Genipin derivative induced the apoptosis and inhibited the invasion and migration of A549 cancer cells via regulation of EGFR/JAK1/STAT3 signaling.

Genipin, a natural compound derived from the fruit of Gardenia jasminoides, has demonstrated anticancer effects in various malignancies, including gastric, cervical, breast, and lung cancers. In this study, a series of genipin derivatives was designed, synthesized, and evaluated for their anticancer activity against A549 non-small-cell lung cancer (NSCLC) cells to identify more potent analogs and elucidate their mechanisms of action. Several derivatives exhibited stronger antiproliferative effects than genipin, with compound 2b showing the most potent activity (IC₅₀ = 117 μM) and effectively suppressing colony formation. Further investigations revealed that 2b induced cell cycle arrest and apoptotic cell death. Mechanistically, 2b inhibited the phosphorylation of EGFR, JAK1, and STAT3, and modulated epithelial-mesenchymal transition (EMT)-related protein expression, thereby attenuating cell migration and invasion. Notably, although 2b did not inhibit ATP-dependent EGFR kinase activity in vitro, molecular docking simulations indicated its binding to the EGFR extracellular domain (domain III), suggesting an alternative, ATP-independent mechanism-likely via interference with EGF binding. Collectively, these results highlight 2b (MRC-G-001) as a promising lead-like compound for further optimization and preclinical development targeting EGFR-driven A549 cancer cells.