Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) constitute major global health challenges worldwide. Phillygenin (PHI) possesses anti-inflammatory and anti-oxidant capabilities. This investigation sought to clarify the therapeutic effect and pathways of PHI on lipopolysaccharide (LPS)-triggered ALI models, both in vivo and in vitro. 

In vitro, we confirmed PHI as a pregnane X receptor (PXR) agonist in alveolar epithelial cells. We thoroughly analyzed PHI's regulatory effects on PXR/NF-κB signaling, including assays of PXR target gene level, CYP3A4 luciferase activity, and NF-κB-mediated pro-inflammatory and pro-apoptotic gene levels. Additionally, we assessed the nuclear translocation of PXR and NF-κB, along with their ability to bind RXRα. In vivo, we evaluated PXR/NF-κB signaling in lung tissue to assess the protective efficacy of PHI against LPS-induced ALI.

PHI, through the activation of PXR, enhanced the PXR-RARα binding mechanism, thereby reducing inflammation, apoptosis, and oxidative stress. Additionally, PHI inhibited NF-κB activity, prevented its nuclear translocation, and competitively blocked NF-κB from binding to RXRα. Notably, suppressing PXR hindered the anti-inflammatory action of PHI on NF-κB.

PHI exerts its protective effect in ALI by activating PXR, which inhibits the NF-κB signaling pathway, ultimately preventing and mitigating LPS-induced alveolar epithelial injury. These observations suggest PHI represents a promising therapeutic approach for ALI/ARDS.