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<p>Bisphenol A (BPA) is a ubiquitous environmental pollutant, but its relationship with chronic obstructive pulmonary disease (COPD) and the underlying toxicological mechanisms remain unclear. To address this, we employed an integrative multi-omics strategy that included cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) data, Mendelian randomization, network toxicology, molecular docking, molecular dynamics simulation, single-cell transcriptomic analysis, and in vitro experimental validation. Cross-sectional analysis revealed a significant positive association between BPA exposure and COPD prevalence. In the fully adjusted model, each one-unit increase in ln‑transformed BPA (ng/mg creatinine) was associated with a 34% increase in the odds of COPD (OR = 1.34, 95% CI: 1.17–1.54). Mendelian randomization analysis showed that BPA was a potential risk factor for COPD. Through network toxicology and five machine-learning methods, NQO1, HSPA5, and CXCL12 were identified as the hub targets in BPA-induced COPD. Among these, molecular docking and molecular dynamics simulation showed that BPA exhibited the highest binding affinity for NQO1. Single-cell transcriptomic analysis of human lung tissue revealed that NQO1 was predominantly expressed in airway epithelial cells. Real-time PCR and western blot confirmed that BPA exposure significantly decreased NQO1 expression levels in airway epithelial cells. In BPA-treated airway epithelial cells, NQO1 overexpression significantly suppressed mitochondrial reactive oxygen species (ROS) production, prevented mitochondrial membrane potential decline, alleviated intracellular ATP depletion, mitigated mitochondrial structural damage, reduced intracellular ROS accumulation, and attenuated cell viability reduction. Our findings suggest that BPA is a potential risk factor for COPD, and downregulation of NQO1 contributes to the pathogenesis of BPA-induced COPD, potentially through mitochondrial damage in airway epithelial cells.</p>

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Integrative multi-omics reveals NQO1-mediated airway epithelial injury as a key mechanism of bisphenol A–induced COPD

  • 期刊论文

  • 发表日期：

    2026年7月23日

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  • Rui Li,
  • Shaobo Ge,
  • Jin Liu,
  • Yuer Li,
  • Shiyuan Yao,
  • Shuhan Ma,
  • Yuanliang Sun,
  • Xiao Li,
  • Xia Yang,
  • Jie Zhang,
  • Ming Zhang

摘要

Bisphenol A (BPA) is a ubiquitous environmental pollutant, but its relationship with chronic obstructive pulmonary disease (COPD) and the underlying toxicological mechanisms remain unclear. To address this, we employed an integrative multi-omics strategy that included cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) data, Mendelian randomization, network toxicology, molecular docking, molecular dynamics simulation, single-cell transcriptomic analysis, and in vitro experimental validation. Cross-sectional analysis revealed a significant positive association between BPA exposure and COPD prevalence. In the fully adjusted model, each one-unit increase in ln‑transformed BPA (ng/mg creatinine) was associated with a 34% increase in the odds of COPD (OR = 1.34, 95% CI: 1.17–1.54). Mendelian randomization analysis showed that BPA was a potential risk factor for COPD. Through network toxicology and five machine-learning methods, NQO1, HSPA5, and CXCL12 were identified as the hub targets in BPA-induced COPD. Among these, molecular docking and molecular dynamics simulation showed that BPA exhibited the highest binding affinity for NQO1. Single-cell transcriptomic analysis of human lung tissue revealed that NQO1 was predominantly expressed in airway epithelial cells. Real-time PCR and western blot confirmed that BPA exposure significantly decreased NQO1 expression levels in airway epithelial cells. In BPA-treated airway epithelial cells, NQO1 overexpression significantly suppressed mitochondrial reactive oxygen species (ROS) production, prevented mitochondrial membrane potential decline, alleviated intracellular ATP depletion, mitigated mitochondrial structural damage, reduced intracellular ROS accumulation, and attenuated cell viability reduction. Our findings suggest that BPA is a potential risk factor for COPD, and downregulation of NQO1 contributes to the pathogenesis of BPA-induced COPD, potentially through mitochondrial damage in airway epithelial cells.