Integrative Multi-Omics and Experimental Approaches Identify SRC as a Central Target of Garcinia atroviridis Flavonoids in Lung Cancer

Garcinia atroviridis (GA) is widely used in Southeast Asia, but its anticancer potential is less studied than that of other Garcinia species. This work aimed to investigate the flavonoid constituents of GA and their molecular mechanisms against lung cancer using an integrated systems pharmacology and experimental approach. Phytochemical profiling was performed by LC–HRMS, and flavonoid-associated targets were predicted using SwissTargetPrediction. Lung cancer–related genes were collected from GSE19188 and GeneCards, with overlapping targets identified through Venn analysis. Protein–protein interaction (PPI) analysis defined hub genes, while molecular docking and dynamics simulations assessed ligand–target interactions. Finally, cytotoxicity of the GA ethanolic extract was evaluated in A549, H460, and BEAS-2B cells after 72 h treatment. Our investigation revealed the presence of 5 major flavonoids, including icariin. Network analysis revealed 142 overlapping targets, with SRC, HSP90AA1, CTNNB1, PIK3R1, and AKT1 emerging as hubs. Docking showed strong binding affinities, particularly between quercetin-3β-D-glucoside and SRC, which was confirmed by stable molecular dynamics simulations. In vitro, GA extract reduced the viability of A549 and H460 cells with lower IC₅₀ values than in BEAS-2B. GA exerts selective anticancer effects against lung cancer primarily through targeting SRC, with supportive modulation of HSP90AA1, CTNNB1, PIK3R1, and AKT1. These findings position SRC as the key mechanistic anchor and highlight GA as a promising source for multi-targeted cancer therapy.