Intranasal Curcumin and N-Acetyl l-Cysteine (NAC) Attenuates Dibutyl Phthalate (DBP)-Aggravated Airway Inflammation by Targeting Ferroptosis via Nrf-2/GPx4-SLC7A11.

Ferroptosis plays a significant role in the pathophysiological development of several diseases. It is an iron-dependent type of controlled cell death triggered by oxidative stress and lipid peroxidation. Nrf2, a key regulator of the antioxidant response, protects cells from ferroptosis by regulating genes involved in iron metabolism and the synthesis and breakdown of glutathione (GSH). This study was undertaken to investigate the relationship between Nrf2-mediated oxidative stress and ferroptosis in allergic asthmatic mice, particularly when the environmental toxin DBP is present. DBP disrupts iron homeostasis and causes asthma exacerbation by inducing iron accumulation and increasing hemosiderin-loaded macrophage numbers in the lungs. N-acetylcysteine (NAC) and curcumin antioxidant treatments significantly reduced ferroptotic damage, increased downstream targets such as GPx4, SLC7A11, and SLC40A1, and activated the Nrf2 pathway. On the other hand, ferroptosis and lung damage were exacerbated by Nrf2 suppression. In addition to elevating reactive oxygen species (ROS), nitric oxide (NO), and 8-oxoguanine (8-oxodG), DBP exposure also decreased GSH, GPx, and SOD, which led to lipid peroxidation and increased levels of malondialdehyde (MDA). These results demonstrate the therapeutic potential of Nrf2 targeting to prevent oxidative lung injury and ferroptosis in asthma triggered by DBP.