Glutathione (GSH) has long been recognised for its antioxidant and detoxifying effects on the liver. The hepatoprotective effect of GSH involves the activation of antioxidative systems such as NRF2; however, details of the mechanisms remain limited. A comparative analysis of the biological events regulated by GSH under physiological and oxidative stress conditions has also not been reported. In this study, DNA microarray analysis was performed with four experiment arms including Control, GSH, hydrogen peroxide (HP), and GSH + HP treatment groups. The GSH-treated group exhibited a significant upregulation of genes clustered in cell proliferation, growth, and differentiation, particularly those related to MAPK, when compared with the Control group. Additionally, liver functions such as alcohol and cholesterol metabolic processes were significantly upregulated. On the other hand, in the HP-induced oxidative stress condition, GSH (GSH + HP group) demonstrated a significant activation of cell proliferation, cell cycle, and various signalling pathways (including TGFβ, MAPK, PI3K/AKT, and HIF-1) in comparison to the HP group. Furthermore, several disease-related pathways, such as chemical carcinogenesis–reactive oxygen species and fibrosis, were significantly downregulated in the GSH + HP group compared to the HP group. Collectively, our study provides a comprehensive analysis of the effects of GSH under both physiological and oxidative stress conditions. Our study provides essential insights to direct the utilisation of GSH as a supplement in the management of conditions associated with oxidative stress.

Glutathione (GSH) is present in almost all human cells and has a beneficial effect on human skin brightness. Cysteinylglycine (Cys-Gly) and γ-glutamylcysteine (γ-Glu-Cys) are GSH synthesis components. In this study, we defined glutathione (GSH), cysteinylglycine (Cys-Gly), and γ-glutamylcysteine (γ-Glu-Cys) as cysteine peptide and performed a randomized, double-blind, placebo-controlled study to investigate the effects of orally administered cysteine peptide on human skin brightness using a CM-26d portable spectrophotometer in healthy males and females aged between 20 and 65 years old. Eligible participants were randomly allocated into three groups (cysteine peptide 45 mg: n = 16, 90 mg: n = 15, and placebo: n = 16). Each subject ingested six tablets every day for 12 weeks, and skin brightness was measured at 0, 4, 8, and 12 weeks. As a result, the 45 mg group exhibited arm brightening in a time-dependent manner, and a significant difference was observed compared to the placebo at week 12 (p = 0.028). Moreover, no serious adverse events and changes related to 270 mg study food were observed in the safety trial. Here, we suggest that cysteine peptide is a promising and safe compound for human skin brightness.

Melanin, the principal component of skin pigmentation, is produced through tyrosinase activity. Recently, supersulphides have been identified in human cells and found to play a role in maintaining cellular activities. Glutathione trisulphide (GSSSG), a supersulphide with antioxidant properties, has various biological effects. However, the influence of melanin production on intracellular persulphide levels remains unclear, and no studies have reported the anti-melanogenic effects of GSSSG. Therefore, we aimed to elucidate the impact of melanogenesis on intracellular persulphide abundance and synthesis, as well as the efficacy of GSSSG in inhibiting melanogenesis in melanoma cells. In this study, B16-F0 cells were used to evaluate the melanin and intracellular persulphide levels by alpha-melanocyte-stimulating hormone (α-MSH). Moreover, the effects of GSSSG on melanin production were studied. The results revealed that α-MSH-induced melanogenesis significantly increased melanin production and decreased intracellular persulphide levels. Furthermore, the expression of persulphide synthesis genes, including Cars2 and Cbs, was significantly downregulated by α-MSH. In contrast, GSSSG significantly suppressed α-MSH-induced melanin production. Notably, GSSSG restored the intracellular persulphide levels reduced by α-MSH and upregulated Cars2 and Cbs expression. These findings suggest that GSSSG exerts anti-melanogenesis effects, maintains intracellular persulphide levels, and improves skin brightness.

Ultraviolet B (UVB) irradiation induces hyperpigmentation and contributes to skin photoaging. Glutathione trisulphide (GSSSG), a naturally occurring supersulphide with anti-inflammatory and antioxidant properties, has been shown to suppress α-melanocyte-stimulating hormone-induced melanogenesis and improve skin brightness. However, its efficacy under physiologically relevant UVB-induced pigmentation conditions and its skin-brightening potential in human skin-like systems remain unclear. Therefore, this study evaluated the anti-melanogenic effects of GSSSG in UVB-stimulated melanogenesis and assessed its skin-brightening efficacy in a three-dimensional (3D) skin model while investigating the relationship between melanogenesis and intracellular endogenous supersulphide levels. UVB irradiation increased melanin production while decreasing intracellular supersulphide levels. GSSSG suppressed UVB-induced melanogenesis and restored intracellular supersulphide levels. Furthermore, Cars2 knockdown reduced intracellular supersulphide levels and melanin production, suggesting a role for endogenous supersulphides in pigmentation. In addition, 0.1% GSSSG significantly improved skin brightness in a 3D skin model. These findings demonstrate the efficacy of GSSSG in both UVB-induced melanogenesis and a human skin-like model and suggest that supersulphides play context-dependent roles in melanogenesis, suppressing excessive pigmentation while supporting physiological melanin synthesis.

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.