CC16 alleviates PM2.5-induced airway inflammation in asthmatic mice by targeting the E-cadherin-mediated ferroptosis regulatory axis.

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.