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

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.<h4>Significance</h4>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.