Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease (IBD) that primarily affects the colon and rectum [1]. UC is usually recurrent, with clinical manifestations including abdominal pain, diarrhea, tenesmus, mucus blood and pus [2]. Until now, it has been generally accepted that UC is mainly caused by intestinal epithelial dysfunction [3]. Therefore, the integrity of the intestinal epithelium is essential for maintaining intestinal health. Current therapies for UC include aminosalicylic acid drugs, glucocorticoids, immunosuppressants, and biologics [4]. UC treatment is accompanied by serious reactions such as diarrhea, cramps, fever, abdominal pain, and hypertension [5]. Therefore, the prevention or therapy of UC requires alternative therapies or drugs with minimal side effects.

At present, the pathogenesis of UC is not clear, but there is evidence that restraining ferroptosis has a remarkable improvement in UC [6]. Ferroptosis is a type of cell death that differs from traditional necrosis, apoptosis, or autophagic cell death [7]. Ferroptosis is majorly caused by iron-dependent lipid peroxidation (LPO), which is intimately related to glutathione peroxidase 4 (GPX4) inhibition and reactive oxygen species (ROS) accumulation [8]. A mounting body of evidence indicated that GPX4 is associated with the pathogenesis of inflammatory diseases, such as UC and IBD [9], [10]. Therefore, further research on the potential mechanism of ferroptosis in colonic epithelial cells (CECs) is of great significance for ameliorating the clinical efficacy of UC.

N6-methyladenosine (m6A) is one of the commonest modification forms of eukaryotic messenger RNA [11]. The molecular composition of m6A RNA methylation regulatory factors includes m6A methyltransferase, m6A demethylase, and m6A recognition factor [12]. Among them, m6A recognition factor is a known factor that regulates mRNA splicing, nuclear output, decay/degradation, translation, and stability, also known as “m6A reader” [12]. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an m6A reader belonging to the IGF2BP family, whose function is to advance the stability and translation of target mRNAs [13]. Research presented that m6A modification is involved in the progression of inflammatory diseases. For instance, Wang et al. indicated that IGF2BP2 modulated the activation of macrophage phenotype and inflammatory diseases via the stability of tuberous sclerosis 1 (TSC1) and peroxisome proliferator activated receptor‐γ (PPARγ) [14]. Yet, the effect and mechanism of IGF2BP2 in UC are not sure.

The m6A reader presents a crucial role in modulating ferroptosis [15]. Downregulation of GPX4 expression is a meaningful feature of ferroptosis. It was predicted that GPX4 has highly reliable m6A modification sites through SRAMP（https://www.cuilab.cn/sramp). And it was found that there is a potential binding relationship between IGF2BP2 and GPX4 by ENCORI (https://starbase.sysu.edu.cn/).

In this study, we analyzed the effect of IGF2BP2 on ferroptosis in CECs and evaluated its regulation of GPX4 m6A. This study provides new evidence for targeting IGF2BP2 in the treatment of UC.