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

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.

Keywords: Cancer stem cells; Epithelial-mesenchymal transition (EMT); Nrf2; Oxidative stress; ROS.

Fig. 1

EMT and Key Biomarkers (Created with PowerPoint). This schematic depicts EMT, highlighting morphological and molecular shifts. Epithelial cells (left) exhibit cuboidal shape, E-cadherin-based junctions, and epithelial markers (E-Cadherin, Mucin-1, CK19/18/8, Occuluding and Desmoplakin). Mesenchymal cells (right) adopt a spindle-like structure with upregulated mesenchymal markers (N-cadherin, Vimentin, α-SMA, and MMP2/9)

Fig. 2

Domain Architecture and Functional Motifs of Nrf2 (Created with PowerPoint). This schematic illustrates the multi-domain structure of Nrf2, a master regulator of cellular defense against oxidative stress. The protein comprises seven conserved Neh domains (Neh1-Neh7), each contributing distinct functional roles. This architecture highlights Nrf2’s dual regulation (Keap1/β-TrCP) and its role in orchestrating antioxidant gene networks

Fig. 3

Function of the Nrf2 protein (Created with PowerPoint). This schematic illustrates the dual roles of Nrf2 in cancer biology. Key elements include Nrf2-mediated antioxidant/cytoprotective effects via ARE-driven genes (e.g., GCLC, NQO1) and its tumor-promoting functions through proliferation (NOTCH1, PDGFC), anti-apoptosis (BCL-2, BCL-xL), and drug resistance (MRP transporters, DNA repair pathways). The figure highlights Nrf2’s paradoxical impact: while transient activation protects normal cells, its hyperactivation in tumors drives chemoresistance and progression, underscoring its therapeutic relevance as a target for sensitizing cancer cells to treatment

Fig. 4

Role of ROS in normal cells (Created with PowerPoint). This figure illustrates the dual role of ROS as redox messengers in cellular regulation. Moderate levels regulate proliferation, differentiation, and autophagy (left), while excess ROS (right) cause oxidative damage, genomic instability, oncogenesis and even cell death. Balanced ROS homeostasis is vital for cell survival; dysregulation drives pathological transformation

Fig. 5

Dual Role of ROS in Tumor Regulation (Created with PowerPoint). ROS exhibit context-dependent effects: moderate levels promote tumor growth (PI3K/AKT, MAPK pathways) and metastasis (TGF-β1/MMP activation, angiogenesis), while excessive ROS induce apoptosis (mitochondrial/death receptor pathways) and ferroptosis (lipid peroxidation via iron/ROS interplay). The threshold of ROS accumulation dictates their pro- or anti-tumor activity, emphasizing the therapeutic potential of ROS modulation