<p>Pulmonary inflammation is a key feature of chronic obstructive pulmonary disease (COPD), contributing to disease progression and morbidity. However, the molecular mechanisms underlying therapeutic interventions remain to be fully elucidated. This study aimed to investigate the mechanisms of naringenin in modulating COPD-related pulmonary inflammation. Using an integrated approach combining network pharmacology, molecular docking, and in vitro/in vivo models, we systematically explored the effects of naringenin. Network pharmacology analysis identified NF-κB as a central target, which was validated through molecular docking and dynamics simulations showing stable binding between naringenin and NF-κB. In vitro, cigarette smoke extract-challenged lung epithelial cells treated with naringenin exhibited reduced cytotoxicity, downregulated TNF-α, phospho-NF-κB p65, and NLRP3 expression, inhibited Caspase-1 activation, and attenuated IL-1β maturation, and suppressed Gasdermin D cleavage. In vivo, naringenin-treated COPD mice displayed diminished pulmonary inflammatory cell infiltration, milder histopathological lung damage, decreased serum TNF-α/IL-1β levels, and inhibited activation of the NF-κB/NLRP3/Caspase-1 axis in lung tissue. Collectively, these findings reveal that naringenin alleviates COPD pulmonary inflammation and pyroptosis by targeting the NF-κB/NLRP3/Caspase-1 signaling cascade, providing mechanistic insights for traditional Chinese medicine-based COPD therapies.</p> Graphical abstract <p></p>