Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 protein–protein interaction interface (KEAP1–Nrf2 PPI)

The KEAP1–Nrf2 protein–protein interaction (PPI) interface is a fundamental regulatory mechanism for the cellular antioxidant response (NIH, 2020). Under normal physiological conditions, the homodimeric KEAP1 protein acts as a substrate adaptor for the Cullin 3-based E3 ubiquitin ligase complex, binding to the Nrf2 transcription factor and targeting it for proteasomal degradation (UniProt, 2024; NIH, 2019). When cells encounter oxidative or electrophilic stress, specific cysteine residues on KEAP1 are modified, or the PPI is directly inhibited, allowing Nrf2 to stabilize and translocate to the nucleus (Frontiers, 2024). In the nucleus, Nrf2 binds to Antioxidant Response Elements (ARE) to induce the expression of cytoprotective and detoxifying enzymes like NQO1 and HMOX1 (MDPI, 2021). Pharmacological targeting of this interface is a major strategy for treating chronic inflammatory and neurodegenerative diseases, with drugs like dimethyl fumarate and omaveloxolone already in clinical use (NIH, 2023). Direct inhibitors of the PPI interface are being developed as more selective alternatives to traditional electrophilic activators to avoid off-target effects (PubMed, 2017). However, the 'Nrf2 paradox' presents a significant therapeutic challenge, as chronic Nrf2 activation can promote the survival and chemoresistance of established tumor cells (NIH, 2011). This interface is also implicated in metabolic disorders and chronic kidney disease, highlighting its broad clinical relevance (MDPI, 2019).

Other names

KEAP1–NFE2L2 interactionNrf2–KEAP1 complexKEAP1–Nrf2 axisKEAP1–Nrf2–ARE pathway

Inhibition of the KEAP1–Nrf2 interaction, either through direct non-covalent binding to the KEAP1 Kelch domain or indirect covalent modification of KEAP1 sensor cysteines, prevents Nrf2 ubiquitination and degradation, leading to its nuclear translocation and activation of the antioxidant response element (ARE) gene battery.