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

The **Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 interaction** is a critical cytoplasmic regulatory mechanism that controls cellular responses to oxidative and electrophilic stress. Under basal conditions, **Keap1** binds **Nrf2** via two motifs (ETGE and DLG) on Nrf2. This binding recruits the Cul3-Rbx E3 ubiquitin ligase complex through Keap1’s BTB domain, resulting in polyubiquitination and proteasomal degradation of Nrf2. Upon exposure to oxidative or electrophilic agents—which modify cysteine residues on Keap1—this inhibitory complex dissociates or changes conformation. As a result, newly synthesized Nrf2 escapes degradation, translocates into the nucleus, binds antioxidant response elements (AREs), and drives transcriptional activation of numerous cytoprotective genes involved in glutathione synthesis, detoxification enzymes like HO‑１and GSTs, NADPH regeneration pathways among others. Disruption or pharmacological inhibition of this protein-protein interface is being explored therapeutically for diseases where enhanced antioxidant defense is beneficial—including neurodegeneration and inflammation—as well as targeted modulation in cancer where aberrant pathway activation can contribute to tumor progression or therapy resistance.

Other names

Keap1–Nrf2 complexKEAP1-NFE2L2 interactionKelch-like ECH-associated protein 1 and NFE2L2 (NRF2) interaction

Inhibition of the Keap1–Nrf2 protein-protein interaction, leading to stabilization and nuclear translocation of Nrf2, which activates antioxidant response element (ARE)-driven gene expression