Dietary Zinc activates the Nrf2 signaling pathway to inhibit pyroptosis and attenuate the lung inflammatory response in COPD.

Abstract

Pyroptosis and inflammation play crucial roles in the development of chronic obstructive pulmonary disease (COPD), and Zinc deficiency is commonly observed in COPD patients. In this study, we aimed to explore the impact of Zinc supplementation on pyroptosis and inflammation in a cigarette smoke (CS)-induced COPD mouse model, as well as the underlying mechanisms. The COPD mouse model was established through CS exposure, and mouse pulmonary epithelial cells (MLE-12) were exposed to cigarette smoke extract (CSE) to further validate the effects of Zinc supplementation. CS exposure resulted in significant alveolar wall damage, increased thickening of the alveolar walls, and elevated levels of interleukin-1β (IL-1β), IL-6, IL-18, and tumor necrosis factor-α (TNF-α) in the lung tissues of COPD mice. However, treatment with dexamethasone (a positive control) or Zinc supplementation alleviated these damages. Furthermore, the expressions of pyroptosis markers, including NLRP3, cleaved-Caspase-1, and GSDMD-N proteins, were upregulated in the lung tissues after CS exposure. Zinc supplementation, however, reversed these changes. Additionally, Zinc supplementation upregulated the protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1), and quinone oxidoreductase-1 (NQO-1), and promoted the ubiquitination of Kelch-like ECH-associated protein 1 (Keap1) mediated by tripartite motif 25 (TRIM25) in the lung tissues of CS-induced mice. Importantly, the Nrf2 signaling inhibitor ML385 abolished the beneficial effects of Zinc in CS-exposed mice. Similar results were observed in MLE-12 lung epithelial cells exposed to CSE. In summary, Zinc supplementation inhibits pyroptosis and attenuates inflammation in COPD mice by activating the Nrf2 pathway.

Supplementary information: The online version contains supplementary material available at 10.1007/s10616-025-00725-7.