DNA Methylation-Regulated ZDHHC17 Promotes the Risk of Facial Skin Aging

Emerging evidence suggests that protein palmitoylation plays a critical role in regulating cellular signaling, yet its involvement in skin aging remains largely unexplored. Additionally, the epigenetic regulation of palmitoylation-related genes in age-related dermal changes has not been systematically studied. This research aimed to investigate the causal relationship between palmitoylation genes, DNA methylation, and facial skin aging using Mendelian randomization (MR) methods.

We performed an integrated genetic analysis using two-sample MR and summary-data-based MR (SMR) to identify palmitoylation-related genes with a potential causal role in facial skin aging. For significant genes, we further conducted a two-step MR mediation analysis to investigate whether DNA methylation influences facial aging by altering these palmitoylation genes, complemented by sensitivity tests to evaluate the robustness of findings. Analyses utilized large-scale datasets, including facial aging genome-wide association study (GWAS) summary statistics (n = 423,992), gene expression data from eQTLGen, and methylation profiles from GoDMC.

The initial two-sample MR identified a significant positive association between ZDHHC17 expression and facial aging risk (p = 0.0112). SMR analysis confirmed the link between ZDHHC17 transcription and facial aging traits. Further mediation analysis revealed that DNA methylation at cg23935522 positively regulates ZDHHC17 expression (p = 0.00188), indirectly increasing facial aging susceptibility (p = 0.0227). The mediation effect accounted for 25.29% of the total association between the methylation site and facial aging risk. Sensitivity analyses demonstrated no evidence of horizontal pleiotropy, and the MR-PRESSO global test showed no significant outliers for ZDHHC17. Heterogeneity tests showed consistent effect estimates across genetic instruments, supporting the robustness of the results.

Collectively, this study offers new insights into the molecular mechanisms of skin aging and highlights ZDHHC17 methylation as a potential biomarker or therapeutic target in age-related dermatological intervention.