YTHDC2缺失通过稳定RBMS1 mRNA驱动上皮铁死亡加重溃疡性结肠炎
YTHDC2 Deficiency Exacerbates Ulcerative Colitis by Stabilizing RBMS1 mRNA to Drive Epithelial Ferroptosis.
摘要(中文译文)
溃疡性结肠炎是一种发病机制复杂的慢性炎症性肠病。本研究旨在鉴定溃疡性结肠炎中新型铁死亡相关生物标志物，并探讨其潜在的转录后调控机制。通过对公共转录组数据集的整合生物信息学分析，鉴定了关键铁死亡相关枢纽基因。利用葡聚糖硫酸钠诱导的小鼠结肠炎模型和脂多糖刺激的结肠上皮细胞进行实验验证。采用RNA免疫沉淀、mRNA稳定性检测和蛋白质印迹等分子技术阐明调控轴。我们鉴定出RNA结合基序单链相互作用蛋白1（RBMS1）是溃疡性结肠炎中显著上调的铁死亡相关枢纽基因。抑制RBMS1可减轻体外结肠上皮细胞和体内小鼠结肠炎模型中的炎症损伤和铁死亡。在机制上，发现N6-甲基腺苷阅读蛋白YTH结构域包含蛋白2（YTHDC2）可结合RBMS1转录本并促进其降解。YTHDC2在结肠炎中表达下调，其过表达可减轻疾病严重程度和铁死亡，而同时过表达RBMS1则可逆转这些保护效应。我们的研究揭示了YTHDC2-RBMS1调控轴在溃疡性结肠炎发病中的关键作用，其中YTHDC2减少可增强RBMS1 mRNA稳定性，从而促进铁死亡和炎症。该调控轴是溃疡性结肠炎干预的一个有前景的治疗靶点。
Abstract
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.
如何引用
AMA
Bo Qiu, Zhongbiao Fu, Haihua Wang, Feihu Bai. YTHDC2 Deficiency Exacerbates Ulcerative Colitis by Stabilizing RBMS1 mRNA to Drive Epithelial Ferroptosis.. Inflammation. 2026; doi:10.1007/s10753-026-02480-z.
APA
Bo Qiu, Zhongbiao Fu, Haihua Wang, Feihu Bai (2026). YTHDC2 Deficiency Exacerbates Ulcerative Colitis by Stabilizing RBMS1 mRNA to Drive Epithelial Ferroptosis.. Inflammation. https://doi.org/10.1007/s10753-026-02480-z
GB/T 7714
Bo Qiu, Zhongbiao Fu, Haihua Wang, Feihu Bai. YTHDC2 Deficiency Exacerbates Ulcerative Colitis by Stabilizing RBMS1 mRNA to Drive Epithelial Ferroptosis.[J]. Inflammation, 2026 doi:10.1007/s10753-026-02480-z.
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