Perioperative esketamine is associated with attenuated sleep deprivation-related cognitive dysfunction: a retrospective biomarker cohort study of the ferroptosis–neuroinflammation axis
Year: 2026
Type: article
Study design: Observational Study
Abstract: Background Sleep deprivation is common in older surgical patients and may increase vulnerability to postoperative neurocognitive dysfunction through oxidative stress, neuroinflammation, and regulated cell-death pathways. Experimental studies increasingly implicate hippocampal ferroptosis, particularly disruption of the SLC7A11–GSH–GPX4 defense axis, in sleep-deprivation-related cognitive injury. Esketamine has antioxidant and anti-inflammatory properties, but whether its perioperative neurocognitive benefit is associated with a ferroptosis-related molecular phenotype in clinical patients remains uncertain. Methods We conducted a retrospective biomarker cohort study of 398 adults aged 60–80 years who underwent elective major non-cardiac surgery between January 2022 and December 2025. Patients were classified according to preoperative sleep deprivation (total sleep time <4 h and sleep efficiency <70% during the night before surgery) and perioperative esketamine exposure, generating four groups: NSD-C, NSD-E, SD-C, and SD-E. The primary outcome was early postoperative cognitive decline on postoperative day (POD) 7, defined by a ≥1-SD deterioration in a composite neuropsychological Z score. In a biomarker subcohort, plasma 4-hydroxy-2-nonenal (4-HNE), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase activity, inflammatory cytokines, neuronal injury markers, and PBMC expression of GPX4, SLC7A11, and ACSL4 were analyzed. Confounding was addressed using multivariable models and inverse-probability-of-treatment weighting. Bootstrap mediation models examined a ferroptosis-related redox score and IL-6 as candidate mediators. Results In the cohort, cognitive decline occurred in 32.5% of sleep-deprived patients without esketamine and 17.7% of sleep-deprived patients exposed to esketamine. After adjustment, esketamine exposure in the sleep-deprivation subgroup was associated with lower odds of cognitive decline (adjusted OR 0.49, 95% CI 0.26–0.92). Sleep deprivation was associated with higher 4-HNE, MDA, ACSL4, IL-6, TNF-α, and NSE and lower GSH, GPX activity, GPX4, and SLC7A11; these abnormalities were attenuated in the esketamine-exposed group. The exploratory ferroptosis-related redox score was independently associated with cognitive decline. Under the specified exploratory mediation model, the estimated total mediated proportion was 54%; this model-based decomposition does not establish causal biological mediation. Conclusion Perioperative esketamine was associated with less pronounced early postoperative cognitive decline in sleep-deprived patients and a less pronounced peripheral ferroptosis-related/inflammatory phenotype.
Institution: Hebei North University
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225383506