| Summary: | Skin is a direct target of fine particulate matter (PM<sub>2.5</sub>), as it is constantly exposed. Herein, we investigate whether Korean red ginseng (KRG) can inhibit PM<sub>2.5</sub>-induced senescence in skin keratinocytes. PM<sub>2.5</sub>-treated human keratinocyte cell lines and normal human epidermal keratinocytes showed characteristics of cellular senescence, including flat and enlarged forms; however, KRG suppressed them in both cell types. Moreover, while cells exposed to PM<sub>2.5</sub> showed a higher level of p16<sup>INK4A</sup> expression (a senescence inducer), KRG inhibited its expression. Epigenetically, KRG decreased the expression of the ten-eleven translocation (TET) enzyme, a DNA demethylase induced by PM<sub>2.5</sub>, and increased the expression of DNA methyltransferases suppressed by PM<sub>2.5</sub>, resulting in the decreased methylation of the <i>p16<sup>INK4A</sup></i> promoter region. Additionally, KRG decreased the expression of mixed-lineage leukemia 1 (MLL1), a histone methyltransferase, and histone acetyltransferase 1 (HAT1) induced by PM<sub>2.5</sub>. Contrastingly, KRG increased the expression of the enhancer of zeste homolog 2, a histone methyltransferase, and histone deacetyltransferase 1 reduced by PM<sub>2.5</sub>. Furthermore, KRG decreased TET1, MLL1, and HAT1 binding to the <i>p16<sup>INK4A</sup></i> promoter, corresponding with the decreased mRNA expression of p16<sup>INK4A</sup>. These results suggest that KRG exerts protection against the PM<sub>2.5</sub>-induced senescence of skin keratinocytes via the epigenetic regulation of <i>p16<sup>INK4A</sup></i>.
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