Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating respiratory disorder associated with high global mortality. Dehydrocostus lactone (DHLC), a natural sesquiterpene lactone derived from Saussurea lappa Clarke (a medicinal plant), possesses documented antioxidant and anti-inflammatory properties. This study aimed to investigate the potential therapeutic role and mechanism of action of DHLC in COPD. For in vivo experiments, male wild-type and Nrf2-knockout C57BL/6J mice were randomized into control, cigarette smoke extract (CSE), and CSE + DHLC treatment groups. Pulmonary function was assessed by measuring airway resistance and dynamic compliance Histopathological changes were assessed by hematoxylin and eosin staining, and emphysema severity was quantified by mean linear intercept and mean alveolar area measurements. Matrix metalloproteinase-9 (MMP-9) expression was detected by immunofluorescence, while oxidative stress markers superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were measured using commercial kits. For in vitro experiments, mouse alveolar epithelial MLE-12 cells were cultured and exposed to 5% CSE for 24 h. Cell viability was determined by CCK-8 assay, intracellular ROS generation was detected using the DCFH-DA probe, and inflammatory cytokine levels in cell supernatants and BALF were quantified by ELISA. Protein expression of Nrf2, HO-1, LC3, p62, and other targets was analyzed by western blotting; Nrf2 subcellular localization was visualized by immunofluorescence staining; and mRNA expression was measured by RT-qPCR. DHLC significantly improved pulmonary function, alleviated inflammatory cell infiltration and pulmonary emphysema, and reduced MMP-9 expression in the lungs of COPD mice. In both CSE-induced MLE-12 cells and murine COPD models, DHLC attenuated inflammation, oxidative stress, and excessive autophagy by decreasing pro-inflammatory factor levels, ROS generation, the LC3-II/I ratio, and MDA co