A review on Nrf2 and antioxidant metalloproteins

Nrf2 (nuclear factor erythroid 2–related factor 2) is a crucial transcription factor that regulates cellular defense against oxidative and electrophilic stress. Under basal conditions, Nrf2 binds to Keap1 (Kelch-like ECH-associated protein 1), which promotes its ubiquitination and degradation. The primary cellular response to oxidative or electrophilic stress is mediated through a redox-sensitive protein complex in which actin-associated Keap1 interacts with Nrf2. Upon exposure to stress-inducing agents, critical cysteine residues of Keap1 undergo modification, leading to conformational changes that disrupt the Keap1-Nrf2 interaction. As a result, Nrf2 escapes ubiquitination, stabilizes, and accumulates in the cytoplasm before translocating to the nucleus. Metalloproteins are well recognized as essential reservoirs and protective agents for trace metals such as iron, zinc, and copper, which are critical cofactors for numerous antioxidant enzymes. By controlling the expression of genes encoding metalloproteins and metal-binding proteins, Nrf2 contributes to the precise regulation of intracellular metal balance. This coordination is particularly important because, while essential metals are required for antioxidant defense, their dysregulation can promote oxidative damage through redox cycle reactions. Therefore, Nrf2-mediated regulation of metalloproteins represents a crucial interface between redox homeostasis and metal metabolism, reinforcing its central role in cellular protection.