Eukaryotic initiation factor 4E (eIF4E) has been known to play a critical role in the regulation of gene expression and essential cellular processes, such as proliferation, apoptosis and differentiation. In this study, we explored its role in the pathophysiology of psoriasis. The inhibition of eIF4E by small interfering RNA or briciclib, an eIF4E small molecule inhibitor, downregulated the expression of eIF4E itself and its two complex partners eIF4A and G, as well as other eIFs (eg, eIF1A, eIF2α, eIF3A, eIF3B, eIF5, and eIF6). This inhibition also abolished psoriatic inflammation in both the imiquimod and TGFß mouse model, as well as in a human 3 dimensional–psoriasis tissue model. Downregulation of eIF4E and the other eIFs by application of briciclib (particularly when given topically) was linked to the normalization of cellular proliferation, epidermal hyperplasia, levels of proinflammatory cytokines (eg, TNFα, IL-1b, IL-17, and IL-22), and keratinocyte differentiation markers (eg, KRT16 and FLG). These results demonstrate translational imbalance and underline the crucial role played by eIF4E and other eIFs in the pathophysiology of psoriasis. This work opens up avenues for the development of novel topical antipsoriatic treatment strategies by targeting eIF4E.

中文翻译：

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真核起始因子 4E (eIF4E) 作为抗银屑病治疗的靶点


已知真核起始因子 4E (eIF4E) 在基因表达和增殖、凋亡和分化等重要细胞过程的调节中发挥着关键作用。在这项研究中，我们探讨了它在牛皮癣病理生理学中的作用。小干扰 RNA 或 eIF4E 小分子抑制剂 briciclib 对 eIF4E 的抑制，下调了 eIF4E 本身及其两个复合体伴侣 eIF4A 和 G，以及其他 eIF（例如 eIF1A、eIF2α、eIF3A、eIF3B、eIF5、和 eIF6)。这种抑制作用还消除了咪喹莫特和 TGFβ 小鼠模型以及人类 3 维银屑病组织模型中的银屑病炎症。应用briciclib（特别是局部给药时）下调eIF4E和其他eIF与细胞增殖、表皮增生、促炎细胞因子（例如TNFα、IL-1b、IL-17和IL-22）水平的正常化有关）和角质形成细胞分化标记物（例如，KRT16 和 FLG）。这些结果证明了翻译失衡，并强调了 eIF4E 和其他 eIF 在银屑病病理生理学中发挥的关键作用。这项工作为通过靶向 eIF4E 开发新型局部抗银屑病治疗策略开辟了途径。