The skin represents a physical barrier between the organism and the environment that has evolved to confer protection against biological, chemical, and physical insults. The inner layer, known as dermis, is constituted by connective tissue and different types of immune cells whereas the outer layer, the epidermis, is composed by different layers of keratinocytes and an abundant number of melanocytes, localized in the stratum basale of the epidermis. Oxidative stress is a common alteration of inflammatory skin disorders such as vitiligo, dermatitis, or psoriasis but can also play a causal role in skin carcinogenesis and tumor progression. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) has emerged as a crucial regulator of cell defense mechanisms activating complex transcriptional programs that facilitate reactive oxygen species detoxification, repair oxidative damage and prevent xenobiotic-induced toxicity. Accumulating evidence suggests that the keratinocytes, melanocytes, and other skin cell types express high levels of NRF2, which is known to play a pivotal role in the skin homeostasis, differentiation, and metabolism during normal and pathologic conditions. In the present review, we summarize the current evidence linking NRF2 to skin pathophysiology and we discuss some recent modulators of NRF2 activity that have shown a therapeutic efficacy in skin protection against tumor initiation and common inflammatory skin conditions such as vitiligo or psoriasis, with a particular emphasis on natural compounds.
© 2022 International Union of Biochemistry and Molecular Biology.