Corticotropin-Releasing Factor: A Key Player in Intestinal Barrier Dysfunction of Diarrhea-Predominant Irritable Bowel Syndrome—A Narrative Mechanistic Review

Corticotropin-Releasing Factor (CRF) plays a crucial role in the pathophysiology of diarrhea-predominant irritable bowel syndrome (IBS-D) primarily by disrupting intestinal barrier function. In this narrative review of PubMed and Web of Science literature published through January 2026, we summarize the mechanisms by which CRF mediates intestinal barrier dysfunction in IBS-D and discuss potential therapeutic strategies. This review examines the mechanisms by which CRF impairs the intestinal barrier through several signaling pathways, including GC/NR3C1, MAPK/ERK, and Rho/ROCK/MLC. These pathways cause the downregulation of tight junction proteins, increased intestinal permeability, and dysregulated immune responses. Additionally, CRF induces immune inflammation via TLR signaling and promotes the activation of immune cells, further exacerbating barrier dysfunction. The disruption of epithelial barrier integrity is central to IBS-D, leading to visceral hypersensitivity and worsening gastrointestinal symptoms. Current therapeutic approaches for IBS-D often begin with lifestyle interventions. However, preclinical evidence suggests that interventions such as metformin, Eritoran, Puerarin, and anakinra may restore barrier integrity and alleviate symptoms by ameliorating CRF-mediated intestinal barrier dysfunction. Nevertheless, the mechanisms underlying CRF-induced IBS-D and the relevant therapeutic approaches have not been fully elucidated, and the available evidence is predominantly derived from animal and cell models, thus requiring further clinical validation. Future studies should further dissect CRF-related signaling pathways and develop intervention strategies aimed at restoring the intestinal barrier, thereby facilitating clinical translation and improving the prognosis of patients with IBS-D.