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Thus, p62 competes with Nrf2 for Keap1 binding at the bottom of the DC domain, dislocating Nrf2 from Keap1 and leading to the accumulation of Nrf2 (Figure 1) ( Keap1-independent Mechanism of Nrf2 Regulation Although the majority of Nrf2 is mainly moderated by Keap1 in answer to ROS/electrophiles, some researchers found that the PI3K-AKT signaling pathway could also stimulate Nrf2 (Figure 1) ( Oxidative stress-induced PKC can catalyze the serine and threonine residues on Ser40 in Neh2, dissociating the Keap1 homodimer, and transporting Nrf2 into the nucleus to recognize and bind the ARE/EpRE response element (Figure 1) ( in vitro studies have shown that regardless of the phosphorylation status of Nrf2, the affinity of Nrf2-sMaf heterodimers to ARE is similar ( Development of Nrf2 Inducers For exploring the preventive and alleviating efforts of Nrf2 in mouse disease models, the whole world is striving to isolate or develop effective and potentially specific Nrf2 inducing chemicals from natural sources