NRF2 as a Therapeutic Target in Dermatological Disorders: Mechanisms and Molecules

The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcription factor that orchestrates cellular defense against oxidative and electrophilic stress. Dysregulation of the KEAP1-NRF2-ARE pathway has been implicated in several dermatological disorders, including vitiligo, psoriasis, atopic dermatitis, photoaging, and radiation dermatitis. This review summarizes recent advances in the understanding of NRF2 activation mechanisms and highlights pharmacological and natural compounds with potential dermatological applications. A comprehensive analysis of natural, semisynthetic, and synthetic NRF2 modulators is provided, describing their chemical structures, synthetic approaches, mechanisms of action, preclinical and clinical evidence, and therapeutic relevance for skin disorders. Multiple classes of NRF2 activators, including isothiocyanates such as sulforaphane, triterpenoids such as omaveloxolone, flavonoids including baicalein and apigenin, alkaloids such as berberine, glycosides like afzelin and paeoniflorin, stilbenoids such as tapinarof, and α,β-unsaturated fumaric acid esters such as dimethyl fumarate, have demonstrated antioxidant, anti-inflammatory, and cytoprotective effects in keratinocytes and melanocytes. Some of these agents, particularly dimethyl fumarate and tapinarof, have advanced to clinical development or commercialization, whereas others remain at the preclinical stage but show encouraging results in animal models and cell culture systems. Overall, pharmacological activation of NRF2 represents a promising therapeutic strategy to counteract oxidative stress-driven skin damage and inflammation; however, continued translational and clinical research is required to optimize formulations, dosing regimens, and safety profiles for integration into dermatological practice.