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Given that the proton-pump inhibitor omeprazole exerts its mechanism of action through covalent inhibition, it serves as an ideal model to investigate the relationship between off-target protein binding and T-cell activation. Binding of omeprazole, omeprazole metabolites, and alternative proton-pump inhibitors to antigen-presenting cells and GST-pi was characterized by mass spectrometry. Omeprazole-responsive clones were generated and assessed in terms of cytokine secretion, pathways of T-cell activation, and crossreactivity with omeprazole metabolites, alternative proton-pump inhibitors, and unrelated drugs. Omeprazole stimulated CD4+ and CD8+ T-cell clones to proliferate and secrete cytokines and cytolytic molecules. HLA-restricted T-cell activation was dependent on processing of omeprazole protein adducts by antigen-presenting cells. Omeprazole-modified CYS-containing peptides derived from 36 off-target proteins were detected within antigen-presenting cells. Omeprazole metabolites and alternative protein pump inhibitors that form protein adducts also activated omeprazole-responsive T-cells. In conclusion, T-cells were activated with omeprazole via a hapten mechanism and exhibited considerable promiscuity to metabolites and structurally related drugs of the same pharmacological class. Similar off-target binding interactions may be a relevant concern for the increasing number of covalent inhibitor drugs receiving regulatory approval.<\/jats:p>","DOI":"10.1093\/toxsci\/kfag046","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T11:39:51Z","timestamp":1776944391000},"source":"Crossref","is-referenced-by-count":0,"title":["Omeprazole activation of CD4+ and CD8+ T-cells through off-target covalent modification of cellular proteins"],"prefix":"10.1093","volume":"209","author":[{"given":"Sophie","family":"Grice","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, University of Liverpool , Liverpool L69 3GE,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sa\u2019d","family":"Albashtawy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, University of Liverpool , Liverpool L69 3GE,","place":["United 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