Nrf2 pathway mediates copper oxide nanoparticle-induced exacerbation of allergic asthma.

Copper oxide nanoparticles (CuONPs), widely used across various industries, pose inhalation risks to industrial workers and consumers through respiratory exposure. Although exposure to CuONPs has been implicated in the initiation and progression of respiratory disorders, the molecular mechanisms underlying these effects remain poorly defined. In this study, we investigated the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in CuONP-induced respiratory toxicity and asthma exacerbation. Exposure to CuONPs resulted in pronounced inflammatory cell infiltration, elevated cytokine production, and excessive mucus secretion, accompanied by disrupted redox balance, as evidenced by increased malondialdehyde (MDA) levels and decreased glutathione (GSH) concentrations. These changes were associated with upregulation of Nrf2 and its downstream antioxidant enzymes, including heme oxygenase-1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM). Although this antioxidant response is consistent with an expected oxidative stress-adaptive pathway, it was not sufficient to prevent CuONP-associated inflammatory and redox disturbances. Consistently, in NCI-H292 cells, CuONP treatment increased the expression of Nrf2, HO-1, and GCLM, whereas siRNA-mediated Nrf2 knockdown abrogated these inductions. In an ovalbumin (OVA)-induced asthma model, CuONP exposure further intensified airway inflammation and oxidative stress, despite elevated Nrf2 expression. However, adeno-associated virus (AAV)-mediated Nrf2 overexpression significantly attenuated CuONP-induced airway inflammatory responses and redox imbalance in asthmatic mice. Taken together, our results indicate that endogenous Nrf2 response is insufficient to counteract CuONP-driven asthma exacerbation, whereas pharmacological or genetic augmentation of Nrf2 signaling may constitute a viable strategy to alleviate nanoparticle-induced respiratory injury.