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.