Tryptophan Metabolism in Heart Failure: Mechanisms, Biomarker Potential, and Therapeutic Implications.

Heart failure (HF) is a complex clinical syndrome characterized by progressive cardiac remodeling, metabolic dysregulation, and high morbidity and mortality worldwide. Emerging evidence suggests that metabolic reprogramming plays a central role in HF progression, among which tryptophan (TRP) metabolism has attracted increasing attention due to its involvement in inflammation, immune regulation, oxidative stress, mitochondrial dysfunction, and gut microbiota imbalance. TRP is mainly metabolized through the kynurenine pathway (KP), serotonin pathway, and gut microbiota-derived indole pathway, generating a series of bioactive metabolites with distinct cardiovascular effects. Recent studies have demonstrated that abnormal activation of the indoleamine 2,3-dioxygenase (IDO)-driven KP contributes to HF progression by promoting inflammatory activation, oxidative stress, myocardial fibrosis, and ventricular remodeling. In parallel, gut microbiota-derived TRP metabolites participate in the gut-heart axis and influence mitochondrial function, immune homeostasis, and cardiometabolic remodeling. In addition, TRP-related metabolites, particularly kynurenine (KYN) and the kynurenine-to-tryptophan ratio (KTR), exhibit promising potential as biomarkers for HF severity assessment and prognostic stratification. This review systematically summarizes the activation characteristics of TRP metabolic pathways in HF and discusses their mechanistic involvement in inflammation, immune regulation, gut microbiota dysbiosis, myocardial injury, oxidative stress, and mitochondrial dysfunction. Furthermore, emerging therapeutic strategies targeting TRP metabolism are highlighted, including pharmacological modulation, microbiota-targeted interventions, exogenous metabolite supplementation, and exercise-based metabolic regulation. Collectively, TRP metabolism represents a promising metabolic hub integrating immune, inflammatory, and mitochondrial signaling networks in HF and may provide novel opportunities for precision diagnosis and targeted therapy.