Abstract

This study aimed to investigate the role of YTHDF1, a key m6A reader protein, in ulcerative colitis (UC) pathogenesis and its potential involvement in ferroptosis through ACSL4 regulation. Clinical serum and tissue samples from UC patients, as well as dextran sulfate sodium (DSS)- and oxazolone (OXZ)-induced colitis mouse models, were used to assess YTHDF1 expression and its correlation with disease severity. Ferroptosis markers, including reactive oxygen species (ROS), lipid peroxidation products, and iron levels, were assessed in both colonic tissues and DSS-treated Caco-2 cells. RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP) assays were performed to explore YTHDF1-mediated mRNA stabilization of ACSL4. Data showed that YTHDF1 was significantly upregulated in the serum and colonic tissues of UC patients, with expression levels correlating positively with disease severity. In UC mouse models, YTHDF1 expression was increased, and its knockdown reduced colitis severity. Mechanistically, YTHDF1 knockdown suppressed ferroptosis by reducing lipid peroxidation, ROS accumulation, and iron overload. Additionally, ACSL4, a key ferroptosis regulator, was identified as a downstream target of YTHDF1, with YTHDF1 stabilizing ACSL4 mRNA through m6A modifications. Collectively, YTHDF1 promotes ferroptosis in UC by stabilizing ACSL4 mRNA through m6A modifications and highlights its potential as a therapeutic target for UC treatment.