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The pharmacological effects of a drug are determined not only by its direct protein targets but also by genes involved in its metabolism and transport. Using two\u2010sample Mendelian randomization and multi\u2010ancestry cohorts (UKB\/FinnGen), we systematically assessed genes encoding both direct targets of PPIs and key proteins involved in PPI pharmacokinetics across 24 gastrointestinal diseases. Validation included colocalization\/SMR analyses, disease stratification, anatomical stratification, and HPA\u2010based tissue expression profiling. Single\u2010cell sequencing further elucidated target distribution. Finally, meta\u2010analysis validates the correlation between PPI and gastrointestinal disorders. CYP2D6 emerged as the most pleiotropic locus (nine disease endpoints), demonstrating dose\u2010dependent carcinogenic effects in hepatocellular\/pancreatic cancers (OR\u2009=\u20091.36\u20131.58,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20098.45\u2009\u00d7\u200910\n                    <jats:sup>\u221224<\/jats:sup>\n                    , OR\u2009=\u20091.43\u20131.56,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20092.31\u2009\u00d7\u200910\n                    <jats:sup>\u221272<\/jats:sup>\n                    ) yet protective against acute\/chronic pancreatitis (OR\u2009=\u20090.72\u20130.75,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20091.26\u2009\u00d7\u200910\n                    <jats:sup>\u2212196<\/jats:sup>\n                    , OR\u2009=\u20090.62\u20130.67,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20091.39\u2009\u00d7\u200910\n                    <jats:sup>\u2212111<\/jats:sup>\n                    ). ABCB1\/SLC22A1 exhibited pan\u2010gastrointestinal risk modulation. Anatomical stratification revealed context\u2010dependent gene effects: SLC22A1 (esophageal), CYP2D6 (hepatic), and CYP2C19 (colorectal) showed opposing roles in carcinogenesis versus precancerous states. HPA profiling identified SLC22A3 as a pan\u2010cancer candidate (moderate\u2010high expression in 4 tumor types). Single\u2010cell tumor data indicated AHR was enriched in tumor cells and significantly higher than in normal cells in all five tumor tissues. The finding suggests that AHR may be related to the potential gastrointestinal carcinogenicity of PPIs. The meta\u2010analysis confirms a significant link between PPI use and increased gastrointestinal cancer risk. Further research is needed on PPI and benign gastrointestinal diseases. Our multi\u2010omics integration reveals tissue\u2010specific PPI pharmacodynamics, identifying targets with dual therapeutic\/carcinogenic potential that may explain epidemiological discordances.\n                  <\/jats:p>","DOI":"10.1096\/fj.202503152r","type":"journal-article","created":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T12:23:53Z","timestamp":1766233433000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Proton\u2010Pump Inhibitor Use and Gastrointestinal Disease Risk: A Mendelian Randomization Study of Omics and Pharmacological Pathways"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7247-8111","authenticated-orcid":false,"given":"Weixiong","family":"Zhu","sequence":"first","affiliation":[{"name":"The Second Clinical Medical College Lanzhou University  Gansu 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