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.