Glutathione Trisulfide Protects Human Epidermal Keratinocytes from UVB-Induced Damage via Restoration of Intracellular Supersulfide Levels

Ultraviolet B (UVB) irradiation induces oxidative stress and inflammation in keratinocytes, contributing to skin damage and photoaging. Although supersulfides have recently emerged as important regulators of cellular redox homeostasis, their role in UVB-induced skin damage remains poorly understood. In this study, we investigated the effects of glutathione trisulfide (GSSSG), a representative supersulfide, in UVB-exposed normal human epidermal keratinocytes (NHEKs). UVB irradiation significantly reduced cell viability and intracellular supersulfide levels while increasing reactive oxygen species (ROS) production and the expression of IL-1α, prostaglandin E2, and p21. Pretreatment with GSSSG significantly restored intracellular supersulfide levels, improved cell viability, suppressed ROS accumulation and inflammatory mediator production, and attenuated p21 induction. Furthermore, GSSSG significantly promoted nuclear factor erythroid 2-related factor 2 nuclear translocation and increased heme oxygenase-1 production, indicating activation of antioxidant defense pathways. Knockdown of cysteinyl-tRNA synthetase 2 (CARS2), a key enzyme involved in endogenous supersulfide biosynthesis, increased cellular susceptibility to UVB-induced cytotoxicity, whereas GSSSG restored the viability of CARS2-deficient cells. Collectively, these findings suggest that GSSSG protects keratinocytes against UVB-induced oxidative stress, inflammation, and cytotoxicity. This protective activity may be mediated, at least in part, through restoration of intracellular supersulfide levels and activation of the NRF2-mediated antioxidant response.