Volume 4,Issue 3
Identification of Key Targets for Proton Pump Inhibitors Induced Tubulointerstitial Nephritis Based on Pharmacovigilance and Network Toxicology Analysis
Objective: Although previous studies have demonstrated that proton pump inhibitors (PPIs) can induce tubulointerstitial nephritis (TIN), the specific mechanism of action remains incompletely understood. Methods: We integrated data from Q1 2004 to Q4 2025 in the FAERS database; the associations between PPIs and TIN were quantified by four disproportionality algorithms. The potential targets for PPIs-induced TIN were identified by combining network toxicology and protein-protein interaction networks. Moreover, molecular docking between key targets and PPIs was conducted. Results: Five PPIs had significantly associated with TIN: lansoprazole (ROR = 49.13, 95% CI = 46.51-51.90), pantoprazole (ROR = 33.71, 95% CI = 31.73-35.82), dexlansoprazole (ROR = 32.39, 95% CI = 27.86-37.65), omeprazole (ROR = 30.12, 95% CI = 28.45-31.88), and esomeprazole (ROR = 26.77, 95% CI = 25.58-28.02). Three key targets for PPI-induced TIN were determined: CDC42, PDGFRA, and MAPK8. Among these targets, the binding between CDC42 and esomeprazole was the most stable (binding energy: -7.44 kcal/mol). Conclusion: These findings suggest that PPIs may trigger TIN through multi-target interactions. This study provides potential mechanistic clues and novel targets for the early warning and precise intervention of PPI-related kidney injury.
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