acid, and picolinic acid. These metabolites modulate glutamatergic signalling, neuroinflammation, oxidative stress, immune responses, and cellular metabolism.Dysregulation of the kynurenine pathway has been increasingly implicated in a broad range of neuropsychiatric and neurological disorders, including schizophrenia, major depressive disorder, suicidality, cognitive impairment, epilepsy, and neurodegenerative diseases. Altered levels of kynurenine metabolites may contribute to excitotoxicity, impaired synaptic plasticity, neuroimmune activation, and changes in mood, cognition, and behaviour.At the same time, tryptophan metabolism has emerged as a key mechanism of immune escape in cancer. Tumour cells and tumour-associated immune cells can upregulate enzymes such as indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase, resulting in local tryptophan depletion and accumulation of immunomodulatory kynurenine metabolites. These processes suppress anti-tumour immune responses and may also contribute to neurological and psychiatric complications associated with cancer and cancer therapy.This dual role places the tryptophan–kynurenine axis at a critical intersection between oncology, neuropharmacology, immunology, and translational neuroscience. Pharmacological modulation of this pathway, including the development of IDO1, TDO2, and kynurenine aminotransferase inhibitors, represents a promising but complex therapeutic strategy. Clinical experience with IDO1 inhibitors, including epacadostat, has highlighted the importance of target engagement, patient selection, pathway redundancy, CNS penetrance, and combination treatment strategies.In parallel, the gut–brain axis has become increasingly relevant to the study of tryptophan metabolism. Microbiome-derived regulation of tryptophan availability and kynurenine pathway activity may influence both CNS function and tumour immunity, opening new opportunities for biomarker discovery and therapeutic intervention.This Research Topic welcomes original research articles, reviews, systematic reviews, and translational studies investigating the neuropharmacology of tryptophan metabolism, with particular emphasis on the interface between neuropsychiatric disorders, neurological diseases, and cancer pharmacology.We welcome submissions addressing, but not limited to, the following themes:- Kynurenine pathway pharmacology, including IDO1, TDO2, KATs, and other enzyme targets- Development of inhibitors and modulators of tryptophan metabolism for CNS disorders- IDO1/TDO2 inhibitors in neurooncology, including lessons from clinical and preclinical studies- Kynurenine pathway dysregulation in brain tumours, CNS metastases, and neuro-oncological complications- Tryptophan metabolism in depression, schizophrenia, suicidality, cognitive impairment, epilepsy, and neurodegeneration- Serotonergic modulation, tryptophan availability, 5-HT synthesis, mood regulation, and cognition- Neuroimmune mechanisms linking kynurenine metabolites to neuroinflammation and immune-mediated psychiatric symptoms- Tumour immune evasion mediated by tryptophan depletion and kynurenine accumulation- Gut–brain–immune interactions involving microbiome regulation of tryptophan pathways- Kynurenic acid, quinolinic acid, picolinic acid, and related metabolites as diagnostic, prognostic, or pharmacodynamic biomarkers- Clinical and preclinical models targeting tryptophan metabolism in neurological, psychiatric, oncological, and neuro-oncological conditions- Aging, metabolic dysfunction, and tryptophan catabolism in Parkinson’s disease, Alzheimer’s disease, and age-related cognitive declineOverall, this Research Topic aims to promote interdisciplinary research on tryptophan metabolism as a shared biological substrate linking brain function, immune regulation, and cancer biology, with the goal of advancing biomarker development and novel therapeutic strategies for CNS disorders. Topic editors: Stefano Comai Source: https://www.frontiersin.org/research-topics/81524/targeting-tryptophan-metabolism-via-serotonin-and-kynurenine-pathways-in-neuropsychiatric-neurological-and-neuro-oncological-disorders