Systems pharmacology unravels the synergic target space and therapeutic potential of Cinnamomum tamala essential oil in treating non-small-cell lung cancer

Cinnamomum tamala (Buch.-Ham.) T.Nees & Eberm., commonly known as Indian Bay Leaf, is a traditionally valued Ayurvedic medicinal plant with wide therapeutic use, yet its molecular mechanism in non-small-cell lung cancer (NSCLC) remains largely uncharacterized. The present study employed an integrative systems biology pipeline combining spatial transcriptomics, network pharmacology, bioinformatics, molecular modeling, and experimental validation to elucidate the anticancer mechanisms of C. tamala essential oil (CTEO) in treating NSCLC. GC-MS profiling identified 49 phytoconstituents in CTEO, with 44 meeting drug-likeness criteria. Spatial transcriptomics data from NSCLC tissues (GSE21933) revealed 3,438 differentially expressed genes, including 1,894 upregulated and 1,548 downregulated genes. From public databases, 3,961 CTEO-related and 4,588 NSCLC-associated targets were retrieved, with 68 overlapping genes used to construct a protein–protein interaction network. CytoHubba analysis identified JUN, TP53, IL6, MAPK3, HIF1A, and CASP3 as key hub genes. Compound–target network analysis highlighted cinnamaldehyde, ethyl cinnamate, and acetophenone as core components of CTEO. Functional enrichment revealed pathways related to apoptosis, MAPK, TNF, IL-17 signaling, and cancer progression. Survival analysis showed that HIF1A and CASP3 were significantly associated with poor overall survival in lung adenocarcinoma patients. Immune cell deconvolution via TIMER revealed a strong correlation between neutrophil infiltration and hub genes HIF1A (cor = 0.500), IL6 (cor = 0.445), and CASP3 (cor = 0.325), indicating their role in modulating the NSCLC immune microenvironment. Molecular docking and dynamics studies demonstrated stable binding of cinnamaldehyde and ethyl cinnamate to MAPK3, supported by MM/PBSA analysis showing van der Waals forces as primary contributors. In vitro studies in A549 cells revealed that CTEO selectively inhibited cancer cell proliferation and induced apoptosis via ROS generation, mitochondrial depolarization, and caspase activation. These findings support the potential of C. tamala essential oil as a promising adjuvant therapy in NSCLC.