Ubiquitin-Modifying Enzymes as Cell-Fate Regulators in Intestinal Inflammation.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Intestinal homeostasis relies on the intricate balance of cell fate decisions within the intestinal epithelium and immune compartments. Ubiquitin-modifying enzymes (UMEs), including E2 conjugating enzymes, E3 ubiquitin ligases, and deubiquitinating enzymes (DUBs), have emerged as pivotal molecular regulators of these processes by orchestrating post-translational modifications that dictate protein stability, activity, and localization. In this review, we systematically summarize the essential roles of UMEs in modulating diverse cell-fate outcomes and their subsequent effects on intestinal barrier integrity and immune responses. Furthermore, we discuss the pathogenic dysregulation of specific UMEs in IBD and highlight their potential as diagnostic biomarkers and therapeutic targets. Finally, we explore emerging strategies, including small-molecule inhibitors and PROTAC technology, for targeting UMEs in clinical applications. By integrating current advances, this review provides novel insights into the ubiquitin-mediated regulation of intestinal cell fate and offers new perspectives for the management of IBD and the prevention of colitis-associated cancer (CAC).