Ac4C Acetylation Facilitates lncRNA MEG3 to Ameliorate Hyperglycemia-Induced Ferroptosis of Hippocampal Neurons

Diabetes mellitus has been a global health concern, deteriorating central nervous system to induce diabetes-associated cognitive impairment (DACI). To date, the understanding of DACI is still in the infancy stage. Hyperglycemia reduces long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) level in hippocampal neuron, and overexpression of MEG3 attenuates DACI by inhibiting hyperglycemia-induced hippocampal neuron death. However, the mechanisms of hyperglycemia inducing hippocampal neuron death by downregulating MEG3 remain unclear. Here, HT22 cells were cultured in a high glucose concentration (50 mM D-glucose) to establish in vitro DACI model. Besides, acetylated RNA immunoprecipitation (acRIP) was used to detected N4-acetylcytidine (ac4C) acetylation of MEG3 while MEG3 stability was identified by RNA decay assay. The investigation indicates that N-acetyltransferase 10 (NAT10)-mediated ac4C acetylation alleviates hyperglycemia-induced decrease in MEG3 level by improving its stability in hippocampal neurons. Mechanistically, hyperglycemia disrupts the interaction of MEG3 and NAT10. Moreover, NAT10-driven MEG3 suppresses hyperglycemia-induced ferroptosis of hippocampal neurons. Our findings suggest that NAT10-mediated ac4C acetylation improves MEG3 stability to inhibit hyperglycemia-induced ferroptosis of hippocampal neurons, which should provide novel targets for DACI treatment.