Citation: Kang, K.A.; Piao, M.J.; Fernando, P.D.S.M.; Herath, H.M.U.L.; Yi, J.M.; Hyun, J.W. Korean Red Ginseng Attenuates Particulate Matter-Induced Senescence of Skin Keratinocytes. Antioxidants 2023, 12, 1516. https://doi.org/10.3390/ antiox12081516 Academic Editor: Jiankang Liu Received: 27 June 2023 Revised: 24 July 2023 Accepted: 27 July 2023 Published: 28 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antioxidants Article Korean Red Ginseng Attenuates Particulate Matter-Induced Senescence of Skin Keratinocytes Kyoung Ah Kang 1,2,† , Mei Jing Piao 1,2,† , Pincha Devage Sameera Madushan Fernando 1 , Herath Mudiyanselage Udari Lakmini Herath 1 , Joo Mi Yi 3 and Jin Won Hyun 1,2, * 1 Department of Biochemistry, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea; legna07@jejunu.ac.kr (K.A.K.); mjpiao@jejunu.ac.kr (M.J.P.); sameera@stu.jejunu.ac.kr(P.D.S.M.F.); lakmini@stu.jejunu.ac.kr (H.M.U.L.H.) 2 Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea 3 Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Republic of Korea; jmyi76@inje.ac.kr * Correspondence: jinwonh@jejunu.ac.kr; Tel.: +82-64-754-3838 † These authors contributed equally to this work. Abstract: Skin is a direct target of fine particulate matter (PM 2.5 ), as it is constantly exposed. Herein, we investigate whether Korean red ginseng (KRG) can inhibit PM 2.5 -induced senescence in skin ker- atinocytes. PM 2.5 -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 2.5 showed a higher level of p16 INK4A 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 2.5 , and increased the expression of DNA methyltransferases suppressed by PM 2.5 , resulting in the decreased methylation of the p16 INK4A promoter region. Additionally, KRG decreased the expres- sion of mixed-lineage leukemia 1 (MLL1), a histone methyltransferase, and histone acetyltransferase 1 (HAT1) induced by PM 2.5 . Contrastingly, KRG increased the expression of the enhancer of zeste homolog 2, a histone methyltransferase, and histone deacetyltransferase 1 reduced by PM 2.5 . Fur- thermore, KRG decreased TET1, MLL1, and HAT1 binding to the p16 INK4A promoter, corresponding with the decreased mRNA expression of p16 INK4A . These results suggest that KRG exerts protection against the PM 2.5 -induced senescence of skin keratinocytes via the epigenetic regulation of p16 INK4A . Keywords: fine particulate matter; skin cellular senescence; Korean red ginseng; epigenetic alteration 1. Introduction Air pollutants in cities represent a serious health problem, with fine particulate mat- ter (PM 2.5 ) accounting for a large portion, owing to coal combustion and diesel exhaust fumes [1]. Both indoors and outdoors, PM 2.5 damages several human systems, including the cardiovascular, central nervous, and pulmonary immune systems [2–5]. PM 2.5 mainly penetrates the skin barrier via the appendix pathway and stratum corneum, which can interfere with skin protection activities, resulting in wrinkles and thickening [6,7]. Further- more, PM 2.5 may induce both oxidative stress and inflammation, leading to skin aging [8]. Previously, we have reported that PM 2.5 contributes to senescence in human keratinocytes through oxidative-stress-dependent epigenetic regulation [9]. Changes in the external environment, such as exposure to PM 2.5 , have been reported to affect gene expression through epigenetic regulation [10,11]; wherein, PM exposure leads to hypo-methylation in the promoters of genes involved in oxidative stress, inflammation, DNA repair, and cell cycle regulation. In mammals, gene expression is strictly controlled by epigenetic modifications, such as DNA methylation and histone modifications. In general, the methylation of DNA via DNA Antioxidants 2023, 12, 1516. https://doi.org/10.3390/antiox12081516 https://www.mdpi.com/journal/antioxidants