Quercetin alleviates ferroptosis accompanied by reducing M1 macrophage polarization during neutrophilic airway inflammation

Ferroptosis is a kind of regulated cell death, supporting the pathological process of lung inflammation, including asthma. Quercetin (QCT), a kind of natural dietary flavonoid, exerts anti-inflammatory and anti-ferroptosis effects in various diseases. However, the role of QCT in ferroptosis-associated airway inflammation of neutrophilic asthma remains to be described. Our study aimed to investigate the therapeutic effects of QCT on neutrophilic airway inflammation of asthma. Ferrostatin-1 (Fer-1), as a kind of ferroptosis inhibitor, was used to demonstrate whether neutrophilic airway inflammation of asthma relied on ferroptosis. In our study, the alleviation effect of QCT on neutrophilic airway inflammation was similar to Fer-1. Moreover, the significantly decreased levels of ferroptosis anti-oxidant protein (GPX4 and SLC7A11), increased malondialdehyde (MDA) levels, upregulated levels of 4-hydroxynonenal (4-HNE) expression by immunohistochemistry, and distorted mitochondria morphological changes in the lung tissues suggested lung ferroptosis in neutrophilic airway inflammation, which could be reversed by QCT treatment. In vitro experiments showed that QCT reduced LPS-induced ferroptosis through upregulating cell viability and levels of ferroptosis anti-oxidant protein (SLC7A11 and GPX4), reducing inflammatory cytokines, and decreasing the levels of MDA. Furthermore, ferroptosis was accompanied by enhancing M1 phenotype in neutrophilic airway inflammation, and QCT suppressed ferroptosis by inhibiting the pro-inflammatory M1 profile in vitro and in vivo, just as Fer-1 did. In conclusion, our study found that QCT ameliorated ferroptosis-associated neutrophilic airway inflammation accompanied by inhibiting M1 macrophage polarization. QCT may be a promising ferroptosis inhibitor for neutrophilic airway inflammation.