The clinical efficacy of indomethacin, a nonsteroidal anti-inflammatory drug, is hindered by its high ulcerogenic potential. Linagliptin, a dipeptidyl peptidase-4 inhibitor, has demonstrated anti-inflammatory properties through NLRP3 inflammasome modulation
however, its possible antiulcerogenic effect remains unclear. This study aimed to examine the potential prophylactic effect of linagliptin against indomethacin-induced gastric ulcers with a focus on NLRP3 inflammasome signaling. Gastric ulcers were induced using indomethacin and compared to pretreatment with linagliptin or the standard prophylactic omeprazole. Gastric injury was confirmed by gross morphology, ulcer scoring, and histopathological assessments. Additionally, redox status markers glutathione reductase (GSH), malondialdehyde (MDA), and Nrf2/Keap-1/HO-1 were evaluated in the gastric tissue. Immunohistochemical analysis of pNF-κB, NLRP3, and Caspase-1 inflammasome parameters was also conducted. Finally, measurement of gastric levels of Gasdermin-D was performed, as well as immunohistochemical and gene expression of IL-1β. Pretreatment with linagliptin suppressed all features of mucosal damage as well as inflammatory cell infiltration. The antioxidant effect of linagliptin was evident in low MDA, high GSH gastric levels, and high immunohistochemical reactivity of gastric tissues against Nrf2 and HO-1 antibodies, as well as low gastric levels of keap1. The overly active inflammasome pathway observed in indomethacin-induced ulcerated samples was reinstated by linagliptin, as seen in the suppression of pNF-κB, NLRP3, Caspase-1, and IL-1β immunohistochemical reactivity as well as Gasdermin-D levels. Our study showed that NLRP3 inflammasome contributes to the pathogenesis of indomethacin-mediated gastric injury and that linagliptin exhibits a protective effect against indomethacin-induced gastric ulcers, possibly through activation of the Nrf2/HO-1 antioxidant pathway and inhibition of the NLRP3 inflammasome axis.