YTHDF2 contributes to psoriasis by promoting proliferation and inflammatory response through regulation of the Wnt signaling pathway.

Abstract

YT521-B homology domain family 2 (YTHDF2), a pivotal m6A-binding protein, is now understood to significantly influence a diverse array of biological functions, including cell migration, proliferation, differentiation, and inflammatory responses. Additionally, YTHDF2 participates in mRNA decay and pre-rRNA processing. This study explored the specific role of YTHDF2 in the pathogenesis of psoriasis and its underlying mechanisms. Our preliminary findings revealed upregulation of YTHDF2 expression in psoriasis. Subsequent silencing of YTHDF2 in a psoriatic cell model resulted in a marked decrease in mRNA expression of IL-17A, S100A8, and S100A9, accompanied by a reduction in cell proliferation. Conversely, overexpression of YTHDF2 led to the opposite effects. Treatment with DC-Y27-13, a YTHDF2 inhibitor, demonstrated a therapeutic effect in psoriasis mice. Next, mRNA sequencing analysis identified significant enrichment of differentially expressed genes within the Wnt signaling pathway. Further investigation revealed that deletion of YTHDF2 increased the half-life and expression of Dickkopf homolog 3 (DKK3), a potent inhibitor of the Wnt signaling pathway. Consequently, the inhibition of Wnt signaling attenuated the inflammatory response and inhibited cell proliferation.