PYR-41 是一个不可逆的穿透细胞的泛素激活酶E1抑制剂，已报告能够抑制IκB蛋白的降解。以往的研究表明，PYR-41 具有抗炎效应，但它是否对过敏性皮炎具有治疗效果尚不清楚。本研究的目的是探讨 PYR-41 对特应性皮炎的治疗效果。通过西方印迹和定量PCR测试 HaCat 细胞中 PYR-41 对 NF-κB 信号通路的激活和炎性基因的表达的影响。构建小鼠模型，使用 2,4-二硝基氯苯(DNCB) 诱导 AD 样皮损。然后通过皮肤严重程度评分、耳部肿胀、ELISA 和定量PCR 来检验 PYR-41 的治疗效果。结果表明，PYR-41 能显著降低核因子-κB 必需调节因子 (NEMO) 和肿瘤坏死因子受体相关因子 6 (TRAF6) 的 K63-泛素化水平，抑制 IκBα 的泛素蛋白酶降解，从而激活 HaCat 细胞中 TNF-α 诱导的 NF-κB 信号通路。此外，经 PYR-41 治疗的 DNCB 处理的小鼠症状明显减轻，包括耳部变厚和皮肤损伤减轻。血清检测显示，PYR-41 显著降低了 IgE、IFN-γ 和 TNF-α 的表达。综上所述，当前结果表明 PYR-41 在缓解特应性皮炎症状方面具有潜力。© 2023 Federation of American Societies for Experimental Biology.

PYR-41 is an irreversible and cell permeable inhibitor of ubiquitin-activating enzyme E1, and has been reported to inhibit the degradation of IκB protein. Previous studies have shown that PYR-41 has effects on anti-inflammatory, but whether it has therapeutic effects on allergic dermatitis is unclear. The aim of this research was to explore the therapeutic effects of PYR-41 on atopic dermatitis. The effects of PYR-41 on the activation of NF-κB signaling pathway and the expression of inflammatory genes in HaCat cells were tested by western blot and qPCR. A mouse model was built, and the AD-like skin lesions were induced by 2,4-dinitrochlorobenzene (DNCB). Then, the treatment effects of PYR-41 were examined by skin severity score, ear swelling, ELISA, and qPCR. The results showed that PYR-41 can significantly reduce the K63-linked ubiquitination level of nuclear factor-κB essential modulator (NEMO) and tumor necrosis factor receptor associated factor 6 (TRAF6), inhibit the proteasomal degradation of IκBα, thereby activate TNF-α-induced NF-κB signaling pathway in HaCat cells. In addition, DNCB-treated mice have significant reduction in symptoms after treated by PYR-41, including reduced ear thickening and reduced skin damage. Serum tests showed that PYR-41 significantly reduced the expression of IgE, IFN-γ, and TNF-α. In conclusion, the current results suggest that PYR-41 has potential to reduce the symptoms of atopic dermatitis.© 2023 Federation of American Societies for Experimental Biology.