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<p>Airway remodeling is a critical cause of chronic asthma that is difficult to control. Cell death contributes to the development and progression of chronic asthma. However, the novel copper-dependent cell death, cuproptosis, and especially cuproptosis of bronchial epithelial cells, its role, and underlying mechanisms in airway remodeling are unclear. Repetitive OVA exposure was used to establish a mouse model of chronic asthma. The human bronchial epithelial cell line BEAS-2B (BEAS-2B cells) was incubated with recombinant human IL-4 (rhIL-4) and TGF-β1 to simulated airway remodeling in vitro. Cuproptosis increased after repetitive OVA exposure in chronic asthmatic mice, evidenced by increased Cu<sup>2+</sup> levels in bronchoalveolar lavage fluid (BALF) and increased protein expression of cuproptosis-related genes (FDX-1, LIAS, and DLAT), followed by increased airway responsiveness, lung inflammation, area of subepithelial fibrosis and mucus hypersecretion and expression of epithelial-mesenchymal transition (EMT)-related proteins (MMP-2, MMP-9, N-cadherin, vimentin and α-SMA). However, a cuproptosis blocker, the mitochondrion-targeted antioxidant, Szeto-Schiller (SS)-31, substantially inhibited the above mentioned processes. Meanwhile, we observed that proteins of the key regulator of cuproptosis (ferredoxin-1, FDX-1) and bronchial epithelial marker, Keratin 8/18, were partially colocalized in bronchial epithelial which demonstrated that OVA may mediate airway remodeling through cuproptosis of bronchial epithelial. Next, we simulated airway remodeling in vitro through coincubation of rhIL-4 and TGFβ1 in BEAS-2B cells and found that cuproptosis increased after rhIL-4 and TGFβ1 mediation, indicated by increased Cu<sup>2+</sup> levels in supernatant and cytoplasm and increased protein expression of FDX-1, LIAS, and DLAT, whereas addition of SS-31 (10&#xa0;ng/mL) 30&#xa0;min before rhIL-4 and TGFβ1 treatment attenuated cuproptosis. Moreover, our results revealed increased cell migration and protein expression of above EMT-related proteins in response to induction of rhIL-4 and TGFβ1. Furthermore, silencing FDX-1 significantly inhibited above mentioned responses. Cuproptosis of bronchial epithelial cells participates in airway remodeling in chronic asthma by EMT induction through FDX-1 regulation and may be a therapeutic target in chronic asthma.</p>

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Cuproptosis of bronchial epithelial cells triggers airway remodeling in chronic asthma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Min Wang,
  • Chen Liu,
  • Zheng Li,
  • Yue Wang,
  • Yanling Li,
  • Fengyi Pei

摘要

Airway remodeling is a critical cause of chronic asthma that is difficult to control. Cell death contributes to the development and progression of chronic asthma. However, the novel copper-dependent cell death, cuproptosis, and especially cuproptosis of bronchial epithelial cells, its role, and underlying mechanisms in airway remodeling are unclear. Repetitive OVA exposure was used to establish a mouse model of chronic asthma. The human bronchial epithelial cell line BEAS-2B (BEAS-2B cells) was incubated with recombinant human IL-4 (rhIL-4) and TGF-β1 to simulated airway remodeling in vitro. Cuproptosis increased after repetitive OVA exposure in chronic asthmatic mice, evidenced by increased Cu2+ levels in bronchoalveolar lavage fluid (BALF) and increased protein expression of cuproptosis-related genes (FDX-1, LIAS, and DLAT), followed by increased airway responsiveness, lung inflammation, area of subepithelial fibrosis and mucus hypersecretion and expression of epithelial-mesenchymal transition (EMT)-related proteins (MMP-2, MMP-9, N-cadherin, vimentin and α-SMA). However, a cuproptosis blocker, the mitochondrion-targeted antioxidant, Szeto-Schiller (SS)-31, substantially inhibited the above mentioned processes. Meanwhile, we observed that proteins of the key regulator of cuproptosis (ferredoxin-1, FDX-1) and bronchial epithelial marker, Keratin 8/18, were partially colocalized in bronchial epithelial which demonstrated that OVA may mediate airway remodeling through cuproptosis of bronchial epithelial. Next, we simulated airway remodeling in vitro through coincubation of rhIL-4 and TGFβ1 in BEAS-2B cells and found that cuproptosis increased after rhIL-4 and TGFβ1 mediation, indicated by increased Cu2+ levels in supernatant and cytoplasm and increased protein expression of FDX-1, LIAS, and DLAT, whereas addition of SS-31 (10 ng/mL) 30 min before rhIL-4 and TGFβ1 treatment attenuated cuproptosis. Moreover, our results revealed increased cell migration and protein expression of above EMT-related proteins in response to induction of rhIL-4 and TGFβ1. Furthermore, silencing FDX-1 significantly inhibited above mentioned responses. Cuproptosis of bronchial epithelial cells participates in airway remodeling in chronic asthma by EMT induction through FDX-1 regulation and may be a therapeutic target in chronic asthma.