YTHDC2 Deficiency Exacerbates Ulcerative Colitis by Stabilizing RBMS1 mRNA to Drive Epithelial Ferroptosis.

Ulcerative colitis is a chronic inflammatory bowel disease with a complex pathogenesis. This study aims to identify novel ferroptosis-related biomarkers and investigate the underlying post-transcriptional regulatory mechanisms in ulcerative colitis. Integrated bioinformatics analysis of public transcriptomic datasets identified key ferroptosis-related hub genes. A dextran sulfate sodium-induced murine colitis model and lipopolysaccharide-stimulated colonic epithelial cells were utilized for experimental validation. Molecular techniques, including RNA immunoprecipitation, mRNA stability assays, and western blot, were employed to elucidate the regulatory axis. We identified RNA Binding Motif Single Stranded Interacting Protein 1 (RBMS1) as a significantly upregulated ferroptosis-related hub gene in ulcerative colitis. Its suppression alleviated both inflammatory injury and ferroptosis in colonic epithelial cells in vitro and in a murine colitis model in vivo. Mechanistically, the N6-methyladenosine reader YTH Domain Containing 2 (YTHDC2) was found to bind RBMS1 transcripts and promote their degradation. YTHDC2 was downregulated in colitis, and its overexpression attenuated disease severity and ferroptosis, whereas concurrent RBMS1 overexpression reversed these protective effects. Our findings reveal a crucial YTHDC2-RBMS1 regulatory axis in ulcerative colitis pathogenesis, wherein decreased YTHDC2 enhances RBMS1 mRNA stability, thereby promoting ferroptosis and inflammation. This axis represents a promising therapeutic target for ulcerative colitis intervention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10753-026-02480-z.