Mesenchymal stem cell–derived extracellular vesicles alleviate immunoparalysis in sepsis-associated ARDS via reprogramming the lactate–H3K18 lactylation–PSMD14 axis

Here, we show that elevated lactate induces P300-dependent H3K18 lactylation, which enhances PSMD14 transcription. Increased PSMD14 activates the AKT/mTOR pathway, leading to macrophage immunosuppression, including reduced inflammatory cytokine production, impaired phagocytosis, increased M2 polarization, and T cell dysfunction.Integrated analyses of public datasets, RNA-seq, and ChIP-seq identified PSMD14 as a key immune-related gene associated with poor outcomes and reduced HLA-DR expression in patients.

Extracellular vesicles derived from P300 inhibitor (C646)-preconditioned mesenchymal stem cells suppress the H3K18la–PSMD14 axis, restore immune function, and improve survival.