Integrated Network Pharmacology and Molecular Dynamics Reveal Multi-Target Anticancer Mechanisms of Myrtus communis Essential Oils

Background: Cancer’s multifactorial complexity demands innovative polypharmacological strategies that can simultaneously target multiple oncogenic pathways. Natural products, with their inherent chemical diversity, offer promising multi-target therapeutic potential. This study comprehensively investigates the anticancer mechanisms of Tunisian Myrtus communis essential oils (McEOs) using an integrated computational-experimental framework to elucidate their polypharmacological basis and therapeutic potential. Methods: McEO composition was characterized via GC-MS analysis. Antiproliferative activity was evaluated against HeLa (cervical), MCF-7 (breast), and Raji (lymphoma) cancer cell lines using MTT assays. A multi-scale computational pipeline integrated network pharmacology, molecular docking against eight key oncoproteins, and 100 ns all-atom molecular dynamics simulations to elucidate molecular mechanisms and target interactions. Results: GC-MS revealed a 1,8-cineole-rich chemotype (38.94%) containing significant sesquiterpenes. McEO demonstrated potent differential cytotoxicity: HeLa (IC₅₀ = 8.12 μg/mL) > MCF-7 (IC₅₀ = 19.59 μg/mL) > Raji cells (IC₅₀ = 27.32 μg/mL). Network pharmacology quantitatively explained this differential sensitivity through target overlap analysis, showing higher associations with breast (23%) and cervical (18.3%) versus lymphoma (5.5%) cancer pathways. Molecular docking identified spathulenol as a high-affinity Androgen Receptor (AR) antagonist (XP GScore: −9.650 kcal/mol). Molecular dynamics simulations confirmed exceptional spathulenol-AR complex stability, maintaining critical hydrogen bonding with Asn705 for 96% of simulation time. Conclusions: McEO exerts sophisticated multi-target anticancer effects through synergistic constituent interactions, notably spathulenol’s potent AR antagonism. This integrated computational-experimental approach validates McEO’s polypharmacological basis and supports its therapeutic potential, particularly for hormone-dependent malignancies, while establishing a robust framework for natural product bioactivity deconvolution.