Histone H3K18 Lactylation Contributes to Perioperative Neurocognitive Disorder Through Immune Checkpoint Lymphocyte Activation Gene 3 Mediated Microglial Pyroptosis

Aims This study investigates whether histone H3K18 lactylation (H3K18la) contributes to perioperative neurocognitive disorders (PND) by upregulating immune checkpoint Lymphocyte activation gene 3 (Lag3) and microglial pyroptosis, thereby aggravating neuroinflammation in the hippocampus. Methods Lactate levels and H3K18la expression were measured in mouse hippocampus after surgery. H3K18la downstream targets were identified by CUT&Tag and RNA-seq. After Lag3 silencing in BV2 cells, downstream pathways were screened and validated by RNA-seq and in vitro assays. Glycolysis inhibitors and Lag3 antibody were used to assess cognitive function and pyroptosis-related protein expression in postoperative mice. Results Surgery significantly elevated hippocampal lactate and H3K18la levels in mice. Inhibiting glycolysis led to a reduction in H3K18la and mitigated cognitive impairments in the PND model mice. CUT&Tag and RNA-seq revealed that H3K18la transcriptionally activates Lag3 by enriching at its promoter, and Lag3 blockade improved postoperative cognition. Furthermore, Lag3 upregulation triggered microglial pyroptosis via NOD-like receptor protein 3 (NLRP3) signaling, thereby aggravating neuroinflammation and promoting PND. Conclusions Surgical trauma-induced increase of H3K18la in microglia promotes PND by upregulating Lag3 and triggering NLRP3-dependent microglial pyroptosis, highlighting the H3K18la–Lag3–NLRP3 axis as a therapeutic target for PND.