Perioperative esketamine is associated with attenuated sleep deprivation-related cognitive dysfunction: a retrospective biomarker cohort study of the ferroptosis–neuroinflammation axis

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.

The authors' abstract, as published at the source. Frontiers in Cell and Developmental Biology, 2026 · DOI ↗