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

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

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Roger I.
  • Estornut C.
  • Montero P.
  • Aparici M.
  • Puig C.
  • Davis A.M.
  • Albericio F.
  • Milara J.
  • Cortijo J.

Grupos

Abstract

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. © 2026 Elsevier B.V.

Datos de la publicación

ISSN/ISSNe:
0014-2999, 1879-0712

European Journal of Pharmacology  ELSEVIER

Tipo:
Article
Páginas:
-
PubMed:
41786067
Enlace a otro recurso:
www.scopus.com
Factor de Impacto:
0,930 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 6

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Keywords

  • Aged; Epithelial Cells; Female; Humans; Kelch-Like ECH-Associated Protein 1; Lung; Male; Middle Aged; Neutrophils; NF-E2-Related Factor 2; Oleanolic Acid; Oxidative Stress; Peptides; Pulmonary Disease, Chronic Obstructive; Signal Transduction; bardoxolone methyl; beta 2 adrenergic receptor stimulating agent; cigarette smoke; corticosteroid; enzyme; gelatinase B; glutathione; heme oxygenase 1; interleukin 8; kelch like ECH associated protein 1; LAS200813; NQO1; omaveloxolone; protein inhibitor; reactive oxygen metabolite; transcription factor Nrf2; unclassified drug; KEAP1 protein, human; kelch like ECH associated protein 1; NFE2L2 protein, human; oleanolic acid; peptide; transcription factor Nrf2; aged; airway cell; apoptosis; Article; cell viability; chronic bronchitis; chronic obstructive lung disease; confocal fluorescence microscopy; controlled study; disease severity; EC50; electrophilicity; enzyme linked immunosorbent assay; female; flow cytometry; fluorescence intensity; forced

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