Inhibition of eukaryotic translation initiation factor 1 A (eIF1A) and 3B (eIF3B) diminishes the psoriatic phenotype in two mouse models and human 3D model samples.

内容摘要

Psoriasis is a systemic inflammatory skin disease for which new topical treatments are needed. Psoriatic inflammation is associated with overexpression of eukaryotic translation initiation factors (eIFs), which regulate gene expression in processes such as proliferation, apoptosis, and differentiation. However, their role in psoriasis remains unclear. To investigate the contribution of eIF1A and eIF3B to psoriasis pathogenesis and evaluate the therapeutic potential of their inhibition via small interfering RNA (siRNA). We used two mouse models reflecting different mechanisms of psoriasis: (i) topical application of imiquimod (IMQ) and (ii) K5.TGFβ transgenic mice promoting keratinocyte proliferation. eIF1A and eIF3B were inhibited by either topical or systemic siRNA administration. A 3D human psoriasis model was also used for validation. Inhibition of eIF1A and eIF3B reduced inflammation in both mouse models and the 3D human model. Downregulation of these factors normalized keratinocyte proliferation, epidermal thickness, and cytokine expression (e.g., TNFα, IL-1β, IL-17, IL-22). Differentiation markers such as KRT16 and FLG were restored. These findings suggest that eIF1A and eIF3B play a key role in maintaining the psoriatic inflammatory phenotype. Our findings reveal a translational imbalance in psoriasis and identify eIF1A and eIF3B as crucial regulators of disease pathophysiology. Targeting these factors represents a promising new therapeutic strategy for psoriasis treatment.