Shionone attenuates lipopolysaccharide-induced acute lung injury by inhibiting ferroptosis via Keap1/Nrf2/SLC7A11/GPX4 signaling pathway.

Abstract

Acute lung injury (ALI) is a respiratory disease with a high mortality rate. Shionone, derived from the Chinese herbal medicine Aster tataricus, has anti-inflammatory and antioxidant effects. However, its protective effect on ALI remains unclear. In this study, we aimed to assess the protective effect of shionone on lipopolysaccharide (LPS)-induced ALI and to elucidate its underlying mechanisms. In this study, male C57BL/6 mice aged 8-10 weeks were randomly divided into five groups (10 mice per group) including control group, LPS group, LPS + shionone (50 mg/kg) group, LPS + shionone (100 mg/kg) group, and LPS + Dexamethasone (1 mg/kg) group. In mice with LPS-induced ALI, shionone significantly reduced lung index, lung wet/dry weight ratio, production of inflammatory cytokines, nitric oxide (NO) content, malondialdehyde (MDA) production, and increased superoxide dismutase (SOD) activity and nicotinamide adenine dinucleotide phosphate (NADPH) level. Shionone improved lung histopathological injury by inhibiting inflammatory cell infiltration and edema in LPS-induced ALI in mice. In vitro, shionone inhibited oxidative stress and inflammation in LPS-induced BEAS-2B cells. Shionone improved the protein expression of anti-ferroptosis proteins, including glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), in mice lung tissues and BEAS-2B cells. Additionally, GC-MS-based metabolomic analysis showed that shionone increased the levels of various metabolites, such as fructose, glucose, and lactic acid. Shionone ameliorated LPS-induced ALI by downregulating Kelch-like ECH-associated protein 1 (Keap1) and upregulating Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme oxygenase-1 (HO-1), and quinone oxidoreductase 1 (NQO1) in both in vivo and in vitro study. In conclusion, this study demonstrated that shionone mitigated LPS-induced ALI by inhibiting ferroptosis through regulation of Keap1/Nrf2/SLC7A11/GPX4 pathway, indicating that shionone may be a promising agent for ALI.