Targeting PARK7: Sodium 4-Phenylbutyrate Shields Endothelial Cells from GSDME-Mediated Pyroptosis in Acute Lung Injury

Summary Sodium 4-phenylbutyrate (Na-PBA), a histone deacetylase inhibitor, shows potential in mitigating acute lung injury (ALI) by addressing endothelial cell injury. In a lipopolysaccharide (LPS)-induced ALI mouse model, Na-PBA pretreatment reduced lung damage, pulmonary edema, and inflammatory markers, while decreasing oxidative stress and endothelial pyroptosis via the cytochrome c-caspase9-caspase3-GSDME pathway. In vitro studies with human umbilical vein endothelial cells (HUVECs) confirmed that Na-PBA enhanced PARK7 expression, which is crucial for its protective effects against oxidative damage and pyroptosis. The mechanism involves PARK7 stabilizing mitochondria and inhibiting cytochrome c leakage, leading to reduced caspase activation. Na-PBA's effects are mediated through upregulation of PARK7, potentially within a positive feedback loop involving NRF2. These findings identify a novel therapeutic strategy to alleviate endothelial injury in lung diseases. For primary pulmonary endothelial cells, 6-week to 8-week C57BL/6 mice were administered PBS or 5 mg/kg lipopolysaccharide (LPS) via the trachea, executed 3 days later, and endothelial cells were sorted from lung tissue for RNA-seq. For HUVECs, cells in the treatment group were pre-treated with 0.5 mM Na-PBA, followed by stimulation of injury with LPS and Nigericin in both the treatment and injury groups.