Network pharmacology and experimental validation to explore the effects and mechanisms of flavonoids luteolin and chrysoeriol against non‑small cell lung cancer.

Luteolin and chrysoeriol, active flavonoids found in Fagopyrum dibotryis Rhizoma (FDR), possess similar molecular structures and demonstrate anti-tumor activity; however, their efficacy and mechanisms in non-small cell lung cancer (NSCLC) are still incomplete. This research aimed to reveal the therapeutic potential and mechanisms of these phytoconstituents in NSCLC through an integrated strategy of network pharmacology, molecular docking, and experimental validation. We used network pharmacology to discover possible targets and pathways for luteolin and chrysoeriol in NSCLC, which involved predicting targets, constructing protein-protein interaction (PPI) networks, and performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and dynamics simulations assessed the binding affinities of both phytoconstituents to core targets. Hub gene expression in NSCLC tissues was further examined using bioinformatics tools. The anti-NSCLC effects were evaluated by measuring A549 and PC9 cell viability, migration, apoptosis, and modulation of the PI3K/AKT pathway. We identified 64 potential therapeutic targets for NSCLC. Enrichment analysis revealed the PI3K-Akt signaling pathway as the most significantly associated. Molecular simulations indicated stable binding of both phytoconstituents to core targets, with luteolin exhibiting stronger binding affinity. In experimental validation, luteolin more potently inhibited NSCLC cell viability and migration, alleviated mitochondrial damage, and induced apoptosis relative to chrysoeriol. Luteolin also more effectively regulated PI3K/AKT signaling. Both luteolin and chrysoeriol represent promising natural agents for NSCLC treatment, with luteolin demonstrating superior bioactivity.