Vitiligo is an acquired skin depigmentation disease in which excessive reactive oxygen species (ROS) play a critical pathogenic role in melanocyte destruction. The complex crosstalk between melanocytes and keratinocytes in vitiligo suggests that treatments aimed at protecting both the cells might be meaningful. In this study, we investigated the effect of 4-octyl itaconate (4-OI), an itaconate derivative, on ultraviolet B- (UVB-) induced apoptosis in HaCaT and PIG1 cells and the underlying mechanisms. HaCaT and PIG1 cells were pretreated with 4-OI (50 or 100 μM) for 24 h and then exposed to 300 mJ/cm2 UVB (emission range 290–320 nm, emission peak 310 nm). ROS levels and cell apoptosis were investigated using fluorescence microscopy and flow cytometry 24 h after irradiation. In addition, nuclear translocation and the expression of pathway-related proteins and mRNAs were detected using confocal microscopy, western blotting, and qRT-PCR, respectively. Our results demonstrated that UVB induced apoptosis in HaCaT and PIG1 cells, whereas inhibition of ROS production could reverse this effect. Furthermore, 4-OI attenuated UVB-induced apoptosis in HaCaT and PIG1 cells in a concentration-dependent manner by reducing the ROS levels. Moreover, 4-OI induced nuclear translocation and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and Nrf2 silencing reversed the inhibitory effect of 4-OI on the UVB-induced increase in ROS production and apoptosis in HaCaT and PIG1 cells. In addition, in vivo experiments using the Institute of Cancer Research mouse model showed that 4-OI via tail vein injection (10 mg/kg/day for six consecutive days) could reduce skin damage induced by UVB (400 mJ/cm2/day for five consecutive days). In conclusion, 4-OI can protect melanocytes and keratinocytes from UVB-induced apoptosis by Nrf2 activation-dependent ROS inhibition and can potentially treat skin disorders associated with oxidative stress, such as vitiligo.

Vitiligo is an acquired depigmented skin disorder. Though genetic background, autoimmune dysregulation, and oxidative stress were reported involved in the development of vitiligo, the exact pathogenesis remains largely unknown. This study aimed to investigate potential functional proteins, pathways, and serum biomarkers involved in active vitiligo. Patients and Methods: Tandem Mass Tags (TMT) method was used to determine differentially expressed proteins (DEPs) in serum samples between 11 active vitiligo patients and 7 healthy controls of Chinese Han population. Results: A total of 31 DEPs were identified (P < 0.05, fold change >1.2), with 21 proteins upregulated and 10 proteins downregulated in the vitiligo group. DEPs were enriched in GO terms such as "extracellular exosome" and "immunoglobulin receptor binding", as well as KEGG pathways including "cysteine and methionine metabolism" and other immune-related pathways. Furthermore, ALDH1A1 and EEF1G achieved areas under receiver-operating characteristic (ROC) curve of 0.9221 and 0.8571, respectively. The expression levels of these 2 proteins were validated in another active vitiligo patient group. Conclusion: Our research provided novel insight into serum proteomic profile for vitiligo patients, detecting ALDH1A1 and EEF1G as potential biomarkers for active vitiligo and therapeutic intervention. Our work also detected several DEPs and associated pathways in the serum of active vitiligo patients, reinforcing the roles of retinoic acid and exosome processes in vitiligo pathogenesis.