Zebularine Ameliorates Imiquimod‐Induced Psoriasis by Inhibiting Oxidative Stress and Inflammation With Concomitant Inhibition of NF‐κB/MAPK and DNMT1

ABSTRACT In this study, we evaluated the impact of a potent DNA methyl transferase (DNMT) inhibitor zebularine on imiquimod‐induced psoriatic mice, revealing its efficacy in mitigating hyperproliferation and keratinocyte differentiation. Molecular analyses demonstrated a marked inhibition of p38, ERK, and JNK signaling pathways, accompanied by a notable reduction in proliferative markers such as Ki‐67. The crucial regulator of keratinocyte proliferation, Ki‐67, exhibited significant downregulation upon zebularine treatment. Moreover, significant anti‐inflammatory effects were evident through the suppression of the imiquimod‐induced p65 NF‐κB signaling cascade. This robust inhibition extended to the reduction in the cytokine storm associated with psoriasis‐like skin inflammation. Consequently, there was a restoration of the normal epidermal architecture, accompanied by a decrease in epidermal hyperplasia and splenomegaly. Importantly, zebularine's inhibition of DNMT1 underscores its role in modulating epigenetic pathways. By altering DNA methylation, zebularine might effectively inhibit the expression of genes responsible for both inflammation and proliferation, contributing to improved skin structure. These findings collectively highlight zebularine's potential as a therapeutic agent in the management of psoriasis, supported by its anti‐inflammatory effects and observed inhibition of DNMT1.