Network pharmacology, molecular docking, DFT analysis and in-vitro assessment of Syzygium cumini L.as an inhibitor of STAT-3 and JUN against breast cancer

Despite being one of the most lethal cancer, there is an urgent need to develop effective therapeutic strategies that simultaneously target multiple molecular pathways. In the present study, we explored the potential anticancer efficacy of Syzygium cumini L., focusing on its primary bioactive component, ellagic acid using an integrated approach involving network pharmacology, molecular docking, density functional theory (DFT), and molecular dynamics (MD) simulations. Network pharmacology identified key molecular targets of S. cumini L., including STAT-3 and JUN, which play a critical role in breast cancer progression. The molecular docking analysis revealed that ellagic acid exhibit strong binding affinity towards these targets forming stable protein-ligand interactions. DFT analysis was performed to demonstrate the electronic properties, HOMO-LUMO energy gap, and chemical reactivity of ellagic acid and paclitaxel. MD simulation results further demonstrated the stability of ellagic acid-protein, paclitaxel-protein complexes. Binding free energy calculations using MM/GBSA method showed the considerable contribution from van der Waals and electrostatic interactions in the stability of the complexes. In-vitro cytotoxicity assessment using MTT assay demonstrated that the seed extract of S. cumini exhibits dose-dependent anticancer effects on MCF-7 and MDA-MB-231 breast cancer cell lines, where the cells of the MCF-7 line were more sensitive to this treatment. Notably, the seed extract did not exhibit significant cytotoxic effects normal MCF-10 A cells. Overall, these findings suggest that the ellagic acid of Syzygium cumini holds strong potential as a multitarget anticancer agent through inhibition of STAT-3 and JUN signalling pathways. However, further detailed molecular investigation and in-vivo studies are required to validate these findings in breast cancer treatment. • Network pharmacology highlighted STAT-3 and JUN as key oncogenic targets in breast cancer, modulated by Syzygium cumini L. derived Ellagic acid • Ellagic acid exhibited strong binding affinities towards STAT-3 (−8.4 kcal/mol) and JUN (−7.0 kcal/mol), which were comparatively higher than standard drug paclitaxel demonstrating binding affinities of STAT-3 (−7.8 kcal/mol) and JUN (−6.9 kcal/mol) in molecular docking studies. • 200 ns molecular dynamics simulations confirmed the stability of both Ellagic acid and standard (Paclitaxel)-protein complexes, while MM/GBSA analysis revealed strong binding free energies (−53.825 ± 4.34 kcal/mol for STAT-3, −38.191 ± 4.89 kcal/mol for JUN) and for paclitaxel (−49.88 ± 1.74 for STAT-3 and -61.057 ± 0.34 for JUN) predominantly driven by Van der Waals and electrostatic forces. • In-vitro cytotoxicity assays on MCF-7 and MDAMB-231 cells confirmed the anticancer potential of the extract, with higher efficacy observed in MCF-7 cells (IC 50 = 115.6 μg/mL), while no significant toxicity was observed in normal mammary cells MCF-10 A.