Dipeptidyl peptidase 4: A predictor of ferroptosis in ulcerative colitis

Abstract Background With its rapidly increasing incidence and prevalence, ulcerative colitis (UC) has become a major global health challenge. Recent evidence suggests that ferroptosis plays a significant role in the development of UC. However, the relationship between ferroptosis and the progression of UC needs to be extensively studied. Methods The differentially expressed genes in UC patients were screened from the GEO database. The ferroptosis‐related genes were obtained from FErrDB and GeneCards. The UC subtypes were identified with the R package “CancerSubtype” and evaluated with consensus clustering (CC) to identify gene expression patterns in patients with UC. The key genes were detected with qRT‐PCR, Western blot, and immunohistochemistry in vitro and in vivo models. Ferroptosis was identified with western blotting on ferrotic‐associated proteins and staining on Fe 2+ with commercial FerroOrange kits. Results Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a potential biomarker for ferroptosis in UC patients. Transcriptome sequencing data showed a positive correlation between decreased DPP4 expression and proinflammatory cytokines such as TNF‐α, IL‐6, and IL‐β, as well as immune cell infiltration in the colon tissues of UC patients. Furthermore, DPP4 was strongly associated with ferroptosis biomarkers, particularly in Subtype 2 of UC. Interestingly, our study also found that DPP4 expression was significantly reduced in RSL3‐treated ferroptotic intestinal epithelial cells, more so than in LPS‐treated cell models. Inhibition of DPP4 had a significant impact on the expression of ferroptotic biomarkers. Additionally, DPP4 expression was decreased in the colon tissues of DSS‐treated mice, and the ferroptosis inhibitor Ferritin‐1 effectively counteracted the effects of DSS on immune cell infiltration, colon length, and DPP4 expression. Conclusions DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC.