Histone lactylation leads to perioperative neurocognitive disorders by promoting the expression of Ralbp1 and inducing excessive mitochondrial fission in hippocampal neurons.

Perioperative neurocognitive disorders (PND) is the most prevalent central nervous system (CNS) complication in older patients after surgery. Clinical and animal studies have shown that anesthesia/surgery can cause increased glycolysis and lactate production in the CNS, which is closely related to PND. However, the specific molecular mechanism by which lactate affect cognitive function remains unclear. Recent research has demonstrated that lactate can lead to neurodegenerative diseases by regulating target gene transcription through histone lactylation. The involvement of histone lactylation in PND remains to be fully elucidated. Here, we found that anesthesia/surgery induced synaptic plasticity and cognitive deficits in aged mice, accompanied by elevated hippocampal lactate and histone H3 lysine 9 lactylation (H3K9la) in neurons. Inhibiting lactate production with 2-deoxyglucose can effectively reduce synaptic and cognitive damage. To elucidate the involvement and mechanism of H3K9la in PND, we screened the target gene Ralbp1 regulated by H3K9la through CUT&Tag sequencing. The upregulation of RalBP1 can phosphorylate Drp1 Ser616 and promote mitochondrial fission, which leads to synaptic impairment of hippocampal neurons. Knockdown of Ralbp1 inhibits hippocampal neurons excessive mitochondria fission and synaptic impairment of aged mice after anesthesia/surgery, and therefore alleviates cognitive deficits. Thus, the H3K9la-RalBP1-Drp1 Ser616 pathways may provide a prospective intervention target for PND.