Rewiring NADH Metabolism Through NQO1‐Mediated Redox Cycling for Targeted Follicular Lymphoma Therapy

ABSTRACT Follicular lymphoma (FL) remains an incurable B‐cell malignancy with high relapse rates, and conventional therapies are often limited by significant toxicity, highlighting the need for novel treatments. We identified that FL exhibits markedly low expression of NAD(P)H: quinone oxidoreductase 1 (NQO1), a key enzyme required for activating quinone‐based chemotherapeutics. To overcome this, we developed a novel therapeutic strategy that simultaneously upregulates NQO1 expression and provides its quinone substrate within tumor cells. This approach leverages the dual biological function of Cu ^{2 +} , which acts as both an inducer of NQO1 expression via the Nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway and a catalyst for the oxidation of EGCG to its quinone form. Using a CD20‐targeted nanoplatform as a delivery tool, we achieved specific co‐delivery of EGCG and Cu ^{2 +} to follicular lymphoma cells. This strategy triggered a potent NQO1‐mediated redox cycle, resulting in severe NADH depletion and profound oxidative stress. These events activated the GADD45β‐MAPK stress‐signaling pathway, leading to mitochondrial dysfunction and apoptosis activation. In a murine FL xenograft model, this approach achieved 85% tumor growth inhibition, while maintaining a favorable safety profile. This work establishes a new therapeutic paradigm for FL, leveraging intrinsic enzyme deficiency to induce tumor‐specific, self‐amplifying cell death.