Ischemia-induced p300-dependent histone lactylation activates an AP-1-SPP1 program in microglia to exacerbate...

Cerebral ischemia causes profound metabolic disruption, but how ischemia-associated metabolites reshape microglial chromatin and inflammatory function remains unclear. Here we identify histone lactylation as an epigenetic mechanism linking ischemic metabolic stress to pathogenic microglial activation. In transient middle cerebral artery occlusion mice and oxygen-glucose deprivation/reperfusion models, ischemic stress robustly increased H3K18la and H4K12la in microglia. CUT&Tag profiling showed widespread remodeling of both lactylation landscapes, with gained peaks preferentially associated with inflammatory, chemotactic, migratory and efferocytic programs. Integration with microglial RNA sequencing identified a concordantly activated gene network enriched for TNF, NF-κB, IL-17 and cytoskeletal regulatory pathways, with Spp1 emerging as a prominent effector linked to ischemia-induced lactylation. Motif enrichment and locus-level analyses implicated AP-1-associated regulatory elements, and ChIP-qPCR confirmed increased H3K18la and H4K12la at Fos and Spp1 regulatory regions after ischemia-like stress. Mechanistically, p300 depletion or inhibition reduced H3K18la/H4K12la accumulation, impaired AP-1-associated promoter engagement, and suppressed Fos, Spp1 and chemokine induction. Non-lactylatable H3K18R and H4K12R mutants attenuated Fos-Spp1 transcription and microglial migration, supporting cooperative regulation by these two marks. Functionally, microglia-specific Spp1 deletion reduced inflammatory microglial activation, neuronal apoptosis and long-term neurological deficits after ischemic injury. Pharmacological inhibition of p300 or AP-1, and SPP1 neutralization, similarly limited neuroinflammation and improved sensorimotor and cognitive recovery. Together, our findings define a lactate-p300-AP-1-SPP1 axis that couples ischemic metabolism to microglial chromatin remodeling and post-stroke neuroinflammatory injury.