NRF2-Mediated Gene Regulation and Glucose Homeostasis

Transcription factor nuclear factor-erythroid-related factor 2 (NRF2) plays a central role in cytoprotection from various environmental stresses. In unstressed conditions, kelch-like ECH-associated protein 1 suppresses NRF2 activity through leading to degradation in the ubiquitin-proteasome pathway. Upon exposure to the environmental stresses, kelch-like ECH-associated protein 1 cysteine residues are modified and its activity is abrogated. Thereafter, NRF2 escapes from the protein degradation and accumulates in the nucleus, inducing target gene expressions. This system exerts not only cytoprotective effects against stresses but also cellular metabolic regulations. Several NRF2-inducing compounds in plants show antidiabetic effects in human and animal diabetic models, and derivatives of these compounds display strong NRF2 induction and antidiabetic effects, indicating that NRF2 is a promising target of drug development.