Valproic acid remodels phosphatidylglycerol homeostasis and epithelial-macrophage crosstalk in inflammatory signaling.

Pulmonary surfactant lipids support lung homeostasis and innate immunity, and their dysregulation contributes to acute respiratory distress syndrome. Whether mitochondrial phosphatidylglycerol (PG) biosynthesis influences epithelial lipid secretion and inflammatory responses remains unclear. Using A549 cells, we disrupted PGS1, which encodes phosphatidylglycerophosphate synthase, and found that partial loss of PGS1 altered cellular PG levels and changed the secreted phospholipid profile. Valproic acid (VPA), a clinically used antiepileptic drug, similarly remodeled secreted lipids and increased the relative abundance of the anti-inflammatory PG species palmitoyl-oleoyl-phosphatidylglycerol (POPG), an effect not seen with partial PGS1 loss. Functionally, conditioned media from VPA-treated epithelial cells reduced lipopolysaccharide-induced inflammatory responses in PMA-differentiated U937 macrophage-like cells, with lipid extracts contributing to this effect. In a vascularized quail chorioallantoic membrane model, both VPA and POPG decreased inflammation and maintained tissue structure. Overall, these findings connect mitochondrial PG metabolism to epithelial lipid-mediated control of inflammation.