Corynoxine Inhibits Tumor Growth via Targeting NQO1 and Modulating the PTPA–NQO1/PP2A Switch to Activate PP2A

ABSTRACT

Corynoxine (Cory) has been reported to suppress lung cancer progression by activating PP2A, but its molecular targets remain unclear. This study shows that Cory exerts anticancer activity across multiple cancer cell lines. Using compound derivatization, affinity‐based protein fishing, LC‐MS/MS, SPR, CETSA, DARTS, and molecular docking, we demonstrate that Cory directly interacts with NQO1, with Gly193 and His194 contributing to ligand recognition. NQO1 is overexpressed and implicated in tumor progression in multiple cancers, although its precise mechanisms remain poorly defined. We identified a previously unrecognized interaction between NQO1 and PTPA that may contribute to PP2A suppression in tumor cells. Cory binding perturbs the NQO1–PTPA interface and weakens their cellular association, thereby facilitating PTPA‐dependent PP2A activation. This activation inhibits the PI3K/AKT and MAPK/ERK pathways and suppresses tumor cell proliferation. Critically, Cory's anticancer effects are abolished in NQO1‐deficient cells, highlighting the essential role of NQO1. Cory did not impair NQO1 enzymatic activity, supporting a non‐enzymatic mechanism. In vivo, Cory suppressed tumor growth in nude mice without obvious systemic toxicity. Collectively, these findings suggest that Cory exerts anticancer effects by modulating the PTPA–NQO1/PP2A switch to activate PP2A, positioning Cory as a promising lead compound for targeted therapy.