Abstract
Inflammatory Bowel Disease (IBD), driven by mucosal barrier dysfunction and immune regulation disruption, is characterized by chronic gastrointestinal inflammation and frequent disease relapse. While traditional therapies focus on immune suppression, recent evidence identifies ferroptosis-an iron-dependent form of regulated cell death-as a critical driver of intestinal epithelial injury. Central to this process are microRNAs (miRNAs), which act as post-transcriptional "switches" regulating the three metabolic axes of ferroptosis: antioxidant defense (GPX4, System Xc-), iron trafficking, and lipid peroxidation. This review synthesizes emerging evidence on the miRNA-ferroptosis network in IBD. We highlight how specific dysregulated miRNAs, such as miR-129-5p and the IRF7/miR-375 axis, strip the epithelium of its defenses, promoting lethal lipid peroxidation. Furthermore, we examine the clinical transformation of these insights into novel therapies, including the oral small molecule ABX464 (obefazimod) and bioengineered exosome delivery systems. By moving beyond broad immunosuppression to targeted metabolic reprogramming, miRNA-based interventions offer a promising frontier for overcoming resistance to current biologic therapies and achieving deep mucosal healing in IBD.