YTHDF2 regulates pyroptosis and inflammation in ulcerative colitis via modulating CCDC80.

Ulcerative colitis (UC) is a persistent inflammatory disease affecting the colorectum, for which no curative treatment is currently available. Elucidating the molecular mechanisms underlying UC pathogenesis may facilitate the development of novel therapeutic strategies. N6-methyladenosine (m6A) is a significant post-transcriptional RNA modification. YTH domain-containing family protein 2 (YTHDF2), a well-characterized m6A reader, plays a role in disease processes by facilitating the decay of target mRNAs. However, the specific role of YTHDF2 in UC remains largely unknown. In this study, bioinformatics analysis revealed elevated YTHDF2 expression in UC tissues, which was subsequently validated in lipopolysaccharide -stimulated Caco-2 and HT-29 cells as well as in dextran sulfate sodium-induced murine colitis. Knockdown of YTHDF2 alleviated pyroptosis and inflammatory responses both in vitro and in vivo, as revealed by reduced levels of NLRP3, ASC, cleaved caspase-1, and GSDMD-N, decreased caspase-1 activity, and diminished TNF-α, IL-6, IL-1β, and IL-18 secretion. These effects were mediated through suppression of the MAPK/NF-κB signaling axis. Mechanistically, YTHDF2 directly bound to and destabilized CCDC80 transcripts, leading to downregulation of CCDC80 and subsequent activation of MAPK/NF-κB signaling. Functional rescue experiments revealed that silencing CCDC80 partially reversed the anti-pyroptotic and anti-inflammatory effects of YTHDF2 knockdown. Collectively, our findings establish a critical role of YTHDF2 in UC pathogenesis and indicate its potential as a therapeutic target.