Background: Innovative therapies are urgently required for treating insomnia, a prevalent neurological disorder associated with multisystem comorbidities. This study aims to explore the neuroprotective potential of right-sided stellate ganglion block (SGB) against insomnia-induced neuronal damage and cognitive dysfunction, focusing on ferroptosis modulation through the nuclear factor-erythroid 2-related factor 2 (NRF2)/glutathione peroxidase 4 (GPX4) pathway.

Methods: A rat model of insomnia was established through para-chlorophenylalanine (PCPA) induction. Interventions tested in this study included right-sided SGB (1% lidocaine), ferroptosis modulators (RAS-Selective Lethal 3 (RSL3), ferrostatin-1 (Fer-1)), and an NRF2 inhibitor (ML385). Cognitive performance of the rats was evaluated using the Morris water maze. Neuronal integrity was examined through histopathologic assessments (HE/Nissl staining), evaluation of synaptic markers (synuclein (SYN)/postsynaptic density protein 95 (PSD-95) immunohistochemistry), and detection of glial activation (ionized calcium-binding adaptor molecule 1 (Iba-1)/glial fibrillary acidic protein (GFAP) immunofluorescence). Neurotransmitters (serotonin (5-HT)/γ-aminobutyric acid (GABA)/dopamine (DA)/noradrenaline (NE)), brain redox status (malondialdehyde (MDA)/glutathione (GSH)/reactive oxygen species (ROS)), and neuroinflammation (tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/interleukin-6 (IL-6)) were assessed by means of ELISA. Western blotting was used to analyze the expression of proteins related to iron metabolism (ferritin heavy chain (FTH1)/ferritin light chain (FTL)/transferrin receptor 1 (TFR1)) and the NRF2/GPX4 pathway.

Results: SGB treatment reversed PCPA-induced cognitive deficits, as evidenced by reduced escape latency and increased target quadrant dwell time (p < 0.05). Histologic staining revealed that SGB rescued synaptic density and attenuated neuronal loss (p < 0.05). Mechanistically, SGB suppressed ferroptosis by normalizing iron homeostasis, suppressing lipid peroxidation, and inhibiting ROS overproduction, while mitigating neuroinflammation (both p < 0.05). Treatment with ML385 negated SGB's benefits, indicating that these effects can be mediated by NRF2/GPX4 pathway activation, whereas Fer-1 restored the neuroprotective effects of SGB (p < 0.05).

Conclusion: Right-sided SGB alleviates cognitive deficits and neuronal injury in insomniac rats by activating the NRF2/GPX4 pathway to inhibit ferroptosis and neuroinflammation, offering a novel neuromodulatory therapy for insomnia-related neurodegeneration.