Targeting epigenetic and post-translational modifications of NRF2: key regulatory factors in disease treatment

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in regulating cellular antioxidant defense and detoxification mechanisms. It mitigates oxidative stress and xenobiotic-induced damage by inducing the expression of cytoprotective enzymes, including HO-1 and NQO1. NRF2 also modulates inflammatory responses by inhibiting pro-inflammatory genes and mediates cell death pathways, including apoptosis and ferroptosis. Targeting NRF2 offers potential therapeutic avenues for treating various diseases. NRF2 is regulated through two principal mechanisms: post-translational modifications (PTMs) and epigenetic alterations. PTMs, including phosphorylation, ubiquitination, and acetylation, play a pivotal role in modulating NRF2's stability, activity, and subcellular localization, thereby precisely controlling its function in the antioxidant response. For instance, ubiquitination can lead to NRF2 degradation and reduced antioxidant activity, while deubiquitination enhances its stability and function. Epigenetic modifications, such as DNA methylation, histone modifications, and interactions with non-coding RNAs (e.g., MALAT1, PVT1, MIR4435-2HG, and TUG1), are essential for regulating NRF2 expression by modulating chromatin architecture and gene accessibility. This paper systematically summarizes the molecular mechanisms by which PTMs and epigenetic alterations regulate NRF2, and elucidates its critical role in cellular defense and disease. By analyzing the impact of PTMs, such as phosphorylation, ubiquitination, and acetylation, as well as DNA methylation, histone modifications, and non-coding RNA interactions on NRF2 stability, activity, and expression, the study reveals the complex cellular protection network mediated by NRF2. Furthermore, the paper explores how these regulatory mechanisms affect NRF2's roles in oxidative stress, inflammation, and cell death, identifying novel therapeutic targets and strategies. This provides new insights into the treatment of NRF2-related diseases, such as cancer, neurodegenerative disorders, and metabolic syndrome. This research deepens our understanding of NRF2's role in cellular homeostasis and lays the foundation for the development of NRF2-targeted therapies.