Molecular biological analyses of new eIF inhibitors for the topical treatment of psoriasis

Abstract

Background: Psoriasis is a chronic inflammatory skin disease that affects approximately 2 – 3 % of the world’s population. Many patients with mild forms of psoriasis require long-term topical maintenance treatment, which is mainly limited to corticosteroids and vitamin D analogs. However, adverse effects restrict their long-term use. Previous studies have found increased expression of the eukaryotic translation initiation factor eIF4E in psoriatic lesions, suggesting involvement in the pathophysiology of psoriasis. eIF4E regulates essential cellular processes such as cell growth, metabolism, differentiation and survival. The eIF4E inhibitor briciclib has shown good efficacy in treating psoriasis. However, due to the release of a phenolic moiety after hydrolysis, briciclib is not suitable for topical application. Nevertheless, the antipsoriatic potential of eIF4E inhibitors has been demonstrated, supporting further investigation of similar compounds as a promising approach for developing novel topical psoriasis therapeutics. In this study, we investigated the impact of the two eIF4E inhibitor compounds, 4E1RCat and 4EGI-1, using molecular biological analysis methods, to assess their effect on cap-dependent translation and related inflammatory signaling pathways in keratinocytes. Methods: HaCaT cells were treated with increasing concentrations of the inhibitors 4E1RCat or 4EGI-1. The effects on mRNA expression of the initiation factors eIF4E, eIF4A, and eIF4G, as well as the interleukins IL - 22, IL - 17, and IL - 1B, were measured by quantitative polymerase chain reaction. Additionally, protein levels of the initiation factors eIF4E, eIF4A, and eIF4G were determined by Western blot. Measurements were performed after 24 and 48 hours of exposure to eIF4E inhibitors. Results: After 24 h of treatment, interleukin mRNA expression was significantly (p < 0.05) to highly significantly (p < 0.01) reduced in most measurements. Significant suppression of initiation factor mRNA expression was observed only for eIF4E after 24 h of 4E1RCat exposure. Western blot analyses showed significant decreases in protein levels of eukaryotic translation initiation factors across a wide range of treatment concentrations. Conclusion: Our findings demonstrate the suppressive effects of the eIF4E inhibitors, 4E1RCat and 4EGI-1, on the investigated molecular markers, including those involved in cap-dependent translation and inflammatory signaling. These results indicate promising potential for both compounds in the treatment of psoriasis. Moreover, they provide an initial assessment of the therapeutic relevance of these compounds, supporting further development of antipsoriatic compounds based on targeted eIF4E inhibition.

Date of Award	2026
Original language	English
Awarding Institution	Medical University Graz
Supervisor	Nicole Golob-Schwarzl (Supervisor)