Fig 2: Mechanism of Nrf2/ARE pathway. The Nrf2/ARE pathway is an intrinsic mechanism of resistance to oxidative stress. In the pathological inflammatory process, immune cells are first waked. These cells are then recruited to the injury site and produce ROS to destroy the testis. Neh4 and Neh5, a part of functional domains of Nrf2, mutual effect with nuclear cofactor RAC3/AIB1/SRC-3 can result in expression intensity of Nrf2-targeted ARE gene. When oxidative stress occurs, ROS respond to cysteines on Keap1 to induce a conformational change in the release of Nrf2, thereby eliminating its degradation. As a consequence, Keap1-assisted Cullin3/Rbx1-dependent polyubiquitination of Nrf2 is interdicted, and Nrf2 is released and quickly relocated into the nucleus. Once entering the nucleus, Nrf2 is engaged in heterodimerization with minor MAF or JUN proteins and their complexes combine with the ARE. HO-1 is the derivable isomer and limiting velocity enzymes. Nrf2 upregulats mRNA and protein expression through induction of HO-1 gene. Nrf2, Nuclear factor erythroid 2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; ARE, antioxidant response element; MAF, musculoaponeurotic fibrosarcoma; RAC3, receptor-associated coactivator 3; SRC-3, steroid receptor coactivator-3; Neh5, Nrf2-ECH homology 5; Neh4, Nrf2-ECH homology 4; ROS, reactive oxygen species; Rbx1, RING-box protein 1; HO-1, heme oxygenase-1.