Repurposing alogliptin for ulcerative colitis: involvement of MicroRNAs, anti-inflammatory, and barrier-restoring mechanisms.

Ulcerative colitis (UC) is a chronic immune-mediated inflammatory bowel disease characterized by persistent mucosal inflammation, oxidative stress, and epithelial barrier disruption. Despite current therapies, achieving sustained mucosal healing remains difficult, highlighting the need for agents that modulate overlapping immune and oxidative pathways. This study evaluated the prophylactic effects of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in acetic acid-induced UC in rats, focusing on microRNA (miRNA) regulation, cytokine balance, and barrier restoration. Forty-eight male Wistar rats were assigned to six groups: control, alogliptin-only, UC, UC + sulfasalazine, UC + alogliptin (10 mg/kg), and UC + alogliptin (20 mg/kg). UC induction caused severe colonic damage with elevated pro-inflammatory cytokines (TNF-α, IL-6, IL-17), and adhesion molecules (VCAM-1, ICAM-1), together with a significant rise in malondialdehyde (MDA), a key pro-oxidative lipid peroxidation marker, reduced IL-10, diminished antioxidant enzymes (SOD, CAT), and decreased tight-junction proteins (ZO-1, Occludin). Alogliptin markedly attenuated histopathological injury and ulcer index, restored redox homeostasis and rebalanced immune signaling by suppressing TNF-α/IL-17 and enhancing IL-10 expression. It also downregulated ADAM-17 and upregulated HO-1, conferring possible immunoregulatory cyto-protection. Moreover, alogliptin -at higher doses- modulated miR-145, miR-200a, and miR-34a, linking microRNA control to its anti-inflammatory and barrier-preserving effects. These findings reveal alogliptin's microRNA-driven anti-inflammatory, antioxidant and mucosal-protective mechanisms, supporting its repurposing as a DPP-4 inhibitor with therapeutic promise in ulcerative colitis.