The tryptophan-kynurenine pathway in cardiovascular diseases: mechanistic insights and therapeutic opportunities

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, making them crucial to further explore their mechanisms. Beyond traditional risk factors, disturbances in tryptophan metabolism, particularly the imbalance in the kynurenine pathway (KP) which accounts for over 95% of metabolic flux-have garnered significant attention in cardiovascular research. In the human body, tryptophan is primarily metabolized through the KP. This process is catalyzed by key enzymes, indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase, which convert tryptophan into kynurenine and further downstream metabolites such as kynurenic acid and 3-hydroxykynurenine. Studies have shown that levels of multiple key metabolites in KP are dysregulated in patients with CVDs, and by participating in processes such as immune activation, inflammatory responses, reactive oxygen species production, and endothelial dysfunction, and they play a complex role in mediating the pathophysiology of various CVDs, including heart failure, atherosclerosis, and hypertension. This review will systematically outline the physiology of tryptophan metabolism and the KP, summarize how key enzymes and metabolites regulate CVDs, and explore their potential as novel biomarkers for early diagnosis and prognosis and as therapeutic targets. Additionally, the review will discuss the future applications of metabolomics and artificial intelligence in the diagnosis of CVDs and the development of new therapeutics, aiming to provide new perspectives for the prevention and treatment of CVDs.