Abstract

Preclinical investigations have indicated that recurrent sevoflurane exposure induces long-term cognitive deficits in neonatal mice while the effects of inhalational anesthetics on children remain ambiguous. In the current study, Our comprehensive analysis of single-nucleus transcriptomics-guided competing endogenous RNA (ceRNA) networks revealed long-stranded ncRNA (lncRNA) MSTRG.7388 as a pivotal modulator in sevoflurane-mediated cognitive impairment, regulating microglial activation through the inhibition of microRNA miR-410-3p and the promotion of nuclear receptor coactivator 4 (NCOA4) expression. Furthermore, we elucidated that mutual binding of NCOA4 and stimulator of interferon genes (STING) dimers induced microglial ferroptosis independent of the ubiquitination pathway and long-term cognitive impairment in mice exposed to sevoflurane. Notably, either the knockdown of NCOA4 or the administration of Fe2+ scavengers (iron chelators) reversed these effects. Collectively, these findings demonstrate that repeated sevoflurane exposure leads to long-term cognitive impairment in neonatal mice by aggravating microglial ferroptosis via the MSTRG.7388/miR-410-3p/NCOA4/STING signaling axis.