Targeting the Keap1-Nrf2/GPX4 axis to suppress ferroptosis in acute lung injury.

Abstract

Acute lung injury (ALI) is characterized by intense inflammation, high mortality, and a lack of effective therapies, underscoring the urgent need for novel interventions. This study demonstrates that kaempferol-3-O-α-L-(4″-E-p-coumaroyl)-rhamnoside (KAE), isolated from Angelica acutiloba Kitagawa flowers, significantly alleviates LPS-induced ALI by reducing lung edema index, BALF total protein, neutrophil infiltration, and levels of interleukin-1β (IL-1β), IL-6, tumour necrosis factor-α (TNF-α), while enhancing antioxidant capacity in lung tissue. Mechanistically, KAE binds Keap1 in an Arg415-dependent manner; mutation at this residue abolishes its binding, and in Keap1-Δ415-overexpressing MLE-12 cells, KAE fails to activate the Nrf2 pathway or suppress ferroptosis. These findings suggest that KAE alleviates ALI by targeting Keap1 Arg415, disrupting Keap1-mediated inhibition of Nrf2, thereby promoting its nuclear translocation and activating antioxidant and anti-ferroptosis pathways. This work highlights KAE's therapeutic potential and provides a theoretical basis for developing Keap1-Nrf2-targeted drugs.