This study investigates the anticancer activity and pharmacological mechanisms of Corynoxine (Cory) in non-small cell lung cancer (NSCLC). Cory, a natural product derived from the Chinese herbal medicine Uncaria rhynchophylla, demonstrates promising pharmacological activity. Cell proliferation and viability were evaluated via MTT and colony formation assays. Flow cytometry was employed to analyze cell apoptosis, cycle distribution, and mitochondrial membrane potential. Autophagy was detected using fluorescence microscopy and electron microscopy. Western blotting, protein overexpression, gene knockdown, co-immunoprecipitation, and bioinformatics characterized Cory's impact on signaling pathways. The research indicates that Cory inhibits the proliferation of NSCLC cells in vivo and in vitro. Cory enhances PP2A activity, inhibits the AKT/mTOR signaling pathway triggering autophagy, while suppressing the AKT/GSK3β signaling pathway to induce cellular apoptosis in NSCLC. Notably, the activation of PP2A plays a crucial role in Cory's antitumor effects by inhibiting AKT. In vivo experiments validated Cory's efficacy in NSCLC treatment. These findings highlight the promising role of Cory as a lead compound for drug development in NSCLC therapy, providing a viable option for addressing this challenging disease.Copyright © 2024 Elsevier Inc. All rights reserved.