Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and progressive airflow limitation, primarily caused by cigarette smoke (CS) exposure. Current pharmacological interventions for COPD merely slow disease progression, which further underscores the urgent need for innovative therapeutics. Aloperine has demonstrated potent anti-inflammatory properties, yet its therapeutic potential in COPD remains unclear. In this study, we investigated the effects and mechanisms of aloperine using a CS-induced COPD mouse model and a cigarette smoke extract (CSE)-stimulated alveolar macrophage (AM; MH-S cell) model. Aloperine treatment significantly improved pulmonary function and alleviated emphysema in COPD mice. Furthermore, it suppressed CSE-induced alveolar macrophage pyroptosis and inflammatory responses both in vivo and in vitro. Mechanistically, the bromodomain-containing protein 4 (BRD4) inhibitor—JQ1—attenuated CSE-induced pyroptosis; however, this effect was partially reversed by the NLRP3 activator— nigericin. Comprehensive analyses, including results from molecular docking, molecular dynamics simulations, surface plasmon resonance, and in vivo and in vitro experiments, supported that aloperine interacts with BRD4 and attenuates NLRP3-mediated pyroptosis. Collectively, our findings indicate that aloperine alleviates CS-induced airway inflammation and pyroptosis potentially by modulating the BRD4/NLRP3/GSDMD signaling, positioning it as a promising therapeutic candidate for COPD.