Dipeptidyl peptidase 4: A predictor of ferroptosis in ulcerative colitis

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 Fe²⁺ 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.