Hyperglycemia impairs cognitive function by inducing mitochondrial damage through lactylation of LRPPRC at K223

High glucose impairs cognitive function in type 2 diabetes, but the underlying mechanism is unclear. In this study, guided by lactylome analysis, we reveal that high glucose induces LRPPRC K223 lactylation in hippocampal neurons by upregulating lactyltransferase AARS2, which weakens LRPPRC-SLIRP binding, reduces mitochondrial mRNA stability, subsequently leads to mitochondrial dysfunction, and ultimately results in neuronal apoptosis and cognitive decline. Notably, a novel short peptide designed to competitively inhibit LRPPRC K223 lactylation remarkably ameliorates cognitive impairment in diabetic mice. Moreover, through a large prospective cohort study, elevated plasma LRPPRC K224 lactylation (the human homolog of mouse LRPPRC K223) was identified as an independent predictor of cognitive impairment in type 2 diabetes patients. This work uncovers a key mechanism linking high glucose-induced lactylation to mitochondrial dysfunction and neuronal apoptosis, offering new molecular targets for prevention and treatment of diabetes-related cognitive impairment.