ArticleJournal of orthopaedic surgery and research2025
Omeprazole exacerbates intervertebral disc degeneration through Caspase-3 mediated apoptosis of nucleus pulposus cells: a Mendelian randomization, network toxicology, and in vitro experimental study.
Article in Journal of orthopaedic surgery and research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveTo investigate the causal correlation and toxicological mechanisms of omeprazole in intervertebral disc degeneration (IVDD), alongside a particular emphasis on Caspase-3 (CASP3) mediated apoptosis of nucleus pulposus cells (NPCs).
methodsMendelian randomization (MR): GWAS data was employed to assess causal associations between proton pump inhibitors (PPIs) and IVDD. Network toxicology: Shared omeprazole-IVDD targets were identified using STRING, SwissTargetPrediction, and GeneCards databases. Functional enrichment analysis: Biological pathways were explored by employing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Molecular docking: Omeprazole-CASP3 binding affinity was assessed by employing AutoDock Vina. Experimental validation: Rat NPCs were subjected to CCK-8 assay viability, flow cytometry apoptosis, Western blot, and immunofluorescence.
resultsMR analysis suggested omeprazole substantially augmented IVDD risk (OR = 1.058, 95% CI = 1.004-1.115, P = 0.034), with no association observed for esomeprazole or lansoprazole. Network toxicology identified 11 overlapping targets, with CASP3 as the hub gene. Molecular docking revealed strong omeprazole-CASP3 binding (free energy: - 6.725 kcal/mol) via hydrogen bonds, π-π stacking, and π-S interactions. Enrichment analysis highlighted the response to reactive oxygen species, caveolae, endopeptidase activity, and IL-17 signaling pathway as key pathways. As revealed by in vitro experiments, omeprazole dose-dependently lessened NPCs viability (300 µM) and heightened apoptosis (28.99% apoptosis rate). Western blot showed significant upregulation of Cleaved-CASP3/pro-CASP3 ratios (P < 0.001), and immunofluorescence demonstrated CASP3 nuclear translocation in omeprazole-treated NPCs.
conclusionsThis study found that taking omeprazole may exacerbate IVDD, and its potential mechanism is through CASP3 leading to apoptosis of NPCs. These findings advocate cautious long-term omeprazole use in clinical practice and suggest alternative PPIs.
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