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

Summary

Using multi-omic and translational approaches, the authors show that hyperglycemia induces LRPPRC K223 lactylation via AARS2, disrupting mitochondrial mRNA stability and driving neuronal apoptosis and cognitive decline. A competitive inhibitory peptide rescues cognition in diabetic mice, and plasma LRPPRC K224 lactylation predicts cognitive impairment in patients with type 2 diabetes.

Key Findings

• Hyperglycemia increases LRPPRC K223 lactylation via upregulation of AARS2 in hippocampal neurons, weakening LRPPRC–SLIRP interaction and destabilizing mitochondrial mRNAs.
• A designed short peptide that competitively inhibits LRPPRC K223 lactylation ameliorated cognitive impairment in diabetic mice.
• In a large prospective cohort, elevated plasma LRPPRC K224 lactylation independently predicted cognitive impairment in type 2 diabetes.

Clinical Implications

Plasma LRPPRC K224 lactylation may serve as a biomarker to identify type 2 diabetes patients at risk for cognitive decline; targeting the AARS2–LRPPRC lactylation axis could inspire neuroprotective strategies pending clinical translation.

Limitations

• Human cohort sample size and follow-up duration are not specified in the abstract.
• Peptide efficacy and safety remain preclinical; translational applicability requires early-phase trials.

Future Directions

Validate plasma LRPPRC lactylation as a prognostic and pharmacodynamic biomarker, and conduct first-in-human studies targeting the AARS2–LRPPRC axis for diabetes-related cognitive impairment.