Ricerc@Sapienza

The NRF2/KEAP1 pathway is a crucial and highly conserved defensive system required to maintain or restore the intracellular homeostasis in response to oxidative, electrophilic and other types of stress conditions. The tight control of NRF2 function is maintained by a complex network of biological interactions between positive and negative regulators that ultimately ensure context specific activation, culminating in the NRF2-driven transcription of cytoprotective genes. Recent studies indicate that deregulated NRF2 activation is a frequent event in malignant tumors wherein it is associated with metabolic reprogramming, increased antioxidant capacity, chemoresistance and poor clinical outcome. On the other hand, the growing interest in the modulation of the cancer cells redox balance, identified NRF2 as an ideal therapeutic target. For this reason, many efforts have been made to identify potent and selective NRF2 inhibitors that might be used as single agents or adjuvants of anticancer drugs with redox disrupting properties. In this review we will briefly describe the structure and function of the NRF2/KEAP1 system and some of the most promising NRF2 inhibitors, with a particular emphasis on natural compounds and drug repurposing.