AIMS: To investigate the role and potential mechanisms of H4K12 lactylation modifications in diabetes-related cognitive impairment (DACD). METHODS: Behavioral tests, HE staining, and immunohistochemistry were employed to assess cognitive function and the extent of brain tissue injury. Metabolomics and proteomics were applied to profile the metabolic regulatory network. We measured lactic acid and Pan-Kla levels in the brains of T2DM mice and high glucose-treated microglia. CUT&Tag technology was utilized to identify genes regulated by H4K12la. Small interfering RNA (siRNA) sequences and adeno-associated viruses (AAVs) were used to knock down key components in signaling pathways, evaluating the impact of histone lactylation on microglial polarization. RESULTS: Lactic acid levels were significantly higher in the brains of T2DM mice and high glucose-treated microglia compared to controls, leading to an increase in pan histone lysine lactylation (Kla). We found that lactate directly induced an increase in H4K12la. CUT&Tag analysis revealed that elevated H4K12la activates the FOXO1/PGC-1α signaling pathway by enhancing binding to the FOXO1 promoter, promoting mitochondrial oxidative stress. CONCLUSION: This study demonstrated that elevated H4K12la directly activates the FOXO1 signaling pathway, promoting oxidative stress and contributing to DACD phenotypes.