Lung adenocarcinoma (LUAD) is a lethal malignancy with limited treatment options, underscoring the need for novel agents. Forsythiaside A (FSA), a primary active component of Forsythia suspensa, possesses anti-inflammatory and antioxidant properties, but its role in lung adenocarcinoma remains unexplored. This study integrated network pharmacology, molecular docking, and experimental validation to investigate the anti-tumor effects of FSA and its underlying mechanism. Network analysis identified 218 potential targets, with enrichment in the PI3K-Akt signaling pathway. Molecular docking revealed a strong interaction between FSA and ESR1. Functionally, FSA potently inhibited the proliferation, migration, invasion, and colony formation of A549 and H1975 cells in vitro. This anti-tumor activity was confirmed in vivo in a mouse xenograft model. Mechanistically, FSA downregulated ESR1 expression, reduced phosphorylation of PI3K and AKT, and promoted autophagic flux, as evidenced by increased LC3-II/LC3-I ratio, decreased p62 expression, loss of mitochondrial membrane potential (JC-1), enhanced LC3 puncta formation, and ultrastructural changes consistent with autophagy. These findings indicate that FSA induces autophagy via the ESR1/PI3K/AKT axis and exhibits significant anti-tumor effects, highlighting its potential as a novel candidate for LUAD therapy.
Yin et al. (Wed,) studied this question.