GPX4 alleviates airway inflammation by suppressing 5-LO expression and regulating ferroptosis.

Ferroptosis has been increasingly implicated in the pathophysiology of asthma. Glutathione peroxidase 4 (GPX4), the key enzymatic suppressor of ferroptosis, has a role in asthma that remains insufficiently defined. Here, we investigated the regulatory function of GPX4 in asthma airway epithelial cells using an OVA-induced murine model in conjunction with a lipopolysaccharide (LPS)-stimulated BEAS-2B cell system. Upregulation of GPX4 markedly reduced intracellular reactive oxygen species (ROS), malondialdehyde (MDA) levels, and the accumulation of ferrous ions and other ferroptosis-related markers, while concomitantly alleviating mitochondrial abnormalities in LPS-stimulated BEAS-2B cells. GPX4 also inhibited ERK phosphorylation and downregulated 5-lipoxygenase (5-LO) expression. In OVA-induced asthmatic mice, GPX4 conferred significant protection, characterized by alleviated lung histopathological damage, reduced inflammatory responses, and attenuation of ferroptosis-associated alterations.These findings indicate that GPX4 mitigates asthma-related pathological changes primarily through suppression of 5-LO and modulation of ferroptosis-linked oxidative injury, highlighting GPX4 as a potential therapeutic target for asthma management.