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Nrf2与活性氧在调节上皮-间质转化中的相互作用：对癌症转移和治疗的影响

Interplay between Nrf2 and ROS in regulating epithelial-mesenchymal transition: implications for cancer metastasis and therapy.

作者信息

Xu Yi, Hu Shuning, Chen Rui, Xu Sheng, Yu Guangyang, Ji Lili

机构信息

Department of Pathology, Key Laboratory of Microenvironment and Translational Cancer Research, Medical School of Nantong University, Nantong, Jiangsu, 226001, China.

Department of Pathology, Lianyungang Affiliated Hostital Of Nanjing University of Chinese Medicine, Lianyungang, Jiangsu, 222004, China.

出版信息

Mol Biol Rep. 2025 Jun 23;52(1):628. doi: 10.1007/s11033-025-10731-9.

DOI:10.1007/s11033-025-10731-9
PMID:40549063
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12185618/
Abstract

Epithelial-mesenchymal transition (EMT), including developmental (Type I), wound healing (Type II), and pathological (Type III) subtypes, constitutes a critical driver of cancer metastasis. This review analyzes the redox interplay between nuclear factor erythroid 2-related factor 2 (Nrf2) and reactive oxygen species (ROS) in EMT regulation and cancer progression. Nrf2 maintains redox homeostasis through antioxidant gene activation while paradoxically promoting tumor survival and drug resistance via Keap1-dependent degradation and phosphorylation-mediated stabilization. ROS generated through mitochondrial and NADPH oxidase pathways exhibit dual functionality: moderate levels activate EMT transcription factors to drive metastasis and cancer stem cells (CSCs) plasticity, whereas excessive ROS induce apoptosis and ferroptosis. While Nrf2 typically suppresses EMT through ROS neutralization and epithelial integrity preservation, chronic Nrf2 activation in CSCs paradoxically sustains metastatic potential through redox buffering. This synthesis delineates the spatiotemporal regulation of Nrf2-ROS-EMT networks across tumor microenvironments, emphasizing therapeutic opportunities through redox balance modulation and pathway-specific Nrf2 inhibition in advanced malignancies.

摘要

上皮-间质转化（EMT）包括发育性（I型）、伤口愈合性（II型）和病理性（III型）亚型，是癌症转移的关键驱动因素。本综述分析了核因子红细胞2相关因子2（Nrf2）与活性氧（ROS）在EMT调控和癌症进展中的氧化还原相互作用。Nrf2通过激活抗氧化基因维持氧化还原稳态，同时通过Keap1依赖性降解和磷酸化介导的稳定作用促进肿瘤存活和耐药性。通过线粒体和NADPH氧化酶途径产生的ROS具有双重功能：适度水平激活EMT转录因子以驱动转移和癌症干细胞（CSC）可塑性，而过量的ROS诱导细胞凋亡和铁死亡。虽然Nrf2通常通过ROS中和和维持上皮完整性来抑制EMT，但CSC中慢性Nrf2激活通过氧化还原缓冲反而维持转移潜能。本综述阐述了肿瘤微环境中Nrf2-ROS-EMT网络的时空调控，强调了通过调节氧化还原平衡和在晚期恶性肿瘤中特异性抑制Nrf2途径的治疗机会。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/9c00a569cc2f/11033_2025_10731_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/6b80b54ea793/11033_2025_10731_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/6b6db0bbe194/11033_2025_10731_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/e398bf1a4bbe/11033_2025_10731_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/bd42908793b9/11033_2025_10731_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/9c00a569cc2f/11033_2025_10731_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/6b80b54ea793/11033_2025_10731_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/6b6db0bbe194/11033_2025_10731_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/e398bf1a4bbe/11033_2025_10731_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/bd42908793b9/11033_2025_10731_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b66/12185618/9c00a569cc2f/11033_2025_10731_Fig5_HTML.jpg

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