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

Abstract

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.

Beyond Mortality: Exploring the Influence of Plant Phenolics on Modulating Ferroptosis—A Systematic Review

“…The most common treatments for acute lung injury are glucocorticoids, which come with serious side effects. Ferroptosis inhibition is seen as a new potential target for the development of new therapeutics [ 130 , 131 , 132 ]. Chicoric acid was able to alleviate LPS-induced lung injury in mice thanks to its anti-inflammatory and anti-oxidative activities.…”

“…Ferulic acid and Naringenin are other polyphenolics with a proven ability to alleviate acute lung injury through activation of the Nrf2/HO-1 signaling pathway and subsequent inhibition of ferroptosis [ 134 , 135 ]. Also, quercetin alleviated lung injury through ferroptosis inhibition by activating the Sirt1/Nrf2/GPX4 pathway [ 130 ].…”

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

“…But the targets that through them ferroptosis is inhibited are different from those in cancer cells. In acute lung injury and Parkinson's disease, the main mechanism is attributed to the activation of NRF2 signaling (Deng et al, 2023;Lin et al, 2022), while in asthma and spinal cord injury, these effects are exerted through suppressing the immune response and, Id2/transferrin pathway, respectively (Wang, Li, Wang, Chen, & Goh, 2023;Wang, Li, Wang, Zhu, Liu, et al, 2023;Wang, Lin, Huang, Liu, Chen, et al, 2023;Wang, Liu, Li, Zha, Chen, et al, 2023;Wang, Shen, Lian, Deng, Qu, et al, 2023;Wang, Tan, Zhang, Wu, & Shi, 2023;Wang, Wan, Peng, Zhao, Bai, & Hu, 2023). This dual role, modulating NRF2 signaling, suppressing immune response, or affecting specific pathways, emphasizes the need for a nuanced understanding of quercetin's effects in different contexts.…”

Recent Advances in the Inhibition of Membrane Lipid Peroxidation by Food-Borne Plant Polyphenols via the Nrf2/GPx4 Pathway

“…122 Deng et al found that quercetin (40 mg/kg) upregulated the expression of antioxidant enzymes such as Sirt1, Nrf2, GPx4, SOD, and GSH in a mouse model of lipopolysaccharide-induced acute lung injury, which in turn mitigated the lung injury. 123 Another study showed that gallic acid, proanthocyanidins, ellagic acid, and tannic acid had a significant therapeutic effect on dextran-sulfate-sodium-salt (DSS)-induced ulcerative colitis (UC) in C57BL/6 mice. All polyphenols (100 mg/kg) improved the symptoms of UC in mice and the antioxidant capacity of polyphenols correlated with the number of phenolic hydroxyl groups and the structure of the o-phenolic group.…”