Canthaxanthin downregulates EGFR in NSCLC: network pharmacology, molecular docking, dynamics simulations, ADMET, and in-vitro analysis.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with current therapies often limited by toxicity and resistance. Natural compounds like canthaxanthin, a carotenoid with demonstrated anticancer properties, offer a promising alternative. This study investigates canthaxanthin's therapeutic potential in NSCLC through an integrated computational and experimental approach. Network pharmacology identified 34 shared targets between canthaxanthin and NSCLC, with EGFR, SRC, and CASP3 emerging as key hubs. Molecular docking revealed strong binding affinities (- 9.0, - 7.6, and - 8.0 kcal/mol, respectively), supported by 200-ns molecular dynamics simulations demonstrating complex stability. ADMET analysis predicted favourable pharmacokinetics and low toxicity (Class 6). In-vitro validation via MTT assay showed selective cytotoxicity against A549 cells (IC₅₀ = 23.66 µg/mL) compared to normal lung cells (HEL 299; IC₅₀ = 57.77 µg/mL), outperforming 5-fluorouracil in selectivity (SI = 2.64 vs. 2.23). Pathway enrichment implicated cancer-related signaling (PI3K-AKT, MAPK) and apoptosis. Canthaxanthin's multi-target action-inhibiting EGFR proliferation, SRC migration, and activating CASP3-mediated apoptosis-suggests a polypharmacological advantage. Computational predictions aligned with experimental results, confirming dose-dependent cytotoxicity and minimal mutagenic risk. Canthaxanthin exhibits potent, selective anti-NSCLC activity through multi-target modulation, supported by robust binding stability and low toxicity. These findings highlight its potential as an adjunct or alternative therapy, particularly for resistant NSCLC. Future studies should explore in-vivo efficacy, combination regimens, and clinical translation.