Abstract
Discovery of NRF2 in 1994 was once assumed simplistic and classical but the following years witnessed phenomenal breakthroughs that led to a rapid increase in the components of complex molecular web. Emerging evidence has enabled us to develop a better understanding of the spatio-temporally placed molecular machinery both upstream and downstream to the NRF2 in different contexts and diseases. The exciting voyage to unravel the multifaceted roles of NRF2 in human diseases has catalyzed innovations in therapeutic approaches, inspiring the design of compounds for pharmacological modulation of NRF2 in disease prevention and intervention. In this review, we have set the spotlight on sketching a detailed landscape both upstream and downstream to the central signaling node of NRF2. Identification of the natural products having unique ability to pharmacologically target NRF2-associated networks. Later, we expand our discussion about ongoing and completed clinical trials related to multifaceted roles of NRF2 as an oncogene and a tumor suppressor. We argue that a holistic view of NRF2-driven upstream and downstream signaling is necessary for the identification of preventive or therapeutic opportunities.