Crosstalk between Nrf2 and miRNAs in oxidative stress, cancer progression, and therapy resistance

Oxidative stress (OS) is a key feature of a wide range of human disorders, including aging and cancer. The nuclear factor erythroid 2-related factor 2 (Nrf2; NFE2L2) is the master regulator of antioxidant responses via antioxidant response element (ARE)-driven gene expression. Its activity is regulated by Keap1. Under basal conditions, Keap1 binds Nrf2, promoting its degradation; OS disrupts this interaction, enabling Nrf2 stabilization, nuclear translocation, and activation of NRF2 regulated. While protecting in normal cells, persistent activation of Nrf2 in cancer promotes chemoresistance and tumor progression. microRNAs (miRNAs) are key post-transcriptional regulators of Nrf2, via binding to its 3′untranslated region. Databases such as miRBase and Human MiRNA Disease Database, which catalogue thousands of miRNA-disease associations, highlight the complexity and biological relevance of this regulatory network. Several tumor-suppressive miRNAs downregulate Nrf2 and attenuate ARE activity, thereby increasing OS sensitivity, apoptosis, and responsiveness to chemotherapy. Conversely, Nrf2 modulates miRNA networks, forming feedback loops that fine-tune redox homeostasis. While transient Nrf2 activation is generally cytoprotective, sustained Nrf2 hyperactivation in cancer promotes chemoresistance, radioresistance, metabolic reprogramming, metastasis, and poor prognosis, underscoring the need for strategies aimed at limiting Nrf2 signaling and its downstream effects. Given its multifaceted role, Nrf2 has emerged as a promising therapeutic target. Natural Nrf2 modulators and miRNA-based therapeutics (mimics/inhibitors) represent promising strategies to restore redox balance, suppress tumor progression, and overcome multidrug resistance. This review highlights the bidirectional crosstalk between Nrf2 and miRNAs and discusses its therapeutic potential in cancer.