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Histone H3K18 Lactylation Contributes to Perioperative Neurocognitive Disorder Through Immune Checkpoint Lymphocyte
Chenglong Li1, Xi Gou1, Yingying Zhao1
1Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
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.
