Quercetin alleviates lipopolysaccharide-induced acute lung injury by inhibiting ferroptosis via the Sirt1/Nrf2/Gpx4 pathway

Acute lung injury (ALI) causes high morbidity and mortality rates in critically ill patients, and there are currently no effective therapeutic drugs. Ferroptosis is a newly discovered mode of regulated cell death that contributes to the progression of ALI. Quercetin possesses anti-inflammatory and antioxidant properties. However, whether quercetin can protect against lipopolysaccharide (LPS)-induced ALI by inhibiting ferroptosis and its underlying mechanisms remains unclear. The present study evaluated the protective effects of quercetin and underlying molecular mechanisms in LPS-induced ALI by establishing an ALI mouse model and an alveolar epithelial cell injury model via treatment of the mice or alveolar epithelial cells with LPS. Mouse lung injury was assessed by evaluating the histological lung injury score, bronchoalveolar lavage fluid cell count and inflammatory cytokine levels; alveolar epithelial cell injury was assessed by Cell counting kit-8, lactate dehydrogenase and EDU assays; and ferroptosis was assessed by detecting the changes in the levels of malondialdehyde, glutathione, iron, glutathione peroxidase 4 (Gpx4) and 4-hydroxynonenal in vivo and vitro. The present study indicated that quercetin effectively ameliorated LPS-induced ALI in the mouse model by reducing histopathological changes, proinflammatory cytokine release and reactive oxygen species generation and inhibiting ferroptosis. Quercetin significantly decreased ferroptosis and improved the proliferative ability of LPS-treated alveolar epithelial cells. Additionally, it was demonstrated that quercetin markedly enhanced the alveolar epithelial barrier, as evidenced by the upregulation of tight junction protein expression both in vivo and in vitro. Mechanistically, quercetin effectively activated the sirtuin 1 (Sirt1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/Gpx4 signaling pathway, and targeted in vivo inhibition or in vitro knockdown of Sirt1 significantly reduced the anti-ferroptotic functions of quercetin. In conclusion, the results demonstrated that quercetin exerts its therapeutic effects against LPS-induced ALI by inhibiting ferroptosis via the activation of the Sirt1/Nrf2/Gpx4 signaling pathway.