Hyperbaric oxygen alleviates CFS-like cognitive impairment via PLA2G4A-linked glycerophospholipid metabolism.

Chronic fatigue syndrome (CFS) is frequently accompanied by persistent cognitive deficits and neuroinflammation, yet effective interventions remain limited. Here we tested whether hyperbaric oxygen (HBO) improves CFS-related cognitive impairment in mice and examined a glycerophospholipid-metabolic mechanism. CFS was induced by a 3-week multi-stressor paradigm, and mice received HBO (100% O2, 2.5 ATA, 60 min/session, 4 sessions/week for 3 weeks). HBO improved fatigue-/depressive-like behaviors and rescued spatial and recognition memory. Histology and ultrastructure analyses showed that HBO reduced hippocampal neuronal injury and preserved blood-brain barrier (BBB) integrity, accompanied by decreased pro-inflammatory cytokines and attenuated microglial activation. Untargeted LC-MS metabolomics revealed that HBO partially reversed CFS-associated metabolic shifts and enriched glycerophospholipid metabolism. Hippocampal Western blot further showed that HBO reduced CFS-associated elevation of PLA2G4A signaling. In parallel, PGE2 levels were decreased by HBO and by AACOCF3, supporting a PLA2G4A-related downstream inflammatory lipid mediator axis. In BV2 microglia and in vivo CFS mice, pharmacological PLA2G4A inhibition with AACOCF3 attenuated inflammatory and behavioral abnormalities, and subsequent HBO did not confer additional significant benefit. Together, these data support that HBO alleviates CFS-related cognitive impairment in this model, at least in part, through suppression of neuroinflammation involving a PLA2G4A-linked glycerophospholipid metabolic pathway.