Stimulator of Interferon Genes Regulates Ferroptosis and Airway Inflammation via acyl-CoA Synthetase Long-Chain Family Member 4 in Asthmatic Mice

Ferroptosis is closely associated with the various pathological manifestations of asthma. This study aimed to explore the role of the stimulator of interferon genes (STING) in modulating airway inflammation in asthma, with a particular focus on regulating ferroptosis in airway epithelial cells. Using an ovalbumin (OVA)-sensitized mouse model of asthma, the OVA group exhibited significant inflammatory cell infiltration in the airways, increased mucus secretion, and elevated levels of inflammatory cytokines compared with those noted in the normal group. Additionally, the ferroptosis-related protein acyl-CoA synthetase long-chain family member 4 (ACSL4) was upregulated, whereas glutathione peroxidase 4 (GPX4) was downregulated, accompanied by elevated malondialdehyde (MDA) levels and reduced superoxide dismutase (SOD) activity. Furthermore, both messenger ribonucleic acid and protein levels of STING were significantly increased in the lungs of OVA-sensitized mice, with predominant expression in airway epithelial cells. After intervention with STING inhibitor C-176, the OVA + C-176 group demonstrated reduced inflammatory cell infiltration and mucus hypersecretion in the airways, along with decreased serum levels of IgE and Th2-associated cytokines (IL-4 and IL-13), but increased levels of the Th1 cytokine IFN-γ. Moreover, ACSL4 protein and MDA levels were significantly decreased, whereas SOD activity was significantly restored following C-176 intervention. Double immunofluorescence staining revealed the colocalization of STING and ACSL4, with their expression levels significantly reduced following C-176 treatment. Co-immunoprecipitation confirms the interaction between STING and ACSL4. Collectively, these findings indicate that STING regulates airway inflammation in asthma by modulating ferroptosis and lipid peroxidation, highlighting STING as a potential therapeutic target for asthma.