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Objective <p>To 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).</p> Methods <p>Mendelian 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.</p> Results <p>MR analysis suggested omeprazole substantially augmented IVDD risk (OR = 1.058, 95% CI = 1.004–1.115, <i>P</i> = 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&#xa0;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&#xa0;µM) and heightened apoptosis (28.99% apoptosis rate). Western blot showed significant upregulation of Cleaved-CASP3/pro-CASP3 ratios (<i>P</i> &lt; 0.001), and immunofluorescence demonstrated CASP3 nuclear translocation in omeprazole-treated NPCs.</p> Conclusions <p>This 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.</p>

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Omeprazole exacerbates intervertebral disc degeneration through Caspase-3 mediated apoptosis of nucleus pulposus cells: a Mendelian randomization, network toxicology, and in vitro experimental study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月3日

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  • Yuchao Jia,
  • Haifan Zhao,
  • Shengbo Huang,
  • Baoshan Xu

摘要

Objective

To 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).

Methods

Mendelian 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.

Results

MR 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.

Conclusions

This 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.