Integrated Network Pharmacology and Molecular Dynamics Reveal Luteolin from Persea americana as a Multi-Cancer SRC/GSK3β Inhibitor.

Cancer progression is driven by dysregulated kinase signaling and apoptotic evasion across multiple malignancies. Although targeted kinase inhibitors have improved outcomes, resistance and toxicity remain major challenges. Natural phytochemicals offer promising multi-target therapeutic potential. Persea americana contains diverse bioactive compounds; however, its role in multi-cancer kinase targeting remains underexplored. This study aimed to identify and validate anti-cancer kinase targets of Persea americana phytoconstituents across five cancers: lung, breast, cervical, colorectal, and prostate, using integrated network pharmacology and molecular simulation approaches. Cancer-associated genes were retrieved from the Open Targets Platform and prioritized through Gene Ontology analysis. Overlapping targets with 208 predicted human targets of Persea americana were identified. Protein-protein interaction networks revealed hub genes, followed by TCGA-based validation. Twenty-five phytoconstituents were docked against SRC and GSK3β, and top complexes underwent 100 ns molecular dynamics simulations. Enrichment highlighted kinase activity and apoptosis. SRC emerged as a pan-cancer hub, while GSK3β was prominent in breast cancer. Luteolin showed strongest binding to SRC (-11.9 kcal/mol), outperforming the co-crystal inhibitor, while valencene showed affinity toward GSK3β (-8.8 kcal/mol). Simulations confirmed stable interactions. Luteolin exhibits strong multi-target kinase inhibition, particularly against SRC, supporting its potential as a pan-cancer therapeutic candidate.