Identification of crucial genes and biological pathways in lung adenocarcinoma by network pharmacology, molecular docking, and simulation studies

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, largely due to chemoresistance treatment-associated toxicity. This research employed integrated network pharmacology, molecular docking, and molecular dynamics (MD) simulation to investigate the therapeutic potential of bioactive compounds from Pleurotus membranaceus (PM). Four of the 23 bioactive compounds found by literature mining and Swiss ADME-based drug-likeness screening satisfied the criteria for drug-likeness. Using SwissTargetPrediction, SuperPred, PharmMapper, and DIGEP-Pred, 609 possible molecular targets were identified. Cross-referencing with 3,025 LUAD-associated genes from OMIM, DisGeNET, and GeneCards yielded 226 overlapping targets. These targets were further analyzed through Protein-protein interaction (PPI) networks, gene ontology, and pathway enrichment analyses, alongside evaluation of gene expression, overall survival, protein expression, promoter methylation, and immune infiltration profiles. Key hub genes including AKT1, HSP90AA1, IL6, CASP3, and SRC were identified as central regulators of cancer initiation and progression. Molecular docking revealed that AKT1 exhibited the highest binding affinity with Isosorbide (−9.6 kcal/mol). MD simulation confirmed the stability of the AKT1–Isosorbide complex, with a binding free energy of −193.8 kJ/mol. Energy decomposition analysis indicated that complex stabilization was primarily drive by complementarity and hydrophobic interactions. Collectively, these findings suggest that bioactive compounds of Pleurotus membranaceus, particularly isosorbide, hold promising therapeutic potential LUAD by inducing apoptosis, inhibiting angiogenesis, and suppressing metastasis. Future experimental validation is warranted to translate these computational findings into clinical application.