Physiological roles of the KEAP1-NRF2 system
Piles of studies have been published regarding cytoprotective function of NRF2 in various organisms including C. elegans ,Drosophila , mouse, and human (Figure 1). NRF2-deficient mice are susceptible to various exogenous stresses, while they are healthy and fertile in a well-controlled and protected environment in a breeding facility for experimental animals. The vulnerability and susceptibility of the NRF2-deficient mice underscore the critical contribution of NRF2 to the response and adaptation to the environmental factors. For example, Nrf2-mediated protection from electrophilic toxicants, such as cigarette smoke (Rangasamy et al., 2004; Iizuka et al, 2005), and ultraviolet from the sun (Hirota et al., 2005) has been reported in mouse models. CncC, which is a Drosophila orthologue of NRF2, also confers resistance to the lethal effects of the pesticide malathion (Misra et al., 2011). SKN-1, which is a C. elegans orthologue of NRF2, plays beneficial roles in the survival in the presence of oxidative stress generated from paraquat (An & Blackwell, 2003).
In addition to the exogenous environmental factors, NRF2 is also important for the protection from endogenously-generated redox perturbations. In mouse models, NRF2 protects renal cells from reactive oxygen species (ROS) during ischemia-reperfusion injury (Liu et al., 2009; Son et al., 2010; Ashrafian et al., 2012; Nezu et al., 2017), pancreatic beta-cells from proteotoxicity under pathological conditions (Lee et al., 2012; Yagishita et al., 2014; Amin et al., 2021) and neuronal cells from neurodegenerative disorders (Pajares et al., 2016; Rojo et al., 2018; Uruno et al., 2020). Furthermore, inflammation is one of the major causes for the redox disturbance of endogenous origin. NRF2 exerts potent anti-inflammatory function by accelerating resolution of acute inflammation (Itoh et al., 2004; Mochizuki et al., 2005) as well as alleviating chronic inflammation (Suzuki et al., 2017).
Consistent with the antioxidant and anti-inflammatory functions, anti-aging effects of NRF2 activation have been observed in mice (Wati et al., 2020; Oishi et al., 2020; Zhao et al., 2022) andDrosophila (Sykiotis & Bohmann, 2008). In mouse salivary glands during physiological aging, age-related alterations including fibrosis, immune cells infiltration, cell senescence, DNA damage and lipid peroxide accumulation are all suppressed by NRF2 activation (Wati et al., 2020). Age-related hearing loss is also delayed inKeap1 -knockdown mice, in which NRF2 is systemically activated (Oishi et al., 2020). In addition to the effects on age-related functional decline, NRF2 activation by KEAP1 inhibition extends lifespan of Klotho mutant mice, which is a progeria model (Zhao et al., 2022), and alleviates age-related renal phenotypes, such as calcification and fibrosis. The similar lifespan extension can be obsereved inDrosophila (Sykiotis & Bohmann, 2008; Rahman et al., 2013).
Contribution of NRF2 to the health promotion in human has been also implicated, based on the polymorphism in the promoter region ofNFE2L2 gene, which generates difference in the expression level of NRF2. Smokers homozygous in the low expressor allele of NRF2 show higher risk of lung cancer (Suzuki et al, 2013). People homozygous in the high expressor allele of NRF2 show lower risk of noise-induced hearing loss (Honkura et al., 2016). Physiological range of NRF2 activation is beneficial in principle.