The SLCO4A1‐Mediated Transmembrane Transport of Lysionotin Attenuates Acute Lung Injury Through Activating the AMPK/Nrf2 Signaling Pathway

ABSTRACT Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present significant clinical challenges due to high mortality rates and limited treatment options. This study explores the protective effects of Lysionotin, a flavonoid from Lysionia odorata, known for its anti‐inflammatory and antioxidant properties. We aim to elucidate its mechanisms in a murine ALI model. In vitro experiments confirm Lysionotin enhances antioxidant defenses and protects endothelial cells from LPS‐induced injury. Mechanistic studies, including kinase screening and molecular docking, show Lysionotin activates Nrf2 via AMPK binding, facilitated by the Slco4a1 channel. Lysionotin preserves endothelial function and reduces oxidative stress in ALI mice by boosting antioxidant activity and attenuating inflammation. It enhances the antioxidant capacity of LPS‐induced PMVECs via the AMPK/Nrf2 pathway. SLCO4A1 was validated as critical for Lysionotin‐mediated AMPK activation. Pretreatment with Lysionotin significantly enhances antioxidant capacity, reduces oxidative damage and inflammation, and maintains endothelial integrity in ALI mice. This study provides the first evidence of Lysionotin's protective effects against LPS‐induced ALI, offering a foundation for novel therapies and identifying potential clinical targets for further research.