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CC16 alleviates PM2.5-induced airway inflammation in asthmatic mice by targeting the E-cadherin-mediated ferroptosis
Aili Wang1, Shuo Yang1, Fang Xu1
1Pulmonary and Critical Care Medicine, Wuhan No.1 Hospital, 430022 Wuhan, Hubei, China.
Abstract:
Airway epithelial ferroptosis is critically involved in PM2.5-driven asthmatic airway damage, and our previous studies have demonstrated the protective role of club cell protein 16 (CC16) against fine particulate matter (PM2.5)-induced airway inflammation by inhibiting airway epithelial ferroptosis using C57BL/6 J mouse and TC-1 cell model. Nevertheless, it remains unclarified whether CC16 exerts its anti-ferroptotic effects through interacting with E-cadherin, which represents a core research gap absent in our previous studies. Herein, we established PM2.5-intervened asthmatic mice and TC-1 cell models to explore the undiscovered molecular mechanism. Quantitative proteomics combined with bioinformatics screening identified E-cadherin as a pivotal downstream target of CC16. PM2.5 exposure markedly inhibited E-cadherin expression and aggravated epithelial ferroptosis, while CC16 intervention efficiently restored E-cadherin levels, elevated NRF2/GPX4/SLC7A11 expression, suppressed ACSL4, and reduced lipid peroxidation. This study first verified the direct binding interaction between CC16 and E-cadherin via molecular docking, Co-IP and pull-down assays. Furthermore, CDH1 knockdown completely abolished CC16-mediated inhibition of ferroptosis and epithelial injury. Collectively, this work establishes a novel CC16/E-cadherin/ferroptosis signaling axis, demonstrating that E-cadherin is an indispensable mediator for CC16 to relieve PM2.5-triggered airway damage. These findings substantially complement and advance the mechanistic system of CC16-related airway protection, providing novel targets for environmental asthma therapy.
Insights
Club cell protein 16 (CC16) protects against air pollution-induced asthma by interacting with E-cadherin. This interaction inhibits ferroptosis, a key process in airway damage, offering new therapeutic targets for environmental asthma.
Area of Science:
- Environmental Health
- Molecular Biology
- Immunology
Background:
- Airway epithelial ferroptosis is implicated in asthma exacerbation by fine particulate matter (PM2.5).
- Club cell protein 16 (CC16) previously showed protective effects against PM2.5-induced airway inflammation by inhibiting ferroptosis.
- The molecular mechanism linking CC16's anti-ferroptotic effects to E-cadherin remained unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which CC16 alleviates PM2.5-driven asthmatic airway damage.
- To investigate the potential interaction between CC16 and E-cadherin in the context of PM2.5 exposure.
- To identify novel therapeutic targets for environmental asthma.
Main Methods:
- Establishment of PM2.5-intervened asthmatic mouse and TC-1 cell models.
- Quantitative proteomics and bioinformatics screening to identify CC16 targets.
- Molecular docking, Co-immunoprecipitation (Co-IP), and pull-down assays to confirm CC16-E-cadherin binding.
- Assessment of ferroptosis markers, lipid peroxidation, and epithelial injury.
- Gene knockdown experiments (CDH1) to evaluate E-cadherin's role.
Main Results:
- E-cadherin was identified as a key downstream target of CC16.
- PM2.5 exposure reduced E-cadherin expression and increased ferroptosis; CC16 intervention reversed these effects.
- CC16 restored E-cadherin levels, upregulated NRF2/GPX4/SLC7A11, suppressed ACSL4, and reduced lipid peroxidation.
- Direct binding between CC16 and E-cadherin was confirmed.
- CDH1 knockdown abrogated CC16's protective effects against ferroptosis and epithelial injury.
Conclusions:
- A novel CC16/E-cadherin/ferroptosis signaling axis was established.
- E-cadherin is essential for CC16's protective role against PM2.5-induced airway damage.
- This study provides mechanistic insights into CC16's airway protection and suggests E-cadherin as a therapeutic target for environmental asthma.
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