Verza FLáVIA Alves, DA Silva Guilherme Carvalho, Nishimura Felipe Garcia
Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto-SP, 14040-900, Brazil.
Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto-SP, 14040-903, Brazil.
Oncol Res. 2025 Jul 18;33(8):1819-1834. doi: 10.32604/or.2025.065755. eCollection 2025.
Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cancer development, progression, and resistance to therapy. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1)-antioxidant response element (ARE) signaling pathway is central to maintaining redox balance by regulating the expression of antioxidant and detoxification genes. Under physiological conditions, this pathway protects cells from oxidative damage, however, sustained activation of NRF2 in cancer, often due to mutations in KEAP1, supports tumor cell survival, drug resistance, and metabolic reprogramming. Recent studies demonstrate that NRF2 enhances glutathione (GSH) synthesis, induces detoxifying enzymes, and upregulates drug efflux transporters, collectively contributing to resistance against chemotherapy and targeted therapies. The inhibition of NRF2 using small molecules or dietary phytochemicals has shown promise in restoring drug sensitivity in preclinical cancer models. This review highlights the dual role of NRF2 in redox regulation and cancer therapy, emphasizing its potential as a therapeutic target. While targeting NRF2 offers a novel approach to overcoming treatment resistance, further research is needed to enhance specificity and facilitate clinical translation.
癌症仍然是全球主要的健康负担，其发病率和死亡率的上升与人口老龄化以及接触基因毒性物质的增加有关。氧化应激在癌症的发生、发展及治疗耐药性中起着关键作用。核因子红细胞2相关因子2（NRF2）- Kelch样ECH相关蛋白1（KEAP1）-抗氧化反应元件（ARE）信号通路对于通过调节抗氧化和解毒基因的表达来维持氧化还原平衡至关重要。在生理条件下，该通路保护细胞免受氧化损伤，然而，癌症中NRF2的持续激活（通常由于KEAP1的突变）支持肿瘤细胞存活、耐药性及代谢重编程。最近的研究表明，NRF2增强谷胱甘肽（GSH）合成、诱导解毒酶并上调药物外排转运体，共同导致对化疗和靶向治疗的耐药性。在临床前癌症模型中，使用小分子或膳食植物化学物质抑制NRF2已显示出恢复药物敏感性的前景。本综述强调了NRF2在氧化还原调节和癌症治疗中的双重作用，强调了其作为治疗靶点的潜力。虽然靶向NRF2为克服治疗耐药性提供了一种新方法，但仍需要进一步研究以提高特异性并促进临床转化。
