Isoliquiritigenin ameliorates Pseudomonas aeruginosa-induced acute lung injury through inhibiting lung epithelial cell ferroptosis via PPARγ/Nrf2/GPX4 axis.

Pseudomonas aeruginosa, an opportunistic pathogen, is a primary cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in immunocompromised individuals. Isoliquiritigenin (ISL), a natural flavonoid primarily found in liquorice (Glycyrrhiza glabra), has demonstrated protective effects against infection-induced ALI. However, the therapeutic potential and molecular mechanisms of ISL against P. aeruginosa-induced ALI remain unclear. In this study, we established a mouse model of acute bacterial pneumonia and an in vitro lung epithelial cell infection model to assess the therapeutic efficacy and underlying mechanisms of ISL. Results showed that ISL improved the survival and alleviated the P. aeruginosa-induced ALI in mice by reducing neutrophil recruitment, pulmonary cell death and bacterial load. Transcriptomic and enrichment analyses revealed that ISL reversed infection-induced inflammation and oxidative stress, while also providing supporting evidence for ferroptosis-related alterations. Moreover, ISL treatment significantly preserved the structural and functional integrity of the pulmonary epithelial barrier by attenuating pulmonary edema, reducing pulmonary epithelial permeability, and restoring tight junction protein expression. Network pharmacology identified AKT1, EGFR, PPARG and COX-2 as candidate targets of ISL. SPR, molecular docking and molecular dynamics simulation further verified the interaction between ISL and PPARγ. Subsequent mechanistic investigations demonstrated that ISL activated the PPARγ/Nrf2/GPX4 signaling axis and inhibited lung epithelial cell ferroptosis both in vivo and in vitro. Altogether, ISL protects against P. aeruginosa-induced ALI by activating PPARγ/Nrf2/GPX4 axis and suppressing lung epithelial cell ferroptosis, thereby preserving lung epithelial barrier integrity and reducing inflammatory responses.