Identification of hub genes and pathways associated with sevoflurane-induced synaptic loss in diabetic offspring via comprehensive transcriptome analysis.

Vulnerable brain models exhibit heightened susceptibility to anesthetic neurotoxicity, with diabetic offspring warranting particular attention, yet the underlying mechanisms remain unclear. This study integrated bioinformatics and experiments to investigate the molecular basis of sevoflurane-induced neurodevelopmental toxicity in diabetic offspring. Offspring of streptozotocin-induced diabetic dams (gestational diabetes model) and control mice were exposed to sevoflurane (2.5%, 3 × 2 h, P6-P8). Hippocampal tissues underwent RNA sequencing. Bioinformatics analysis identified dysregulated pathways, followed by validation of neuronal apoptosis (TUNEL), synaptic proteins (PSD-95, Synaptophysin), and microglial activity (Iba1+). Hub genes were screened via protein-protein interaction networks. Diabetic-sevoflurane offspring showed aberrant activation of neural crest differentiation, oxidative stress/redox pathways, and microglial pathogen phagocytosis. Compare with the Control group the diabetic-sevoflurane offspring showed increased apoptosis, synaptic loss and enhanced Iba1 + microglial density. Uty, Uba1y, Ddx3y, Kdm5d, and Eif2s3y were identified as key regulators. Gestational diabetes primes microglia via Hub gene networks, amplifying sevoflurane-induced neurotoxicity. Targeting these genes may mitigate risks in diabetic offspring requiring anesthesia.Clinical trial number: Not applicable.