Plant-Derived Dipeptidyl Peptidase-4 Inhibitors in Cardiometabolic Disorders: A Critical Review of Natural Scaffolds and Experimental Evidence

Cardiometabolic disorders, including obesity, insulin resistance and type 2 diabetes mellitus, remain major biomedical problems closely linked to vascular complications. Dipeptidyl peptidase-4 (DPP-4) is a clinically validated therapeutic target because inhibition of this enzyme prolongs the activity of incretin hormones and supports glucose-dependent insulin secretion. This review compiles and critically evaluates plant-derived DPP-4 inhibitors, with emphasis on chemical class, enzyme source, quantitative activity, assay interpretability, and the translational relevance of reported findings. The available literature indicates that flavonoids and polyphenolic compounds dominate the field, although assay heterogeneity, medium effects, potential aggregation, and insufficient selectivity data limit interpretation. Among natural scaffolds, chalcones and aurones, including lanceoletin, leptosidin, xanthoangelol, chalconaringenin 2′-O-β-D-glucopyranoside, and aureusidin 6-O-β-D-glucopyranoside, represent comparatively well-supported lead-like scaffolds that warrant further standardized evaluation. The evidence does not support using plant-derived DPP-4 inhibitors as substitutes for approved antidiabetic drugs. Their greatest value lies in expanding chemical space and providing lead-like scaffolds for standardized potency, selectivity, kinetic and preclinical validation.