核因子红细胞 2 相关因子 2 (NRF2) 的激活已在多种癌症中观察到。然而，其对头颈鳞状细胞癌（HNSCC）发展的确切贡献仍不清楚。我们之前发现NRF2信号对于鳞状基底祖细胞的分化至关重要，而NRF2的破坏会导致基底细胞增生。在这项研究中，我们揭示了 NRF2 活性升高与 HNSCC 患者预后不良之间的相关性。我们证明 NRF2 促进肿瘤增殖、迁移和侵袭，体外和体内研究都证明了这一点。值得注意的是，NRF2 增强了抗氧化酶 GPX2 的表达，从而增强了 HNSCC 细胞的增殖、迁移和侵袭特性。 GPX2 的激活对于通过上调 NOTCH3（癌症进展的关键驱动因素）来维持癌症干细胞 (CSC) 至关重要。这些结果阐明 NRF2 通过 NRF2-GPX2-NOTCH3 轴调节 HNSCC 进展。我们的研究结果表明，NRF2-GPX2-NOTCH3 轴的药理学靶向可能是针对 HNSCC 的潜在治疗方法。© 2024。作者。

The activation of nuclear factor erythroid 2-related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining cancer stem cells (CSCs) by up-regulating NOTCH3, a key driver of cancer progression. These results elucidate that NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.© 2024. The Author(s).