Tryptophan Metabolism in Cardiometabolic Diseases: Focus on the Kynurenine Pathway

Tryptophan (TRP) metabolism has emerged as a critical interface linking inflammation, immune regulation, oxidative stress, and cellular energetics. The kynurenine pathway, the predominant route of TRP degradation, is highly responsive to inflammatory stimuli and generates a spectrum of bioactive metabolites with divergent and context-dependent biological effects. Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated TRP catabolism integrates immune activation with downstream metabolic signaling, influencing redox homeostasis, endothelial function, and mitochondrial energetics, in part by regulating nicotinamide adenine dinucleotide (NAD+) synthesis. Alterations in TRP metabolism are consistently observed across cardiometabolic diseases, including obesity, type 2 diabetes (T2D), atherosclerosis, myocardial infarction (MI), and heart failure with preserved ejection fraction (HFpEF), where they are associated with disease severity and adverse outcomes. Importantly, emerging data suggest that cardiometabolic phenotypes are determined not by pathway activation alone, but by the relative distribution of flux across downstream metabolic branches. Depending on the tissue compartment and stage of the disease, different biological effects may be contributed by redox-active kynurenine 3-monooxygenase (KMO)/3-hydroxykynurenine (3-HK)/quinolinic acid (QA) pathways, 3-hydroxyanthranilic acid (3-HAA)-mediated lipid and inflammasome regulation, microbiome-derived indoles, and NAD+-generating pathways. This review synthesizes current evidence using a branch-specific and context-dependent framework. We discuss the utility and limitations of the kynurenine-to-tryptophan ratio (KTR) as an upstream biomarker, the need for downstream metabolite panels, and therapeutic opportunities aimed at pathway modulation rather than broad inhibition. Future studies integrating temporal profiling, spatial and cell-specific approaches, large-animal models, and pathway-informed clinical trials will be essential to define causal mechanisms and enable precision therapeutic translation.