| Summary: | As a traditional medicine, <i>Angelica decursiva</i> has been used for the treatment of many diseases. The goal of this study was to evaluate the potential of four natural major dihydroxanthyletin-type coumarins—(+)-<i>trans</i>-decursidinol, Pd-C-I, Pd-C-II, and Pd-C-III—to inhibit the enzymes, protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase. In the kinetic study of the PTP1B enzyme’s inhibition, we found that (+)-<i>trans</i>-decursidinol, Pd-C-I, and Pd-C-II led to competitive inhibition, while Pd-C-III displayed mixed-type inhibition. Moreover, (+)-<i>trans</i>-decursidinol exhibited competitive-type, and Pd-C-I and Pd-C-II mixed-type, while Pd-C-III showed non-competitive type inhibition of α-glucosidase. Docking simulations of these coumarins showed negative binding energies and a similar proximity to residues in the PTP1B and α-glucosidase binding pocket, which means they are closely connected and strongly binding with the active enzyme site. In addition, dihydroxanthyletin-type coumarins are up to 40 µM non-toxic in HepG2 cells and have substantially increased glucose uptake and decreased expression of PTP1B in insulin-resistant HepG2 cells. Further, coumarins inhibited ONOO<sup>−</sup>-mediated albumin nitration and scavenged peroxynitrite (ONOO<sup>−</sup>), and reactive oxygen species (ROS). Our overall findings showed that dihydroxanthyletin-type coumarins derived from <i>A</i>. <i>decursiva</i> is used as a dual inhibitor for enzymes, such as PTP1B and α-glucosidase, as well as for insulin susceptibility.
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