Platanoside prevents ferroptosis in acute lung injury through Keap1 degradation-mediated activation of the Nrf2/GPX4 axis

Acute lung injury (ALI) is closely linked to ferroptosis, a form of regulated cell death mediated by lipid peroxidation, with the nuclear factor erythroid 2-related factor (Nrf2)- glutathione peroxidase 4 (GPX4) axis serving as a crucial regulator of cellular antioxidant defenses. However, the therapeutic potential of activating the Nrf2/GPX4 pathway to promote Keap1 degradation in ALI remains unexplored. Here, we reveal that platanoside (PLA), a bioactive flavonoid glycoside, alleviates ferroptosis-associated ALI through autophagy-dependent Keap1 degradation. Furthermore, this process disrupts Keap1-mediated Nrf2 suppression, leading to GPX4 upregulation and inhibition of lipid peroxidation. In lipopolysaccharide-induced ALI model mice, PLA treatment markedly decreased Keap1 protein levels in pulmonary tissues, promoted Nrf2 nuclear translocation, and enhanced GPX4 activity. PLA administration also significantly reduced the levels of ferroptosis markers, including 4-hydroxynonenal and malondialdehyde, attenuated mitochondrial structural damage, and ameliorated histological alterations, with diminished inflammatory infiltration. Mechanistic studies demonstrated that PLA directly interacts with Keap1, facilitating SQSTM1/p62-mediated autophagic degradation through enhanced Keap1-p62 complex formation. Our findings elucidate a novel pharmacological mechanism by which PLA protects against ALI and support its potential application in oxidative stress-related pathologies.