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

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. • KAE alleviates LPS-induced acute lung injury in vivo. • KAE activates Nrf2 signaling and enhances antioxidant defense. • KAE suppresses ferroptosis by restoring GPX4. • KAE directly targets Keap1 at Arg415 to disrupt Keap1–Nrf2 interaction.