Abstract Investigating the cognitive effects of sevoflurane exposure during early development is essential due to its potential long-term neurodevelopmental impacts. This investigation systematically explored the molecular basis of sevoflurane-induced cognitive impairment, with emphasis on m 6 A RNA modifications and ubiquitin-dependent proteostasis involving Mid1 and Syngap1. Using integrated approaches, including methylated RNA immunoprecipitation sequencing (MeRIP-seq), transcriptomic profiling, neurobehavioural testing and molecular analyses, 2091 m 6 A methylation sites were identified that were differentially regulated. Mechanistically, Mid1 was found to orchestrate Syngap1 degradation via the ubiquitin–proteasome pathway, establishing a direct link between protein stability control and cognitive outcomes. Behavioural phenotyping demonstrated that Mid1 suppression ameliorated learning and memory deficits in sevoflurane-exposed mice, which was corroborated by improved neuronal viability and attenuated apoptotic signalling in biochemical assays. Epigenetic regulation studies further revealed that the m 6 A eraser ALKBH5 and the reader YTHDF2 collaboratively modulate Mid1 mRNA stability, thereby contributing to neuropathological progression. Pathway analysis uncovered Mid1 –Syngap1 axis-mediated dysregulation of MAPK signalling cascades, proposing this network as a potential therapeutic target. Collectively, the present findings delineated a novel m 6 A-ubiquitin regulatory circuit centred on Mid1 that drives sevoflurane-associated cognitive dysfunction, offering mechanistic insights for the development of neuroprotective interventions against anaesthesia-related neurotoxicity in paediatric and other at-risk populations.
Shen et al. (Fri,) studied this question.