Histone H3K18 Lactylation Drives Perioperative Neurocognitive Disorder by Activating Microglial Pyroptosis via Lag3-NLRP3 Axis

Perioperative neurocognitive disorders (PND), including postoperative cognitive dysfunction, are significant complications affecting patient recovery and long-term quality of life. Current treatments are often insufficient, highlighting an urgent need for novel therapeutic targets. Recent research points to neuroinflammation as a key driver of PND pathology, particularly involving microglial activation. Epigenetic modifications, such as histone lactylation, are emerging as crucial regulators of gene expression in inflammatory processes. This study explores the role of histone H3K18 lactylation (H3K18la) in PND, specifically its potential to modulate microglial inflammatory responses and contribute to cognitive decline. Understanding this epigenetic mechanism could unlock new strategies for PND prevention and treatment.

Researchers induced PND in mice via surgical trauma, then measured hippocampal lactate levels and H3K18la expression. They used CUT&Tag and RNA-seq to identify H3K18la downstream targets. To confirm the role of Lag3, they performed Lag3 silencing in BV2 microglial cells, followed by RNA-seq and in vitro assays to screen and validate downstream pathways. Finally, they administered glycolysis inhibitors and a Lag3 antibody to postoperative mice to assess cognitive function and pyroptosis-related protein expression, comparing outcomes to untreated controls.