A Noncanonical RNA-Binding Function of NQO1 Drives Angiogenesis in Esophageal Squamous Cell Carcinoma via Extracellular Vesicle–Mediated AGRN Transfer

Abstract Esophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with dismal clinical outcomes and limited treatment options. NAD(P)H quinone oxidoreductase 1 (NQO1) is classically characterized as a cytosolic oxidoreductase that prevents the formation of reactive oxygen species. In this study, we demonstrated that NQO1 promoted ESCC progression and lung colonization via an enzymatic activity–independent mechanism. Integrated transcriptomic and direct RNA-binding analyses revealed that NQO1 acted as an RNA-binding protein to stabilize the mRNA encoding agrin (AGRN), thereby increasing AGRN expression. Upregulation of AGRN enhanced endothelial cytoskeletal organization by interacting with filamin A and stimulated angiogenesis through selective extracellular vesicle–mediated transfer. Structure-based screening identified the clinically approved agent panobinostat as a direct NQO1-binding compound that destabilized NQO1 and suppressed AGRN-dependent angiogenic signaling. Importantly, combined treatment with panobinostat and the antiangiogenic agent anlotinib resulted in superior inhibition of tumor growth and vascularization compared with either monotherapy in patient-derived organoid xenograft models. Together, these findings uncover an enzymatic activity–independent RNA-regulatory function of NQO1 in ESCC and provide a mechanistic rationale for targeting the NQO1/AGRN axis. Significance: The enzyme-independent RNA regulatory function of NQO1 enhances extracellular vesicle-mediated AGRN signaling to drive angiogenesis in esophageal cancer, which induces a therapeutic vulnerability to combinatorial anti-angiogenic treatment with panobinostat and anlotinib.