Ultraviolet‐B Irradiation Induces miR ‐663a and miR ‐4706 Accelerated Photoaging by Targeting Sirtuin 6 in Human Dermal Fibroblasts

BACKGROUND: Ultraviolet (UV) radiation contributes to premature skin aging, and sirtuin 6 (SIRT6) plays key roles in aging, genomic stability, inflammation, and metabolism. However, the specific role of SIRT6 in UV-induced photoaging remains unclear. OBJECTIVE: To investigate the role of SIRT6 in UVB-induced skin photoaging and uncover the molecular mechanisms underlying its regulation. METHODS: A UVB-induced photoaging mouse model was established, and the role of SIRT6 was determined in vivo using histopathological and transcriptomic analyses. Candidate miRNAs targeting SIRT6 were predicted using bioinformatics tools and validated using dual-luciferase reporter assays. SIRT6 protein levels were measured via western blotting, and miRNA expression was analyzed via quantitative real-time polymerase chain reaction. Functional assays were conducted using human dermal fibroblasts (HDF) to assess cellular senescence, reactive oxygen species (ROS) production, and DNA damage. RESULTS: SIRT6 deficiency substantially exacerbated UVB-induced skin aging, characterized by collagen degradation, elastin fragmentation, and dermal structure loss. Moreover, miR-663a and miR-4706 directly targeted the 3'-untranslated region of SIRT6 and were upregulated in HDFs after UVB exposure. Overexpression of these miRNAs promoted HDFs senescence, DNA damage, and ROS accumulation, thus mirroring the effects of SIRT6 silencing. Furthermore, SIRT6 was confirmed as a key regulator of the gene networks involved in skin immune responses and inflammation following chronic UVB exposure. CONCLUSION: The study enriches existing knowledge regarding the molecular connections between miRNAs and SIRT6. Moreover, the study provides new insights into miRNA-mediated SIRT6 regulation and proposes an intervention point for the prevention of UVB-induced photoaging and age-related diseases.