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

Xueyao Cai,1,* Weidong Li,1,* Wenjun Shi,1 Xia Ding,2,3 Yuchen Cai1 1Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xia Ding, Department of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao-Ju Road, Huangpu District, Shanghai, 200011, People’s Republic of China, Email [email protected] Yuchen Cai, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi-Zao-Ju Road, Huangpu District, Shanghai, 200011, People’s Republic of China, Email [email protected]: 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.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.Results: 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.Conclusion: 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. Keywords: facial skin aging, DNA methylation, palmitoylation, ZDHHC17, Mendelian randomization