Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 regulatory interface (Keap1–Nrf2 interface)

The Keap1–Nrf2 regulatory interface is a fundamental cellular defense mechanism that maintains redox and protein homeostasis by sensing oxidative and electrophilic stress [1, 4]. Under normal conditions, the Kelch-like ECH-associated protein 1 (Keap1) acts as a substrate adaptor for the Cullin 3-based E3 ubiquitin ligase complex, which continuously targets the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) for ubiquitination and proteasomal degradation [1, 11]. Upon exposure to stress, specific cysteine sensors on Keap1 are modified, or the protein-protein interaction is directly inhibited, allowing Nrf2 to accumulate and translocate to the nucleus [2, 16]. Once in the nucleus, Nrf2 binds to Antioxidant Response Elements (ARE) to drive the expression of a vast network of cytoprotective genes, including those for antioxidant enzymes and detoxification proteins [13, 15]. This interface is a major therapeutic target for chronic inflammatory, metabolic, and neurodegenerative diseases, with drugs like dimethyl fumarate already approved for multiple sclerosis [2, 14]. Pharmacological strategies include electrophilic activators that modify Keap1 cysteines and non-electrophilic small molecules that directly disrupt the Keap1-Nrf2 protein-protein interaction [2, 12]. However, the pathway's role is complex, as persistent Nrf2 activation in cancer cells can lead to "Nrf2 addiction," where it promotes tumor survival and resistance to therapy [1, 11]. Clinical development has faced challenges, such as the termination of certain trials due to cardiovascular safety concerns, highlighting the need for precise modulation of this axis [3, 6].

Other names

Keap1-Nrf2 PPIKeap1-Nrf2 pathwayNrf2-Keap1 axisKeap1-Nrf2-ARE pathway

Inhibition of Keap1-mediated ubiquitination of Nrf2, leading to Nrf2 stabilization and nuclear translocation to activate antioxidant response elements (ARE).