Domino Effect of the Kynurenine Pathway: Systemic Homeostasis, Metabolic Crosstalk, and Therapeutic Potential

ABSTRACT The kynurenine (KYN) pathway (KP) is a central hub in tryptophan (Trp) metabolism, orchestrating immune regulation, neural signaling, and systemic energy homeostasis. Although KP dysregulation has been linked to multiple diseases, a unifying framework explaining how localized metabolic perturbations propagate across organs ‐a “Domino Effect”‐ is lacking. This review provides a comprehensive synthesis of KP's dual, context‐dependent roles in immunity, neurodegeneration, cardiovascular disease, and gastrointestinal disorders. We critically evaluate the mechanistic basis of KYN as a master regulator via the aryl hydrocarbon receptor (AhR) and NAD + biosynthesis, resolving controversies surrounding its pro–versus anti‐inflammatory and pro–versus antitumorigenic functions. Key findings reveal that KP metabolites determine disease outcomes: KYNA/QA balance in the brain, inflammatory vascular remodeling in the heart, and host‐microbiome crosstalk in the gut. We further assess therapeutic targeting of KP enzymes (IDO1, TDO2, KMO) and AhR, acknowledging both promising preclinical data and clinical translation challenges. Finally, we propose that future strategies must move beyond conventional enzyme inhibition to include upstream regulatory mechanisms. This review proposes a “Domino Effect” framework to provide new avenues for biomarker discovery, precision medicine, and structure‐based drug design targeting the KP.