From metabolism to genome integrity: NRF2 as a key mediator of cancer therapy response

Metabolic rewiring in cancer is sustained by deregulated intracellular signaling, frequently due to genetic mutation of oncogenes, tumor suppressors or oncometabolite genes. These mutations strongly affect the activity of Transcription Factors (TFs) and epigenetic remodelling factors, ultimately leading to different metabolic subtypes. Of note, several metabolites have been proposed to significantly modulate gene expression through post-translational modifications of metabolic enzymes, TFs and histones, sustaining the intracellular feedback loop in cancer cells. Among the TFs involved in metabolic reprogramming of cancer cells, NRF2, a well-characterized factor in the oxidative stress response, emerged as a crucial player. NRF2 is at the crossroads of critical intracellular pathways linking metabolism, DNA damage and chromatin remodelling. These findings point to NRF2 as a pivotal player in cancer therapy resistance, making it a promising target to ameliorate patient survival. Remarkably, high expression and transcriptional activity of NRF2 have been demonstrated in several cancer types, where its expression and activity correlate with poor patient survival. Unfortunately, direct molecular targeting of TFs is still challenging. Therefore, identifying signaling pathways that either drive NRF2 deregulation or are sustained by its hyperactivation has emerged as an alternative strategy to enhance NRF2 targetability and ultimately improve therapeutic outcomes. Here, we aim to summarize the current knowledge on the role of NRF2 in resistance to cancer therapy, focusing on its regulation of gene expression, metabolism, and immune response in cancer, while exploring potential functional links between metabolic rewiring, chromatin remodelling and DNA damage response proficiency.