The Unfolded Protein Response and Its Implications for Novel Therapeutic Strategies in Inflammatory Bowel Disease

The endoplasmic reticulum (ER) is a multifunctional organelle playing a vital role in maintaining cell homeostasis, and disruptions to its functions can have detrimental effects on cells. Dysregulated ER stress and the unfolded protein response (UPR) have been linked to various human diseases. For example, ER stress and the activation of the UPR signaling pathways in intestinal epithelial cells can either exacerbate or alleviate the severity of inflammatory bowel disease (IBD), contingent on the degree and conditions of activation. Our recent studies have shown that EPICERTIN, a recombinant variant of the cholera toxin B subunit containing an ER retention motif, can induce a protective UPR in colon epithelial cells, subsequently promoting epithelial restitution and mucosal healing in IBD models. These findings support the idea that compounds modulating UPR may be promising pharmaceutical candidates for the treatment of the disease. In this review, we summarize our current understanding of the ER stress and UPR in IBD, focusing on their roles in maintaining cell homeostasis, dysregulation, and disease pathogenesis. Additionally, we discuss therapeutic strategies that promote the cytoprotection of colon epithelial cells and reduce inflammation via pharmacological manipulation of the UPR.