Kynurenic Acid MoA
FS2 (KynA), an end-phase metabolite of the tryptophan pathway, prevents and breaks down overproduction of collagen and fibronectin, resulting in progressive and natural tissue regeneration.
Understanding Fibrosis and Antifibrotic Strategies
Fibrosis is a complex and pathological process marked by the excessive formation of scar tissue, primarily due to the abnormal production and accumulation of extracellular matrix (ECM) components. This process is driven by an imbalance between ECM synthesis and degradation, leading to tissue stiffening and impaired function. Excessive ECM deposition is often accompanied by increased cellularity, particularly due to the proliferation of fibroblasts and their differentiation into myofibroblasts. These cells are key players in the fibrotic process, producing large amounts of collagen and fibronectin, which contribute to the formation of dense, fibrous tissue. Effective antifibrotic strategies aim to address these underlying issues by either inhibiting the biosynthesis of ECM or enhancing its degradation, thereby restoring tissue homeostasis.
The Role of Kynurenines in Fibrosis Management
Kynurenic acid (KynA) and Kynurenine (Kyn) are emerging as potent antifibrogenic agents, with significant implications for the treatment of fibrotic disorders. Research has shown that KynA and Kyn can enhance ECM remodeling by upregulating the expression of matrix metalloproteinases (MMP1 and MMP3), which are enzymes responsible for breaking down ECM components. Concurrently, these agents suppress the production of type-I collagen and fibronectin, both of which are major contributors to the fibrotic ECM. Importantly, Kyn and KynA also reduce the proliferation of primary fibroblasts, a critical factor in controlling fibrosis, without compromising cellular viability. Their ability to significantly decrease tissue cellularity and inhibit fibroblast migration further underscores their potential in managing fibrosis, as these processes are central to the excessive tissue buildup seen in fibrotic diseases.
Inhibition of type-I collagen and fibronectin expression in dermal fibroblasts by kynurenines. Type-I Collagen and fibronectin expression at the mRNA and protein level in cultured fibroblasts treated with increasing concentrations (6.25, 12.5, 25, 50, 100 and 150 mg/ml) of KynA, Kyn, L-Kyn or D-Kyn. A&B: Relative type-I collagen and fibronectin mRNA expression in treated fibroblasts, respectively. GAPDH was used as the reference gene.
Therapeutic Potential of Kynurenic Acid
Among the Kynurenines, KynA stands out as a particularly promising antifibrogenic candidate. It has demonstrated potential in improving healing outcomes for patients suffering from atrophic, hypertrophic and keloidal scarring—conditions characterized by excessive and disorganized scar tissue. By targeting the fundamental molecular mechanisms driving fibrosis, such as fibroblast proliferation, ECM accumulation, and cellular migration, KynA offers a novel therapeutic approach to scar management. Its ability to modulate these processes could lead to more effective treatments for fibrotic disorders, ultimately improving patient outcomes by preventing the progression of fibrosis and reducing the formation of pathological scars.