Beyond l-arginine: Uncovering L-tryptophan's cardiovascular therapeutic potential

Loss of nitric oxide (^•NO) bioavailability is a defining feature of cardiovascular disease (CVD), yet therapies targeting this pathway alone have shown limited success. Here, we argue that l-tryptophan (Trp) catabolism, particularly via indoleamine 2,3-dioxygenase-1 (IDO1), represents an underappreciated, mechanistically distinct route to restoring vascular health. Beyond its canonical immunoregulatory role, IDO1-derived metabolites directly modulate plaque stability, blood pressure, and placental vascular function through a variety of signalling mechanisms, positioning Trp catabolism as a genuine complement to l-arginine-nitric oxide biology rather than a peripheral curiosity. Therapeutic strategies range from dietary supplementation to gene delivery and small-molecule catalytic modulators are now emerging, with some already in clinical use for other indications. Although full of potential, the field has key gaps that need addressing, including the potential roles of other enzymes (tryptophan 2,3-dioxygenase [TDO] and indoleamine 2,3-dioxygenase-2 [IDO2]), while sex-specific effects remain almost entirely unexplored. In this review, we present the evidence supporting the potential therapeutic benefits of this pathway, highlight therapeutic strategies, and identify key gaps to be addressed to facilitate advancement in the field.