Neuroscience. 2026 Nov 12:S0306-4522(26)00734-7. doi: 10.1016/j.neuroscience.2026.11.012. Online ahead of print.
ABSTRACT
Quinolinic acid (QA), a downstream metabolite of the tryptophan-kynurenine pathway, has emerged as a critical immunometabolic molecule linking immune activation, inflammation, and tissue pathology across diverse diseases. Recent evidence demonstrates that altered QA production is associated with chronic inflammatory disorders, neurodegenerative diseases, infections, cancer, and immune dysregulation. In the central nervous system (CNS), pathological accumulation of QA has been associated with excessive N-methyl-D-aspartate (NMDA) receptor activation, oxidative stress, mitochondrial dysfunction, and excitotoxicity, contributing to neuronal injury and neuroinflammatory pathology. In inflammatory skin diseases such as psoriasis, microbiota-derived QA modulates NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activity through aryl hydrocarbon receptor (AhR)-dependent mechanisms, highlighting a regulatory role in cutaneous immunity. Studies further identified microglial-derived QA as both a biomarker and mediator of depressive-like behavior, with reductions in QA predicting therapeutic response to ketamine. Beyond inflammatory and neurological disorders, QA and related kynurenine metabolites exhibit anti-proliferative effects in melanoma cells by inducing apoptosis and inhibiting cell-survival signaling pathways. Therapeutic interventions targeting QA-mediated pathways, including microbiota-derived metabolites such as butyrate, have demonstrated neuroprotective and anti-inflammatory effects in experimental models. Understanding the mechanisms governing QA production and signaling may facilitate the development of novel biomarkers and targeted therapies for inflammatory, neurodegenerative, infectious, and malignant diseases.
PMID:43020253 | DOI:10.1016/j.neuroscience.2026.11.012