Recent progress and applications of small molecule inhibitors of Keap1-Nrf2 axis for neurodegenerative diseases.

The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS) damage in various cells and organs. It has garnered significant attention as a potential therapeutic target for neurodegenerative diseases (NDD). Although progress has been achieved in strategies to regulate the Keap1-Nrf2 pathway, the availability of Nrf2 activators applicable to NDD is currently limited. Currently, the FDA has approved the Nrf2 activators dimethyl fumarate (DMF) and Omaveloxolone (Omav) as novel first-line oral drugs for the treatment of patients with relapsing forms of multiple sclerosis and Friedreich's ataxia. A promising alternative approach involves the direct inhibition of Keap1-Nrf2 protein-protein interactions (PPI), which offers numerous advantages over the use of electrophilic Nrf2 activators, primarily in avoiding off-target effects. This review examines the compelling evidence supporting the beneficial role of Nrf2 in NDD and explores the potential of Keap1 inhibitors and Keap1-Nrf2 PPI inhibitors as therapeutic agents, with the aim to provide further insights into the development of inhibitors targeting this pathway for the treatment of NDD.