Paeoniflorin suppresses non-small cell lung cancer by interrupting FGF2-FGFR2-PI3K axis

Non-small cell lung cancer (NSCLC) accounts for 85 % of all lung cancer cases and represents one of the leading causes of cancer-related deaths. Paeoniflorin, a natural compound, exhibits extensive anti-tumor activities. However, the role and underlying mechanisms of paeoniflorin in NSCLC remain unclear. This study aims to investigate the mechanism by which paeoniflorin targets FGFR2 to inhibit NSCLC using CETSA assays, RNA sequencing and Western blotting through cellular assays and animal experiments. We identified paeoniflorin as a novel therapeutic agent that suppresses NSCLC growth and promotes apoptosis. Mechanistically, paeoniflorin directly targeted FGF2, suppressed the expression of the FGF2 receptor FGFR2, and consequently inhibited downstream signaling cascades, thereby suppressing tumor growth. RNA-seq analysis revealed that paeoniflorin exerts its effects through the FGF2-mediated PI3K/AKT pathway. Western blot results confirmed that paeoniflorin significantly reversed the activation of the PI3K/AKT pathway induced by 740 Y-P (a PI3K agonist) in NSCLC cells. Furthermore, the combination of paeoniflorin with LY294002 (a PI3K/AKT pathway inhibitor) synergistically suppressed the phosphorylation of PI3K and AKT to a greater extent than either agent alone. Paeoniflorin inhibited the FGF2-mediated PI3K-AKT-mTOR signaling axis, modulated key autophagy biomarkers and triggered autophagy-regulated apoptosis. Collectively, our findings provide critical mechanistic insights into the antitumor activity of paeoniflorin, highlighting its potential as a safe and effective targeted therapy. This study offers a novel clinical strategy for future cancer treatment and underscores the therapeutic potential of combining paeoniflorin with FGF2-targeted therapies.