Individuals with celiac disease (CeD) on a long-term gluten-free diet (GFD) underwent a 6-week gluten challenge combined with 100mg per day of the transglutaminase 2 enzyme -inhibitor, ZED1227 (PGCd, n = 28) or placebo (PGCp, n = 19). The samples were collected at baseline (GFD) and post-gluten challenge (PGC). Mass spectrometry-based lipidomic and proteomics profiling, along with genome-wide DNA methylation analysis, were applied to plasma samples obtained from 47 CeD patients. Comparative analyses were performed between the groups, with adjustment for BMI, age, sex, and country of origin.