Integrating phytochemical profiling, in vitro studies and network pharmacology to reveal the antidiabetic action mechanism of Punica granatum fruit peel

Despite considerable studies, diabetes continues to affect millions of people worldwide with an increasing rate of morbidity and mortality. Therefore, we aimed to explore the in vitro antidiabetic and antioxidant effects of Punica granatum and also reveal its drug-likeness, toxicity and action mechanism by utilizing SwissADME (absorption, distribution, metabolism and excretion), ProTox-II and network pharmacology, respectively. The results showed that P. granatum has a significant dose-dependent inhibition potential against α-amylase (IC50=131.90 ± 0.44) and α-glucosidase (IC50=149.74 ± 0.58) activity, as well as a significant inhibition in DPPH-free radical scavenging (IC50=108.57 ± 0.52) activity. ADME/Toxicity prediction of the compounds satisfies Lipinski’s rule of five with zero violations and did not find any toxicity. Moreover, network pharmacology revealed that polyphenolic compounds of P. granatum may combat diabetes by acting on key targets such as IRS1, TNF-α, IL6, MAPK3, DPP4, LEPR, GSK3B, PPARA and PIK3CG were strongly involved in glucose metabolism, oxo-inflammatory responses and insulin-related pathways. Based on the finding, we can conclude that P. granatum might be promising therapeutics for the management of diabetes and related disorders.