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Consequently, pharmacological activation of the Nrf-2 pathway may help restore the oxidant-antioxidant balance, thereby improving therapeutic outcomes for chronic skin disorders. This study aimed to investigate the potential effect of novel agent: (5-((4-(4-(methoxycarbonyl)-2-oxopyrrolidin-1-yl)phenyl)carbamoyl)benzene-1,2,3-triyl triacetate (LN-53), synthesized based on the structure of previously developed by our team lead compound SK-119, on Nrf-2 signaling pathway in human epidermal keratinocytes (HEKs) at mRNA and protein level.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>The cytotoxicity of LN-53 was evaluated by MTT, LDH, live\/dead cell staining, and caspase-3,-8,-9 multiplex activity assays. Intracellular ROS production was assessed by DCFH-DA staining. The Nrf-2 gene was silenced by transient transfection using human Nrf-2 siRNA. Nrf-2 and related factors (heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase: quinone-1 (NQO1)) were evaluated at the mRNA level by qPCR and protein level in nuclear and cytosolic fractions by Nrf-2 activation assay and Western blot. The levels of inflammatory cytokines (IL-6 and IL-8) in supernatants were determined by ELISA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Our results indicate that LN-53 effectively reduces intracellular ROS production triggered by <jats:italic>tert<\/jats:italic>-butyl hydroperoxide (TBHP), without leading to any noticeable cell damage. It promoted the nuclear translocation of Nrf-2 and induced the production of Nrf-2, HO-1, and NQO1 at both the mRNA and protein levels. LN-53-mediated alterations in antioxidant gene expressions were blocked by Nrf-2 knockdown. LN-53 treatment also suppressed the release of IL-6 and IL-8 cytokines mediated by TBHP exposure. Additionally, novel compound LN-53 was found to be more stable than the parent compound SK-119.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>LN-53 can effectively induce antioxidant mechanisms by promoting Nrf-2 nuclear translocation and suppressing ROS production in human epidermal keratinocytes. These data may suggest that LN-53 can contribute to maintaining redox balance and homeostasis in the skin.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s43440-025-00757-y","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T03:51:29Z","timestamp":1750737089000},"page":"1347-1363","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A novel 2-oxopyrrolidine derivative (LN-53) efficiently induces Nrf-2 signaling pathway activation in human epidermal keratinocytes"],"prefix":"10.1007","volume":"77","author":[{"given":"Basak Ezgi","family":"Sarac","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Nissim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dilara","family":"Karaguzel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gokhan","family":"Arik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirin","family":"Kahremany","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward E.","family":"Korshin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arie","family":"Gruzman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cagatay","family":"Karaaslan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"issue":"1","key":"757_CR1","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s13045-023-01512-7","volume":"16","author":"J Liu","year":"2023","unstructured":"Liu J, Han X, Zhang T, Tian K, Li Z, Luo F. 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