Phillygenin attenuates inflammatory responses and influences glucose metabolic parameters by inhibiting Akt activity

Phillygenin (Phi) is one of the main chemical constituents of the fruit of Forsythia suspensa (Thunb.) Vahl. It has various bioactivities, including anti-inflammatory, anti-obesity and antipyretic activities. However, its exact targets and molecular mechanism are still poorly understood. Bioinformatics tools were used to explore the potential targets of Phi, and 8 predicted targets, 4 primary pathways (MAPK, PI3K-Akt, T-cell receptor and m-TOR signaling pathway) related to the inflammatory response, and Akt as an important node was mentioned. Moreover, a Phi alkylated molecular probe was synthesized and used to capture the target proteins Akt. Then Akt and its downstream signaling pathway were verified by molecular docking, intracellular enzyme activity evaluation, and accurate pathway analysis. The results indicated that Phi targets an allosteric inhibit pocket on Akt; reduces Akt phosphorylation; alleviates multiple inflammatory-associated downstream signal transduction pathways, including IKKα/β and NF-κB; and influences glucose metabolic parameters associated with the downstream GSK3β protein and glucose uptake. The results suggest that Phi could reduce inflammatory responses and influence glucose metabolic parameters by inhibiting Akt phosphorylation. Moreover, these findings suggest a potential application for Phi in respiratory and metabolic diseases therapy.