Unveiling the antidiabetic activity and potential molecular mechanisms of a polyherbal HP-β-cyclodextrin inclusion complex to reveal the integrated network pharmacology, docking studies against the PP242–mTOR complex and In-Vivo investigations

Type 2 diabetes mellitus (T2DM) is a rapidly increasing global health concern characterized by hyperglycemia, insulin resistance, and increased oxidative stress. Despite the availability of several antidiabetic therapies, long-term management remains challenging due to adverse effects, limited efficacy, and the complex multi-factorial nature of diabetes progression. Therefore, the development of novel multi-target therapeutic strategies using bioactive natural compounds with improved stability and bioavailability has gained significant research interest. This study explored a polyherbal essential oil formulation derived from Psidium guajava , Syzygium cumini , Aegle marmelos , and Tinospora cordifolia , which was encapsulated using hydroxypropyl-β-cyclodextrin (HP-β-CD) to improve the stability and bioavailability of active compounds. Gas chromatography–mass spectrometry (GC-MS) analysis identified 43 phytoconstituents, including linoleic acid, β-caryophyllene, vitamin E, neophytadiene, β-sitosteryl acetate, tocopherol, and oleic acid. Network pharmacology analysis revealed 157 overlapping targets between diabetes-related genes and compound-related genes, indicating a multi-target therapeutic approach. Protein–protein interaction studies highlighted mTOR as a key regulatory hub involved in insulin signaling and glucose metabolism. Molecular docking results showed that compounds such as vitamin E, β-tocopherol, oleic acid, and linoleic acid ethyl ester exhibited stronger binding affinity toward mTOR compared to the control ligand, suggesting their potential modulatory effects. In vivo experiments using alloxan-induced diabetic mice demonstrated significant antidiabetic effects. Administration of the HP-β-CD encapsulated formulation at 300 mg/kg reduced blood glucose levels to 118.7 ± 2.9 mg/dL, closely comparable to glibenclamide (120.3 ± 3.2 mg/dL). Additionally, HbA1c levels improved from 8.2% to 5.9%, along with reductions in total cholesterol and triglycerides. Overall, the study indicates that HP-β-CD encapsulated polyherbal essential oils may offer a promising multi-target strategy for managing T2DM through metabolic modulation at multiple biological levels.