{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T06:07:51Z","timestamp":1778998071168,"version":"3.51.4"},"reference-count":34,"publisher":"Brieflands","issue":"1","license":[{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["brieflands.com"],"crossmark-restriction":false},"short-container-title":["Iran J Pharm Res"],"abstract":"<jats:p>Background: Allergic contact dermatitis (ACD) is initiated by hapten-induced keratinocyte oxidative stress and inflammatory signaling, commonly involving NF-\u03baB activation, NLRP3 inflammasome priming\u2013associated signaling, and inadequate Nrf2-dependent antioxidant responses. Identification of druggable upstream regulators that integrate these pathways could support host-directed pharmacological strategies for dermatitis-like inflammation. Objective: To investigate whether pharmacological inhibition of SIRT2 using AGK2 mitigates hapten-triggered inflammatory\u2013oxidative stress signaling in human keratinocytes and to define the associated molecular mechanisms. Methods: Human Ker-CT keratinocytes were cultured alone or in transwell co-culture with CCD-1064Sk dermal fibroblasts and stimulated with 2,4-dinitrochlorobenzene (DNCB); nickel sulfate served as a comparator sensitizer. Cells were treated with the selective SIRT2 inhibitor AGK2, and target engagement was verified by acetyl-\u03b1-tubulin accumulation. Outcomes included viability (MTT), ROS generation (DCFDA), cytokine expression\/secretion (qPCR\/ELISA), and pathway signaling (Western blotting, immunofluorescence, nuclear\u2013cytoplasmic fractionation), focusing on NF-\u03baB (p65\/I\u03baB\u03b1), NLRP3 priming\u2013associated readouts (NLRP3 expression and IL-1 family cytokine output), and Nrf2 localization with downstream antioxidant enzymes (HO-1, SOD). To strengthen specificity beyond pharmacological inhibition, SIRT2 involvement was genetically validated using siRNA-mediated knockdown (siSIRT2) in Ker-CT cells. In addition, AGK2-alone control groups (without DNCB) were included across major readouts to assess baseline effects on NF-\u03baB, ROS, and Nrf2 signaling, and Keap1 expression was examined as mechanistic support for altered Nrf2 regulation. Results: DNCB produced a reproducible sub-toxic keratinocyte stress phenotype characterized by increased ROS, activation of NF-\u03baB signaling with I\u03baB\u03b1 degradation and p65 nuclear translocation, upregulation of NLRP3 expression with elevated IL-1\u03b2\/IL-18 secretion consistent with enhanced inflammasome-associated inflammatory responses, and impaired Nrf2 nuclear accumulation with reduced antioxidant enzyme expression. AGK2-mediated SIRT2 inhibition significantly attenuated NF-\u03baB activation and reduced pro-inflammatory cytokine outputs, while reducing NLRP3 priming\u2013associated responses and lowering IL-1\u03b2\/IL-18 secretion. In parallel, AGK2 restored Nrf2 nuclear translocation and enhanced expression of HO-1 and SOD, resulting in partial normalization of intracellular redox balance. Importantly, siSIRT2 phenocopied AGK2 effects by reducing DNCB-induced NF-\u03baB activation, ROS accumulation, and restoring nuclear Nrf2 enrichment. AGK2 alone did not significantly alter basal NF-\u03baB signaling, ROS levels, or Nrf2 nuclear localization, supporting that AGK2 effects were stimulus-dependent rather than intrinsic pathway suppression. Consistent with impaired antioxidant competence under DNCB challenge, Keap1 levels increased with DNCB and were partially normalized by SIRT2 inhibition\/knockdown, providing mechanistic context for the ROS\u2013Nrf2 paradox. Conclusion: Pharmacological inhibition of SIRT2 with AGK2 is associated with anti-inflammatory and antioxidant effects in hapten-stimulated human keratinocytes, including attenuation of NF-\u03baB signaling and reduction of NLRP3 priming\u2013associated IL-1 family cytokine responses, together with restoration of Nrf2-dependent cytoprotective signaling. Collectively, these findings suggest that SIRT2 may have pharmacological relevance in ACD-like inflammatory skin stress and warrant further evaluation in preclinical dermatitis models and therapeutic development studies.<\/jats:p>","DOI":"10.5812\/ijpr-169951","type":"journal-article","created":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T05:30:01Z","timestamp":1778995801000},"update-policy":"https:\/\/doi.org\/10.5812\/crossmark_update_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological SIRT2 Inhibition by AGK2 Attenuates Hapten-Induced Keratinocyte Inflammation via NF-\u03baB\/NLRP3 Suppression and Nrf2 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