Dual-Target Insight into Drug Discovery from Natural Products as Modulators of GLP-1 and the TXNIP-Thioredoxin...

Metabolic Syndrome (MetS), a cluster of interconnected metabolic abnormalities, poses a growing global health burden. A well-established therapeutic target for the diseases is the incretin hormone glucagon-like peptide-1 (GLP-1); however, synthetic agonists have drawbacks such as expense, injectable administration, and side effects. Concurrently, one of the main pathogenic characteristics of MetS is oxidative stress, in which the Thioredoxin-Interacting Protein (TXNIP)/thioredoxin system is a critical player. The strong evidence that natural compounds derived from plant, marine, and microbiological sources can simultaneously target the TXNIP-thioredoxin antioxidant axis and GLP-1 signaling is examined in this study. These substances can limit TXNIP expression and increase thioredoxin activity while also stimulating GLP-1 secretion, inhibiting dipeptidyl peptidase-4 (DPP-4), or acting as GLP-1 receptor agonists. A cycle of reinforcement is created by these two actions: Pancreatic β-cell activity and incretin responsiveness are improved by GLP-1-mediated TXNIP downregulation, which also strengthens antioxidant defense. However, translational development must overcome major pharmacological obstacles, especially those related to bioavailability, metabolic stability, and standardization, despite encouraging preclinical effectiveness. To speed up this translational process, integrative computational techniques (such as molecular docking, network pharmacology, and artificial intelligence) are strong tools for lead optimization and creation of hypothesis. Thus, natural products can provide a special chance to discover multi-target treatments that comprehensively address the oxidative and hormonal causes of MetS.