Protective Effects of Liriodendrin Against Oxidative Stress and Ferroptosis in a Mouse Model of Lipopolysaccharide‐Induced Acute Respiratory Distress Syndrome

Liriodendrin, a bioactive lignan diglucoside derived from several medicinal plants, has been demonstrated to exhibit pharmacological activities, such as antioxidative and anti-inflammatory activities. Up to now, no evidence has shown that acute respiratory distress syndrome (ARDS) is improved by liriodendrin. This study was conducted to investigate the protective effects of liriodendrin against oxidative stress and ferroptosis, key mechanisms underlying the pathogenesis of ARDS, in a mouse model of lipopolysaccharide (LPS)-induced ARDS. To investigate the potential of liriodendrin to mitigate oxidative stress and inhibit ferroptosis, adult BALB/c male mice with LPS-induced ARDS were treated with varying concentrations of liriodendrin. Mice received liriodendrin or dexamethasone before LPS administration. The effects of liriodendrin were evaluated by measuring changes in pulmonary histopathology, levels of lipid peroxidation, activities of antioxidative enzymes (superoxide dismutase, catalase, glutathione peroxidase), and expression of ferroptosis-related proteins (heme oxygenase-1, cystine/glutamate antiporter SLC7A11, glutathione peroxidase-4). In addition, we measured the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf-2), a critical regulator of cellular defense mechanisms against oxidative damage. The results indicated that liriodendrin substantially suppressed histopathological damage, reduced lipid peroxidation, and restored antioxidative enzyme activity in a dose-dependent manner. Furthermore, this compound markedly upregulated the expression of ferroptosis-related proteins and promoted the phosphorylation of Nrf-2. Our findings suggest that liriodendrin protects against LPS-induced ARDS by regulating oxidative stress and ferroptosis. The ability of liriodendrin to modulate both antioxidative responses and ferroptosis markers through Nrf-2 phosphorylation highlights its potential as a therapeutic agent in the treatment of ARDS.