Sparaneo Angelo, Torrisi Filippo, D'Angeli Floriana, Giurdanella Giovanni, Bravaccini Sara, Muscarella Lucia Anna, Fabrizio Federico Pio
Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
Department of Drug and Health Sciences, University of Catania, 95123 Catania, Italy.
Antioxidants (Basel). 2025 May 29;14(6):657. doi: 10.3390/antiox14060657.
The Nuclear factor erythroid 2-related factor 2 (NRF2) Neurogenic locus NOTCH homolog protein (NOTCH) crosstalk has emerged as a critical regulatory axis in the progression of solid cancers, especially lung, affecting tumor growth and resistance to therapy. NRF2 is a master transcription factor that orchestrates the cellular antioxidant response, while NOTCH signaling is involved in the cell-cell communication processes by influencing the patterns of gene expression and differentiation. Although frequently altered independently, genetic and epigenetic dysregulation of both NRF2 and NOTCH pathways often converge to deregulate oxidative stress responses and promote tumor cell survival. Recent findings reveal that the NRF2/NOTCH interplay extends beyond canonical signaling, contributing to metabolic reprogramming and reshaping the tumor microenvironment (TME) to promote cancer malignancy. Emerging scientific evidences highlight the key role of biochemical and metabolomic changes within NRF2-NOTCH crosstalk, in contributing to cancer progression and metabolic reprogramming, beyond facilitating the adaptation of cancer cells to the TME. Actually, the effects of the NRF2-NOTCH bidirectional interaction in either supporting or suppressing lung tumor phenotypes are still unclear. This review explores the molecular mechanisms underlying NRF2-NOTCH crosstalk in lung cancer, highlighting the impact of genetic and epigenetic deregulation mechanisms on neoplastic processes, modulating the TME and driving the metabolic reprogramming. Furthermore, we discuss therapeutic opportunities for targeting this regulatory network, which may open new avenues for overcoming drug resistance and improving clinical outcomes in lung cancer.
核因子红细胞2相关因子2（NRF2）与神经源性Notch同源蛋白（NOTCH）的相互作用已成为实体癌进展中的关键调控轴，尤其是在肺癌中，影响肿瘤生长和对治疗的抗性。NRF2是一种主要转录因子，可协调细胞抗氧化反应，而NOTCH信号通路则通过影响基因表达和分化模式参与细胞间通讯过程。尽管NRF2和NOTCH通路的基因和表观遗传失调常常独立发生改变，但两者往往会共同导致氧化应激反应失调并促进肿瘤细胞存活。最近的研究发现表明，NRF2/NOTCH相互作用不仅限于经典信号传导，还会导致代谢重编程并重塑肿瘤微环境（TME）以促进癌症恶性发展。新出现的科学证据强调了NRF2-NOTCH相互作用中生化和代谢组学变化在促进癌症进展和代谢重编程方面的关键作用，而不仅仅是促进癌细胞适应TME。实际上，NRF2-NOTCH双向相互作用在支持或抑制肺癌表型方面的作用仍不清楚。本综述探讨了肺癌中NRF2-NOTCH相互作用的分子机制，强调了基因和表观遗传失调机制对肿瘤形成过程（调节TME并驱动代谢重编程）的影响。此外，我们还讨论了针对这一调控网络的治疗机会，这可能为克服肺癌耐药性和改善临床结果开辟新途径。
