State-of-the-Art Nrf2 Inhibitors: Therapeutic Opportunities in Non-Cancer Diseases

Nuclear factor erythroid 2-related factor (Nrf2) is a cytoprotective transcription factor that induces the transcription of genes responsible for the cell's response to oxidative stress. While Nrf2 activation has led to the development of clinically relevant therapeutics, the oncogenic role of Nrf2 in the proliferation of cancer cells has underscored the complex nature of Nrf2 and the necessity for the development of Nrf2 inhibitors. Although the application of Nrf2 inhibitors appears limited as anticancer agents, recent studies have begun to pinpoint the impairment of autophagy in diseases as a cellular marker that shifts Nrf2 from a protective to a deleterious state. Therefore, the cytoplasmic accumulation of Nrf2 can lead to the accumulation of lipid hydroperoxides and, ultimately, to ferroptosis. However, some studies aimed at elucidating the role of Nrf2 in non-cancer diseases have yielded conflicting results, attributed to differences in approaches used to inhibit or activate Nrf2, as well as variations in in vitro and/or in vivo disease models. Overall, these results highlight the necessity for a deeper evaluation of Nrf2′s role in diseases, especially chronic diseases. In this review, we discuss diseases where Nrf2 inhibition holds potential for beneficial therapeutic effects and summarize recently reported Nrf2 inhibitors exploiting medicinal chemistry approaches suitable for targeting transcription factors like Nrf2.