Targeting the Keap1-Nrf2 Axis in COPD: Comparative analysis of electrophilic and peptide-based Nrf2 activators in airway and immune cells.

BACKGROUND

Chronic obstructive pulmonary disease (COPD) is characterized by sustained oxidative stress, inflammation, and epithelial damage. The transcription factor Nrf2 is a master regulator of antioxidant and cytoprotective defenses, and its dysregulation has been implicated in COPD pathogenesis.

METHODS

We first investigated Nrf2 expression and its downstream antioxidant genes in lung tissue and neutrophils from healthy donors and COPD patients, and examined their association with disease severity (GOLD stage). We then compared the efficacy of two mechanistically distinct Nrf2 activators-omaveloxolone (an electrophilic compound) and LAS200813 (a peptide-based Keap1-Nrf2 protein-protein interaction inhibitor)-using bardoxolone methyl as a high-potency reference. Functional analyses were performed in human bronchial epithelial cells (HBECs) and peripheral blood neutrophils from both groups.

RESULTS

Nrf2 and target gene expression were significantly reduced in COPD samples and correlated with disease severity, indicating pathway dysfunction. Pharmacological activation promoted Nrf2 nuclear translocation, restored redox balance, increased intracellular glutathione, and reduced ROS levels in epithelial and immune cells. Both activators induced HO-1 and NQO1 expression and attenuated cigarette smoke extract-induced release of IL-8, MMP-9, and IL-6, including in COPD-derived cells. In bronchial epithelial cells, Nrf2 activation was also associated with a reduction in CSE-induced apoptosis. Omaveloxolone showed slightly higher potency, while LAS200813 displayed comparable functional efficacy.

CONCLUSION

These results confirm that the Nrf2 pathway is compromised in COPD and support selective Nrf2 activation-particularly via peptide-based approaches-as a promising therapeutic strategy to mitigate oxidative and inflammatory injury in the disease.