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

The Keap1–Nrf2 protein–protein interface is a master regulatory switch for the cellular antioxidant and cytoprotective response. Kelch-like ECH-associated protein 1 (Keap1) functions as a sensor for oxidative stress and a substrate adapter for the Cullin 3-based E3 ubiquitin ligase complex, which targets Nuclear factor erythroid 2-related factor 2 (Nrf2) for degradation under normal conditions [UniProt: Q14145, Q16236]. When the interface is disrupted—either by oxidative modification of Keap1 cysteines or by pharmacological inhibitors—Nrf2 accumulates and translocates to the nucleus to induce the transcription of genes involved in redox balance and detoxification [PMID: 25911081]. This pathway is a major therapeutic target for chronic inflammatory and neurodegenerative conditions, with drugs like dimethyl fumarate and omaveloxolone already approved for multiple sclerosis and Friedreich's ataxia, respectively [FDA: Skyclarys, Tecfidera]. However, the target presents a significant challenge in oncology, as constitutive Nrf2 activation can protect cancer cells from oxidative stress and radiotherapy, a phenomenon known as the Nrf2 paradox [PMID: 30736422]. Current drug development focuses on both electrophilic activators that modify Keap1 and non-electrophilic small molecules that directly block the protein-protein interaction site.

Other names

Keap1-Nrf2 axisKeap1-Nrf2 interactionKeap1-Nrf2 pathwayKeap1-Nrf2 signaling complex

Inhibition of the Keap1-Nrf2 interaction prevents the Keap1-mediated ubiquitination and subsequent proteasomal degradation of Nrf2, leading to Nrf2 stabilization, nuclear translocation, and activation of the antioxidant response element (ARE) gene battery [PMID: 25911081, UniProt: Q14145].