Overexpression of SIRT6 regulates NRF2/HO-1 and NF-κB signaling pathways to alleviate UVA-induced photoaging in skin fibroblasts

Skin photoaging, resulting from prolonged exposure to sunlight, especially UVA rays, has been identified as a key contributor to age-related skin degeneration. However, the mechanism by which UVA radiation induces skin cell senescence has not been fully elucidated. In this investigation, bioinformatics technology was employed to identify SIRT6 as the core hub gene involved in the progression of skin photoaging. The study evinced that prolonged exposure of cutaneous fibroblasts to UVA radiation results in a marked reduction in the expression of SIRT6, both in vivo and in vitro. Knockdown of SIRT6 in skin fibroblasts resulted in the upregulation of genes associated with cellular aging, thereby exacerbating the effects of UVA radiation-induced photoaging. Conversely, overexpression of SIRT6 decreased the expression of cell aging-related genes, indicating that SIRT6 plays a role in the regulation of senescence in skin fibroblasts induced by UVA radiation. We proffer substantiation that overexpression of SIRT6 protects skin fibroblasts from UVA-induced oxidative stress by activating the NRF2/HO-1 signaling cascade. Moreover, SIRT6 overexpression also reduced UVA-induced type I collagen degradation by inhibiting NF-κB signaling cascade. In summary, our findings showed that overexpression of SIRT6 inhibits UVA-induced senescence phenotype and type I collagen degradation in skin fibroblasts by modulating the NRF2/HO-1 and NF-κB signaling pathways. And the regulation of these signaling pathways by SIRT6 may be achieved through its deacetylase activity. Therefore, SIRT6 is a novel and promising therapeutic target for skin aging related to age and UV.