The excessive production of reactive oxygen species (ROS) can lead to single nucleic acid base damage, DNA strand breakage, inter- and intra-strand cross-linking of nucleic acids, and protein-DNA cross-linking involved in the pathogenesis of cancer, neurodegenerative diseases, and aging. G-quadruplex (G4) is a stacked nucleic acid structure that is ubiquitous across regulatory regions of multiple genes. Abnormal formation and destruction of G4s due to multiple factors, including cations, helicases, transcription factors (TFs), G4-binding proteins, and epigenetic modifications, affect gene replication, transcription, translation, and epigenetic regulation. Due to the lower redox potential of G-rich sequences and unique structural characteristics, G4s are highly susceptible to oxidative damage. Additionally, the formation, stability, and biological regulatory role of G4s are affected by ROS. G4s are involved in regulating gene transcription, translation, and telomere length maintenance, and are therefore key players in age-related degeneration. Furthermore, G4s also mediate the antioxidant process by forming stress granules and activating Nrf2, which is suggestive of their involvement in developing ROS-related diseases. In this review, we have summarized the crosstalk between ROS and G4s, and the possible regulatory mechanisms through which G4s play roles in aging and age-related diseases.

Given that the proteome is a major source of therapeutic targets, we conducted a proteome-wide Mendelian randomization (MR) combined with transcriptome sequencing analysis to identify candidate protein markers and therapeutic targets for vitiligo. Based on protein quantitative trait loci (pQTLs) and genetic associations with vitiligo obtained from the European Bioinformatics Institute (EBI) database (60 vitiligo cases and 402,672 controls), and the UK Biobank (95 vitiligo cases and 337,064 controls), bidirectional MR and colocalization analyses identified genetically predicted levels of nine proteins collectively linked to vitiligo risk. Based on the RNA-seq data and single-cell RNA-seq data of vitiligo, bioinformatics analysis and model prediction of genes associated with vitiligo progression evaluated the relationship between candidate core proteins and the development of vitiligo. Four proteins (KLF4, MYL4, TNFRSF13C, TNFSF13B) were associated with lower vitiligo risk, while five proteins (ALPI, CDH1, ITGB1, SERPINH1, TNFSF10) were linked to higher risk. Of these, three proteins (KLF4, TNFRSF13C, and TNFSF10) were high priority with the most convincing evidence. Bioinformatics analysis and model prediction of genes associated with vitiligo progression showed these three protein-coding genes were significantly associated with vitiligo occurrence, and their functions were related to cell cycle, apoptosis, oxidative stress, inflammatory response, and immune infiltration. Mechanistically, the expression of these key candidate molecules was regulated by various miRNAs and transcription factors. The druggability assessment and molecular docking identified some drugs targeting these proteins, such as APTO-2535 and butyric acid. KLF4, TNFRSF13C, and TNFSF10 may be involved in regulating the occurrence and development of vitiligo, providing potential targets for improving the diagnosis and treatment of vitiligo.