Cytosolic phospholipase A2α (PLA2G4A) promotes oxidative stress-mediated endothelial ferroptosis in sepsis-induced acute lung injury.

Sepsis-induced acute lung injury (ALI) is a life-threatening syndrome characterized by the disruption of the pulmonary vascular endothelial barrier; however, the upstream lipid metabolic networks orchestrating endothelial cell death remain incompletely understood. In this study, we investigated the role of cytosolic phospholipase A2α(PLA2G4A) in driving oxidative stress-mediated endothelial ferroptosis during sepsis. Through transcriptomic analysis of clinical datasets, we identified PLA2G4A as a significantly upregulated gene in the septic endothelium. Using lipopolysaccharide (LPS)-induced human endothelial cell models and a cecal ligation and puncture (CLP)-induced murine sepsis model, we demonstrated that PLA2G4A activation acts as a critical molecular switch that disrupts intracellular redox homeostasis. Specifically, aberrant PLA2G4A activity fueled the accumulation of lethal lipid peroxidation products malondialdehyde (MDA) while depleting antioxidant defenses, including glutathione (GSH) and GPX4 activity. This oxidative stress-dependent ferroptotic cascade directly compromised endothelial barrier integrity, evidenced by the degradation of key junctional proteins (ZO-1 and VE-Cadherin) and increased vascular permeability. Conversely, genetic silencing of PLA2G4A or pharmacological inhibition with CAY10650 effectively restored redox balance, suppressed endothelial ferroptosis, preserved pulmonary vascular integrity, and significantly improved survival in septic mice. Collectively, our findings define a novel "PLA2G4A-oxidative stress-endothelial ferroptosis" axis as a key driver of endothelial dysfunction, suggesting that targeting PLA2G4A represents a promising therapeutic strategy to mitigate oxidative injury in sepsis-induced ALI.