Roles of the KEAP1-NRF2 system in mammalian skin exposed to UV radiation

Highlights: • UVR is usually a poor activator of NRF2. • NRF2 can protect mammalian skin from the harmful effects of UVR. • Basal NRF2 activity can protect skin from photoaging by UVR. • Protection of skin by NRF2 from UVR-induced carcinogenesis requires NRF2 activation. • NRF2 can suppress and promote skin carcinogenesis by UVR depending on the situation. The KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (NF-E2-related factor 2) system controls the biochemical defense activity against agents toxic to mammals and responds to exogenous and endogenous stressors such as electrophilic and oxidative substances, which can have destructive and genotoxic effects on affected mammalian tissues. Although this system can be activated by various environmental stressors, it remains unclear whether ultraviolet radiation (UVR), which is one of the major environmental agents that has inflammatory and carcinogenic impacts on human skin and eyes, induces NRF2-dependent defense activity. Here, we review the recent progress in the study of the contributions of NRF2 and related factors to protection against UVR. The KEAP1-NRF2 system is not always efficient in responding to UVR, especially to short wavelengths such as UVC/UVB, indicating that UVR is a poor activator of the KEAP1-NRF2 system. However, sustained activation of NRF2 appears to suppress the harmful effects of chronic UVR exposure, such as photoaging of and carcinogenesis in the skin, indicating that NRF2 activation is beneficial for the protection of the skin from the harmful effects of UVR. However, it should be noted that prolonged and strong activation of NRF2 may also have adverse effects on skin, especially in the case of UVR-induced carcinogenesis. We present working models describing mechanisms underlying the involvement of the KEAP1-NRF2 system in skin photoaging and carcinogenesis.