Targeting tryptophan metabolism in cardiovascular disease: From immune-metabolic crosstalk to precision therapy

Host-microbiota co-metabolism of tryptophan is increasingly recognized as a critical nexus linking diet, gut microbiota, immune function, serving as a core regulatory network governing cardiovascular function and systemic homeostasis. Its catabolism in vivo mainly proceeds through three distinct pathways: the kynurenine pathway, the serotonin pathway, and the gut microbiota-mediated indole pathway. Tryptophan metabolites exert multifaceted physiological and pathophysiological effects on the cardiovascular system via diverse specific receptors and non-receptor signaling pathways. Numerous clinical and basic studies have confirmed that the tryptophan metabolic network plays a dual role in the progression of cardiovascular diseases (CVDs), including atherosclerosis, myocardial ischemia/reperfusion injury, and heart failure. However, existing studies have largely focused on individual pathways or isolated metabolites, and an integrated, systematic view of the entire tryptophan metabolic network in CVDs remains lacking. This review summarizes the tryptophan metabolic pathways, the physiological effects of tryptophan metabolites including potential therapeutic targets, and their impacts on cardiovascular diseases. Furthermore, based on the complex pathophysiological regulatory mechanisms of tryptophan metabolism, we systematically elaborate therapeutic strategies including dietary intervention, gut microbiota modulation, and targeted pharmacological intervention against rate-limiting enzymes and core receptors. These multidimensional approaches hold promise for reshaping the tryptophan metabolic axis and providing novel therapeutic paradigms for the management and treatment of CVDs.