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

Nov 26, 2025International immunopharmacology

Platanoside may protect against cell damage in acute lung injury by activating antioxidant defenses

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Abstract

Platanoside (PLA) treatment significantly decreased Keap1 protein levels in lung tissues of mice with acute lung injury (ALI).

PLA alleviates ferroptosis-associated ALI by promoting autophagy-dependent degradation of Keap1.
This degradation disrupts Keap1-mediated suppression of Nrf2, leading to increased GPX4 levels and reduced lipid peroxidation.
In a mouse model of ALI induced by lipopolysaccharide, PLA enhanced Nrf2 translocation to the nucleus and improved GPX4 activity.
PLA treatment reduced markers of ferroptosis, such as 4-hydroxynonenal and malondialdehyde, and lessened mitochondrial damage.
The study indicates that PLA may interact with Keap1 to facilitate its degradation through enhanced formation of the Keap1-p62 complex.

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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.

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

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