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

The Nrf2-Keap1 pathway is a master regulator of the cellular antioxidant response and plays a critical role in maintaining the host intestinal epithelial barrier and modulating the gut microbiota. Under basal conditions, Keap1 facilitates the ubiquitination and degradation of Nrf2; however, oxidative or electrophilic stress leads to Nrf2 stabilization and nuclear translocation (PMID: 31035454). Once in the nucleus, Nrf2 binds to Antioxidant Response Elements (ARE) to induce the expression of cytoprotective genes, including those involved in detoxification and tight junction formation, which are essential for intestinal integrity (PMID: 33461640). This pathway also interacts bidirectionally with the gut microbiota; microbial metabolites like short-chain fatty acids and urolithins can activate Nrf2, while Nrf2-mediated redox control influences the microbial composition (PMID: 33807177). Dysregulation of this axis is a hallmark of inflammatory bowel diseases (IBD) and is implicated in the progression of colorectal cancer. Therapeutic strategies focus on Nrf2 activators, such as Bardoxolone methyl or Dimethyl fumarate, to restore barrier integrity and reduce inflammation, though concerns remain regarding the potential for Nrf2 to promote the survival of existing malignant cells (PMID: 23729213). Note: The input string describes a complex biological axis rather than a single molecular target.

Other names

NFE2L2-KEAP1 axisAntioxidant Response Element (ARE) pathwayNrf2 signaling pathwayHost-microbiota-Nrf2 axisKeap1-Nrf2-ARE signaling

Activation of Nrf2 signaling by inhibiting Keap1-mediated degradation or blocking the Keap1-Nrf2 protein-protein interaction, allowing Nrf2 to translocate to the nucleus and induce transcription of cytoprotective and antioxidant genes.